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13,600 | 23,758,511 | Interventions providing explicit roles and using supportive group structures were somewhat effective in improving one or more of the following : life satisfaction , social support and activity , physical health and activity , functional health , and cognition .
CONCLUSIONS Social role interventions may improve health and well-being for people in retirement transition . | CONTEXT The marked demographic change toward greater proportions of older people in developed nations poses significant challenges for health and social care .
Several studies have demonstrated an association between social roles in later life and positive health and well-being outcomes .
After retiring from work , people may lose roles that provide purpose and social contacts .
The outcomes of interventions to promote social roles in retirement have not been systematic ally review ed .
METHODS We examined three research questions : ( 1 ) What kinds of intervention have been developed to promote social roles in retirement ? (
2 ) How much have they improved perceived roles ? ( | Population aging portends a crisis of re sources and values . Desired solutions could include intergenerational strategies to harness the untapped potential of older adultsto address societal needs and to generate health improvements for older adults . Despite the desire of many older adults to remain socially engaged and productive , the creation of productive roles has lagged . This report describes the conceptual framework and major design features of a new model of health promotion for older adults called Experience Corps ® . Experience Corps operates at , and leads to benefits , across multiple levels , including individuals , schools , and the larger community . At the individual level , we propose a model based on Erikson ’s concept of generativity to explain bow and why experience Corps works . At the level of schools , we propose a parallel model based on social capital . Experience Corps is a volunteer service program design ed to improve the lives of urban childre and to yield health improvement for older persons . It illustrates how population aging creates new opportunities to address difficult social problems . This article explores how the linkage of concepts at multiple levels motivates a potentially cost-effective , feasible , and high-impact program This report evaluates whether a program for older volunteers , design ed for both benerativity and health promotion , leads to short-term improvements inmultiple behavioral risk factors and positive effects on intermediary risk factors for disability and other morbidities . The Experience Corps ® places older volunteers in public elementary schools in roles design ed to meet schools ’ needs and increase the social , physical , and cognitive activity of the volunteers . This article reports on a pilot r and omized trial in Baltimore , Maryl and . The 128 volunteers were 60–86 years old ; 95 % were African American . At follow-up of 4–8 months , physical activity , strength , people one could turn to for help , and cognitive activity increased significantly , and walking speed decreased significantly less , in participants compared to controls . In this pilot trial , physical , cognitive , and social activity increased , suggesting the potential for the Experience Corps to improve health for an aging population and simultaneously improve educational outcomes for children OBJECTIVES We aim to underst and how human , social , and cultural capitals are associated with the volunteer process , that is , engagement ( starting ) , intensity ( number of hours ) , and cessation ( stopping ) , among older adults . METHOD Data from the 2000 through 2008 Health and Retirement Study and the 2001 through 2009 Consumption and Activity Mail Survey provide a sample of 4,526 respondents . R and om-effects pooled time series analyses incorporate not only the presence of various types of capital but also the quality of that capital . RESULTS Human and cultural capitals were positively associated with increased volunteer involvement . Effects of social capital ( relationships in the family , employment status , and the community ) depended on the quality of the relationships , not necessarily on their presence alone . DISCUSSION Results suggest that bolstering older adults ' capitals , particularly among lower socioeconomic status groups , can increase volunteer engagement and intensity and reduce cessation . Additionally , a variety of organizational policies including respite programs for caregivers and employer policies allowing employees to reduce their work hours might indirectly affect participation rates and commitment . Potential pools of volunteers exist in families , workplaces , and religious organizations , but more research is necessary to identify how to recruit and retain individuals in social networks where volunteer participatory rates are low The effect of a health education course guided by peers aged 55 and over was evaluated . The aim of the course was to empower older adults to participate in society and to promote their wellbeing . Evaluation included determining the effect on attitude toward aging , self-efficacy , perception of the societal opinion regarding the place of the elderly in society ( social influence ) , social participation , perceived social support , and wellbeing of the participants aged 55 to 79 years . A quasi-experimental approach was used . The effect on the experimental group of course participants was studied compared to a control group of older adults on the waiting list . The respondents filled out postal question naires at three time points ( before starting the course ( t0 ) , immediately after termination ( t1 ) and three months later ( t2 ) ) . Using a multivariate analysis procedure , a significant interaction effect between time of measurement and group membership was found with respect to the outcome of social influence . At t1 an effect was absent , but at t2 , the current idea that elderly occupy a marginal position in society , found less favour with the experimental group than the control group . Moreover perceived social support and subjective health improved significantly at t1 and t2 among the course members , when compared to the control group . No effect was found on attitude , self-efficacy , social participation and wellbeing in the short time span of a three months follow-up PURPOSE There is little empirical translation of multimodal cognitive activity programs in " real-world " community-based setting s. This study sought to demonstrate in a short-term pilot r and omized trial that such an activity program improves components of cognition critical to independent function among sedentary older adults at greatest risk . DESIGN AND METHODS We r and omized 149 older adults to Experience Corps ( EC ) or a wait-list control arm . Participants r and omized to EC trained in teams to help elementary school children with reading achievement , library support , and classroom behavior for 15 hr/week during an academic year . We compared baseline and follow-up assessment s of memory , executive function ( EF ) , and psychomotor speed at 4 to 8 months by intervention arm , adjusting for exposure duration . We observed a range of EF abilities at baseline and stratified analyses according to the presence of baseline impairment using established norms . RESULTS Overall , EC participants tended to show improvements in EF and memory relative to matched controls ( ps < .10 ) . EC participants with impaired baseline EF showed the greatest improvements , between 44 % and 51 % in EF and memory at follow-up , compared to declines among impaired-EF controls ( ps < .05 ) . IMPLICATION S Short-term participation in this community-based program design ed to increase cognitive and physical activity in a social , real-world setting may train memory and , particularly , executive functions important to functional independence . This community-based program represents one potentially effective model to bring high doses of sustainable cognitive exercise to the greatest proportion of older adults , particularly those sedentary individuals at elevated risk for health disparities |
13,601 | 29,299,877 | Results Acute , sub-chronic ( 2 weeks ) and chronic ( 3 months ) CF intake reduced exercise-induced oxidative stress .
Evidence on the effect of CF on exercise-induced inflammation and platelet activation was scarce .
Acute CF intake reduced and tempered the exercise-induced increase in blood pressure in obese participants .
Acute and sub-chronic CF intake altered fat and carbohydrate metabolism during exercise .
Acute and sub-chronic CF intake did not have ergogenic effects in athletes , while chronic CF intake improved mitochondrial efficiency in untrained participants .
While combining sub-chronic CF intake and exercise training improved cardiovascular risk factors and vascular function , evidence on the synergistic effects of CF and exercise training on oxidative stress , inflammation , and fat and glucose metabolism was lacking .
Conclusion CF intake may improve vascular function , reduce exercise-induced oxidative stress , and alter fat and carbohydrate utilization during exercise , but without affecting exercise performance . | Background Cocoa flavanols ( CFs ) have antioxidant and anti-inflammatory capacities and can improve vascular function .
It has recently been suggested that CF intake may improve exercise performance and recovery .
This systematic review aim ed to evaluate the literature on the effects of CF intake on exercise performance and recovery and exercise-induced changes in vascular function , cognitive function , oxidative stress , inflammation , and metabolic parameters . | AIMS Flavanol-rich chocolate ( FRC ) is beneficial for vascular and platelet function by increasing nitric oxide bioavailability and decreasing oxidative stress . Congestive heart failure ( CHF ) is characterized by impaired endothelial and increased platelet reactivity . As statins are ineffective in CHF , alternative therapies are a clinical need . We therefore investigated whether FRC might improve cardiovascular function in patients with CHF . METHODS AND RESULTS Twenty patients with CHF were enrolled in a double-blind , r and omized placebo-controlled trial , comparing the effect of commercially available FRC with cocoa-liquor-free control chocolate ( CC ) on endothelial and platelet function in the short term ( 2 h after ingestion of a chocolate bar ) and long term ( 4 weeks , two chocolate bars/day ) . Endothelial function was assessed non-invasively by flow-mediated vasodilatation of the brachial artery . Flow-mediated vasodilatation significantly improved from 4.98 ± 1.95 to 5.98 ± 2.32 % ( P = 0.045 and 0.02 for between-group changes ) 2h after intake of FRC to 6.86 ± 1.76 % after 4 weeks of daily intake ( P = 0.03 and 0.004 for between groups ) . No effect on endothelial-independent vasodilatation was observed . Platelet adhesion significantly decreased from 3.9 ± 1.3 to 3.0 ± 1.3 % ( P = 0.03 and 0.05 for between groups ) 2 h after FRC , an effect that was not sustained at 2 and 4 weeks . Cocoa-liquor-free CC had no effect , either on endothelial function or on platelet function . Blood pressure and heart rate did not change in either group . CONCLUSION Flavanol-rich chocolate acutely improves vascular function in patients with CHF . A sustained effect was seen after daily consumption over a 4-week period , even after 12 h abstinence . These beneficial effects were paralleled by an inhibition of platelet function in the presence of FRC only Background Dark chocolate ( DC ) is abundant in flavanols which have been reported to increase the bioavailability and bioactivity of nitric oxide ( NO ) . Increasing NO bioavailability has often demonstrated reduced oxygen cost and performance enhancement during submaximal exercise . Methods Nine moderately-trained male participants volunteered to undertake baseline ( BL ) measurements that comprised a cycle V.O2max$$ \overset{.}{V}{O}_{2 max } $ $ test followed by cycling at 80 % of their established gas exchange threshold ( GET ) for 20-min and then immediately followed by a two-minute time-trial ( TT ) . Using a r and omised crossover design participants performed two further trials , two weeks apart , with either 40 g of DC or white chocolate ( WC ) being consumed daily . Oxygen consumption , RER , heart rate and blood lactate ( BLa ) were measured during each trial . Results DC consumption increased GET and TT performance compared to both BL and WC ( P < 0.05 ) . DC consumption increased V.O2max$$ \overset{.}{V}{O}_{2 max } $ $ by 6 % compared to BL ( P < 0.05 ) , but did not reach statistical significance compared to WC . There were no differences in the moderate-intensity cycling for V.O2$$ \overset{.}{V}{O}_2 $ $ , RER , BLa and heart rate between conditions , although , V.O2$$ \overset{.}{V}{O}_2 $ $ and RER exhibited consistently lower trends following DC consumption compared to BL and WC , these did not reach statistical significance . Conclusion Chronic supplementation with DC result ed in a higher GET and enhanced TT performance . Consequently , ingestion of DC reduced the oxygen cost of moderate intensity exercise and may be an effective ergogenic aid for short- duration moderate intensity exercise The consumption of a diet rich in certain flavonoids , including the flavanol sub-class , has been associated with a reduced risk for vascular disease . We evaluated the effects of the regular consumption ( 14 d ) of a flavanol-containing milk chocolate ( FCMC ) or cocoa butter chocolate ( CBC ) on variables related to vascular disease risk , oxidative stress and physical activity . Twenty-eight free-living , young ( 18–20 years old ) male soccer players consumed daily 105 g of FCMC ( 168 mg of flavanols ) or CBC ( < 5 mg of flavanols ) , as part of their normal diet . The consumption of FCMC was significantly associated with a decrease in diastolic blood pressure ( -5 mm Hg ) , mean blood pressure ( -5 mm Hg ) , plasma cholesterol ( -11 % ) , LDL-cholesterol ( -15 % ) , malondialdehyde ( -12 % ) , urate ( -11 % ) and lactate dehydrogenase ( LDH ) activity ( -11 % ) , and an increase in vitamin E/cholesterol ( + 12 % ) . No relevant changes in these variables were associated with CBC consumption . No changes in the plasma levels of (-)-epicatechin were observed following analysis of fasting blood sample s. In conclusion , FCMC consumption was associated with changes in several variables often associated with cardiovascular health and oxidant stress . The presence of significant quantities of flavanols in FCMC is likely to have been one of the contributing factors to these results Impaired endothelial vasodilatation may contribute to the exaggerated blood pressure ( BP ) responses to exercise in individuals who are overweight/obese . The present study investigated whether consumption of cocoa flavanols , which improve endothelium-dependent flow-mediated dilatation ( FMD ) , can modify BP responsiveness to exercise . Twenty-one volunteers ( eight females and thirteen males , 54.9 ( se 2.2 ) years , BMI 31.6 ( se 0.8 ) kg/m2 , systolic BP 134 ( se 2 ) mmHg , diastolic BP ( DBP ) 87 ( se 2 ) mmHg ) were r and omised to consume single servings of either a high-flavanol ( HF , 701 mg ) or a low-flavanol ( LF , 22 mg ) cocoa beverage in a double-blind , cross-over design with 3 - 7-d washout between treatments . Two hours after cocoa consumption , FMD was measured , followed by continuous beat-to-beat assessment ( Finapres ) of BP before and during 10 min of cycling at 75 % of age-predicted maximum heart rate . Averaged data from two assessment s on each type of beverage were compared by analysis of covariance using pre-exercise BP as the covariate . Pre-exercise BP was similar after taking LF and HF ( 153 ( se 3)/88 ( se 3 ) v. 153 ( se 4)/87 ( se 2 ) mmHg , respectively , P>0.05 ) . However , the BP response to exercise ( area under BP curve ) was attenuated by HF compared with LF . BP increases were 68 % lower for DBP ( P = 0.03 ) and 14 % lower for mean BP ( P = 0.05 ) . FMD measurements were higher after taking HF than after taking LF ( 6.1 ( se 0.6 ) % v. 3.4 ( se 0.5 ) % , P < 0.001 ) . By facilitating vasodilation and attenuating exercise-induced increases in BP , cocoa flavanols may decrease cardiovascular risk and enhance the cardiovascular benefits of moderate intensity exercise in at-risk individuals Dietary flavanols have been associated with reduced oxidative stress , however their efficacy in promoting recovery after exercise induced muscle damage is unclear . This study examined the effectiveness of acute consumption of cocoa-flavanols on indices of muscle recovery including : subsequent exercise performance , creatine kinase , muscle tenderness , force , and self-perceived muscle soreness . Eight endurance-trained athletes ( VO2max 64.4 ± 7.6 mL/kg/min ) completed a downhill running protocol to induce muscle soreness , and 48-h later completed a 5-K ( kilometer ) time trial . Muscle recovery measurements were taken at PRE , 24 h-POST , 48 h-POST , and POST-5 K . Participants consumed 1.0 g of carbohydrate per kilogram of body weight of a r and omly assigned beverage ( CHOC : 0 mg flavanols vs. CocoaCHOC : 350 mg flavanols per serving ) immediately after the downhill run and again 2 h later . The same protocol was repeated three weeks later with the other beverage . An ANOVA revealed no significant difference ( p = 0.97 ) between trials for 5 K completion time ( CHOC 1198.3 ± 160.6 s , CocoaCHOC 1195.5 ± 148.8 s ) . No significant difference was found for creatine kinase ( CK ) levels ( p = 0.31 ) , or muscle soreness ( p = 0.21 ) between groups over time . These findings suggest that the acute addition of cocoa flavanols to low-fat chocolate milk offer no additional recovery benefits This study investigated the effects of regular consumption of dark chocolate ( DC ) , rich in cocoa polyphenols , on plasma metabolites , hormones , and markers of oxidative stress after prolonged exhaustive exercise . Twenty active men cycled at 60 % maximal oxygen uptake ( VO2max ) for 1.5 hr , with the intensity increased to 90 % VO2max for a 30-s period every 10 min , followed by a ride to exhaustion at 90 % VO2max . In the 2 wk before exercise participants consumed 40 g of DC or an isocarbohydrate-fat control cocoa liquor-free chocolate ( CON ) twice daily and once 2 hr before exercise in a r and omized , counterbalanced , crossover design . Venous blood sample s were taken immediately before exercise , postexercise ( fixed duration ) , postexhaustion , and after 1 hr of recovery . F2-isoprostanes were significantly lower ( post hoc tests : p < .001 ) at exhaustion and after 1 hr of recovery with DC . Oxidized low-density lipoproteins were significantly lower with DC ( p < .001 ) both before and after exercise and at exhaustion . DC was also associated with ~21 % greater rises in free fatty acids during exercise ( main effect : p < .05 ) . Changes in circulating glucose , insulin , glucagon , cortisol , and interleukin (IL)-6 , IL-10 , and IL-1ra were unaffected by treatment . Time to exhaustion at 90 % VO2max was not significantly different between trials ( 398 ± 204 and 374 ± 194 s for DC and CON , respectively ) . These results suggest that regular DC intake is associated with reduced oxidative-stress markers and increased mobilization of free fatty acids after exercise but has no observed effect on exercise performance OBJECTIVES This study was design ed to assess the effect of flavanol-rich food on the circulating pool of bioactive nitric oxide ( NO ) and endothelial dysfunction in smokers . BACKGROUND Studies suggest that smoking-related vascular disease is caused by impaired NO synthesis and that diets rich in flavanols can increase bioactive NO in plasma . METHODS In smokers ( n = 11 ) , the effects of flavanol-rich cocoa on circulating NO species in plasma ( RXNO ) measured by reductive gas-phase chemiluminescence and endothelial function as assessed by flow-mediated dilation ( FMD ) were characterized in a dose-finding study orally administering cocoa containing 88 to 370 mg flavanols and in a r and omized double-blind crossover study using 100 ml cocoa drink with high ( 176 to 185 mg ) or low ( < 11 mg ) flavanol content on two separate days . In addition to cocoa drink , ascorbic acid and NO-synthase inhibitor L-NMMA ( n = 4 ) were applied . RESULTS There were significant increases in RXNO ( 21 + /- 3 nmol/l to 29 + /- 5 nmol/l ) and FMD ( 4.5 + /- 0.8 % to 6.9 + /- 0.9 % , each p < 0.05 ) at 2 h after ingestion of 176 to 185 mg flavanols , a dose potentially exerting maximal effects . These changes correlated with increases in flavanol metabolites . Cocoa-associated increases in RXNO and FMD were reversed by L-NMMA . Ascorbic acid had no effect . CONCLUSIONS The circulating pool of bioactive NO and endothelium-dependent vasodilation is acutely increased in smokers following the oral ingestion of a flavanol-rich cocoa drink . The increase in circulating NO pool may contribute to beneficial vascular health effects of flavanol-rich food Acute exercise-induced improvements in cognitive function are accompanied by increased ( cerebral ) blood flow and increased brain-derived neurotrophic factor ( BDNF ) levels . Acute cocoa flavanol ( CF ) intake may improve cognitive function , cerebral blood flow ( in humans ) , and BNDF levels ( in animals ) . This study investigated ( i ) the effect of CF intake in combination with exercise on cognitive function and ( ii ) cerebral hemodynamics and BDNF in response to CF intake and exercise . Twelve healthy men participated in this r and omized , double-blind , crossover study . Participants performed a cognitive task ( CT ) at 100 min after acute 903-mg CF or placebo ( PL ) intake , followed by a 30-min time-trial . Immediately after this exercise , the same CT was performed . Prefrontal near-infrared spectroscopy was applied during CT and exercise to measure changes in oxygenated ( ΔHbO2 ) , deoxygenated ( ΔHHb ) , and total haemoglobin ( ΔHbtot ) and blood sample s were drawn and analyzed for BDNF . Reaction time was faster postexercise , but was not influenced by CF . ΔHbO2 during the resting CT was increased by CF , compared with PL . ΔHbO2 , ΔHHb , and ΔHbtot increased in response to exercise without any effect of CF . During the postexercise cognitive task , there were no hemodynamic differences between CF or PL . Serum BDNF was increased by exercise , but was not influenced by CF . In conclusion , at rest , CF intake increased cerebral oxygenation , but not BDNF concentrations , and no impact on executive function was detected . This beneficial effect of CF on cerebral oxygenation at rest was overruled by the strong exercise-induced increases in cerebral perfusion and oxygenation Flavan-3-ols are potent antioxidants in vitro , but convincing evidence for antioxidant action in vivo is lacking . We examined whether an oxidative stress-mediated increase in plasma F(2)-isoprostanes is counteracted by a flavanol-rich cocoa beverage . Twenty volunteers were examined in a comparative r and omized double-blind crossover design with respect to ingestion of high-flavanol cocoa drink ( HFCD ; 187 mg flavan-3-ols/100 ml ) vs. low-flavanol cocoa drink ( LFCD ; 14 mg/100 ml ) . With 10 individuals , the treatment was combined with strenuous physical exercise . Total ( esterified plus nonesterified ) F(2)-isoprostanes were analyzed by GC/MS . LFCD caused a slight increase in the mean ( + /- SEM ) plasma concentrations of F(2)-isoprostanes 2 and 4 h after intake ( 2.16 + /- 0.19 nM at 4 h vs. 1.76 + /- 0.11 nM at 0 h , n = 10 ) , which may be attributable to postpr and ial oxidative stress . This increase did not occur with HFCD ( 1.57 + /- 0.06 nM at 4 h vs. 1.65 + /- 0.10 nM at 0 h , n = 10 ) . The difference in F(2)-isoprostanes 2 and 4 h after intake of HFCD vs. LFCD became statistically significant when the intake was combined with physical exercise ( P < 0.01 , ANOVA ) . We conclude that dietary flavanols , using cocoa drink as example , can lower the plasma level of F(2)-isoprostanes , indicators of in vivo lipid peroxidation In heart failure patients the consumption of (-)-epicatechin ( (-)-Epi)-rich cocoa can restore skeletal muscle ( SkM ) mitochondrial structure and decrease biomarkers of oxidative stress . However , nothing is known about its effects on exercise capacity and underlying mechanisms in normal , sedentary subjects . Twenty normal , sedentary subjects ( ∼50 years old ) were r and omized to placebo or dark chocolate ( DC ) groups and consumed 20 g of the products for 3 months . Subjects underwent before and after treatment , bicycle ergometry to assess VO2 max and work , SkM biopsy to assess changes in mitochondrial density , function and oxidative stress and blood sampling to assess metabolic endpoints . Seventeen subjects completed the trial . In the DC group ( n = 9 ) , VO2 max increased ( 17 % increase , p = 0.056 ) as well as maximum work ( watts ) achieved ( p = 0.026 ) with no changes with placebo ( n = 8) . The DC group evidence d increases in HDL levels ( p = 0.005 ) and decreased triglycerides ( p = 0.07 ) . With DC , SkM evidence d significant increases in protein levels for LKB1 , AMPK and PGC1α and in their active forms ( phosphorylated AMPK and LKB1 ) as well as in citrate synthase activity while no changes were observed in mitochondrial density . With DC , significant increases in SkM reduced glutathione levels and decreases in protein carbonylation were observed . Improvements in maximum work achieved and VO2 max may be due to DC activation of upstream control systems and enhancement of SkM mitochondria efficiency . Larger clinical studies are warranted to confirm these observations The flavanol (-)-epicatechin , a component of cacao ( cocoa ) , has been shown to have multiple health benefits in humans . Using 1-year-old male mice , we examined the effects of 15 days of (-)-epicatechin treatment and regular exercise on : ( 1 ) exercise performance , ( 2 ) muscle fatigue , ( 3 ) capillarity , and ( 4 ) mitochondrial biogenesis in mouse hindlimb and heart muscles . Twenty-five male mice ( C57BL/6N ) were r and omized into four groups : ( 1 ) water , ( 2 ) water-exercise ( W-Ex ) , ( 3 ) (-)-epicatechin ( (-)-Epi ) , and ( 4 ) (-)-epicatechin-exercise ( (-)-Epi-Ex ) . Animals received 1 mg kg(-1 ) of (-)-epicatechin or water ( vehicle ) via oral gavage ( twice daily ) . Exercise groups underwent 15 days of treadmill exercise . Significant increases in treadmill performance ( ∼50 % ) and enhanced in situ muscle fatigue resistance ( ∼30 % ) were observed with (-)-epicatechin . Components of oxidative phosphorylation complexes , mitofilin , porin , nNOS , p-nNOS , and Tfam as well as mitochondrial volume and cristae abundance were significantly higher with (-)-epicatechin treatment for hindlimb and cardiac muscles than exercise alone . In addition , there were significant increases in skeletal muscle capillarity . The combination of (-)-epicatechin and exercise result ed in further increases in oxidative phosphorylation-complex proteins , mitofilin , porin and capillarity than (-)-epicatechin alone . These findings indicate that (-)-epicatechin alone or in combination with exercise induces an integrated response that includes structural and metabolic changes in skeletal and cardiac muscles result ing in greater endurance capacity . These results , therefore , warrant the further evaluation of the underlying mechanism of action of (-)-epicatechin and its potential clinical application as an exercise mimetic Purpose Acute antioxidant supplementation may modulate oxidative stress and some immune perturbations that typically occur following prolonged exercise . The aims of the present study were to examine the effects of acutely consuming dark chocolate ( high polyphenol content ) on plasma antioxidant capacity , markers of oxidative stress and immunoendocrine responses to prolonged exercise . Methods Fourteen healthy men cycled for 2.5 h at ~60 % maximal oxygen uptake 2 h after consuming 100 g dark chocolate ( DC ) , an isomacronutrient control bar ( CC ) or neither ( BL ) in a r and omised-counterbalanced design . Results DC enhanced pre-exercise antioxidant status ( P = 0.003 ) and reduced by trend ( P = 0.088 ) 1 h post-exercise plasma free [ F2-isoprostane ] compared with CC ( also , [ F2-isoprostane ] increased post-exercise in CC and BL but not DC trials ) . Plasma insulin concentration was significantly higher pre-exercise ( P = 0.012 ) and 1 h post-exercise ( P = 0.026 ) in the DC compared with the CC trial . There was a better maintenance of plasma glucose concentration on the DC trial ( 2-way ANOVA trial × time interaction P = 0.001 ) , which decreased post-exercise in all trials but was significantly higher 1 h post-exercise ( P = 0.039 ) in the DC trial . There were no between trial differences in the temporal responses ( trial × time interactions all P > 0.05 ) of hypothalamic – pituitary – adrenal axis stress hormones , plasma interleukin-6 , the magnitude of leukocytosis and neutrophilia and changes in neutrophil function . Conclusion Acute DC consumption may affect insulin , glucose , antioxidant status and oxidative stress responses , but has minimal effects on immunoendocrine responses , to prolonged exercise |
13,602 | 27,622,384 | The most frequently reported AEs were mouth and throat irritation , most commonly dissipating over time .
The most commonly reported adverse effects were irritation of the mouth and throat . | BACKGROUND Electronic cigarettes ( ECs ) are electronic devices that heat a liquid into an aerosol for inhalation .
The liquid usually comprises propylene glycol and glycerol , with or without nicotine and flavours , and stored in disposable or refillable cartridges or a reservoir .
Since ECs appeared on the market in 2006 there has been a steady growth in sales .
Smokers report using ECs to reduce risks of smoking , but some healthcare organizations , tobacco control advocacy groups and policy makers have been reluctant to encourage smokers to switch to ECs , citing lack of evidence of efficacy and safety .
Smokers , healthcare providers and regulators are interested to know if these devices can help smokers quit and if they are safe to use for this purpose .
This review is an up date of a review first published in 2014 .
OBJECTIVES To evaluate the safety and effect of using ECs to help people who smoke achieve long-term smoking abstinence . | Background Cigarette smoking is a tough addiction to break . Therefore , improved approaches to smoking cessation are necessary . The electronic-cigarette ( e-Cigarette ) , a battery-powered electronic nicotine delivery device ( ENDD ) resembling a cigarette , may help smokers to remain abstinent during their quit attempt or to reduce cigarette consumption . Efficacy and safety of these devices in long-term smoking cessation and /or smoking reduction studies have never been investigated . Methods In this prospect i ve proof-of-concept study we monitored possible modifications in smoking habits of 40 regular smokers ( unwilling to quit ) experimenting the ' Categoria ' e-Cigarette with a focus on smoking reduction and smoking abstinence . Study participants were invited to attend a total of five study visits : at baseline , week-4 , week-8 , week-12 and week-24 . Product use , number of cigarettes smoked , and exhaled carbon monoxide ( eCO ) levels were measured at each visit . Smoking reduction and abstinence rates were calculated . Adverse events and product preferences were also review ed . Results Sustained 50 % reduction in the number of cig/day at week-24 was shown in 13/40(32.5 % ) participants ; their median of 25 cigs/day decreasing to 6 cigs/day ( p < 0.001 ) . Sustained 80 % reduction was shown in 5/40(12.5 % ) participants ; their median of 30 cigs/day decreasing to 3 cigs/day ( p = 0.043 ) . Sustained smoking abstinence at week-24 was observed in 9/40(22.5 % ) participants , with 6/9 still using the e-Cigarette by the end of the study . Combined sustained 50 % reduction and smoking abstinence was shown in 22/40 ( 55 % ) participants , with an overall 88 % fall in cigs/day . Mouth ( 20.6 % ) and throat ( 32.4 % ) irritation , and dry cough ( 32.4 % ) were common , but diminished substantially by week-24 . Overall , 2 to 3 cartridges/day were used throughout the study . Participants ' perception and acceptance of the product was good . Conclusion The use of e-Cigarette substantially decreased cigarette consumption without causing significant side effects in smokers not intending to quit ( http:// Clinical Trials.gov number NCT01195597 ) Electronic cigarettes ( e-Cigarette ) are battery-operated devices design ed to vaporise nicotine that may aid smokers to quit or reduce their cigarette consumption . Research on e-Cigarettes is urgently needed to ensure that the decisions of regulators , healthcare providers and consumers are evidence based . Here we assessed long-term effectiveness and tolerability of e-Cigarette used in a ‘ naturalistic ’ setting . This prospect i ve observational study evaluated smoking reduction/abstinence in smokers not intending to quit using an e-Cigarette ( ‘ Categoria ’ ; Arbi Group , Italy ) . After an intervention phase of 6 months , during which e-Cigarette use was provided on a regular basis , cigarettes per day ( cig/day ) and exhaled carbon monoxide ( eCO ) levels were followed up in an observation phase at 18 and 24 months . Efficacy measures included : ( a ) ≥50 % reduction in the number of cig/day from baseline , defined as self-reported reduction in the number of cig/day ( ≥50 % ) compared to baseline ; ( b ) ≥80 % reduction in the number of cig/day from baseline , defined as self-reported reduction in the number of cig/day ( ≥80 % ) compared to baseline ; ( c ) abstinence from smoking , defined as complete self-reported abstinence from tobacco smoking ( together with an eCO concentration of ≤10 ppm ) . Smoking reduction and abstinence rates were computed , and adverse events review ed . Of the 40 subjects , 17 were lost to follow-up at 24 months . A > 50 % reduction in the number of cig/day at 24 months was shown in 11/40 ( 27.5 % ) participants with a median of 24 cig/day use at baseline decreasing significantly to 4 cig/day ( p = 0.003 ) . Smoking abstinence was reported in 5/40 ( 12.5 % ) participants while combined > 50 % reduction and smoking abstinence was observed in 16/40 ( 40 % ) participants at 24 months . Five subjects stopped e-Cigarette use ( and stayed quit ) , three relapsed back to tobacco smoking and four up grade d to more performing products by 24 months . Only some mouth irritation , throat irritation , and dry cough were reported . Withdrawal symptoms were uncommon . Long-term e-Cigarette use can substantially decrease cigarette consumption in smokers not willing to quit and is well tolerated . ( http:// Clinical Trials.govnumberNCT01195597 ) Background Electronic cigarettes ( e-cigarettes or electronic nicotine delivery systems [ ENDS ] ) are electrically powered devices generally similar in appearance to a cigarette that deliver a propylene glycol and /or glycerol mist to the airway of users when drawing on the mouthpiece . Nicotine and other substances such as flavourings may be included in the fluid vaporised by the device . People report using e-cigarettes to help quit smoking and studies of their effects on tobacco withdrawal and craving suggest good potential as smoking cessation aids . However , to date there have been no adequately powered r and omised trials investigating their cessation efficacy or safety . This paper outlines the protocol for this study . Methods / design Design : Parallel group , 3-arm , r and omised controlled trial . Participants : People aged ≥18 years resident in Auckl and , New Zeal and ( NZ ) who want to quit smoking . Intervention : Stratified blocked r and omisation to allocate participants to either Elusion ™ e-cigarettes with nicotine cartridges ( 16 mg ) or with placebo cartridges ( i.e. no nicotine ) , or to nicotine patch ( 21 mg ) alone . Participants r and omised to the e-cigarette groups will be told to use them ad libitum for one week before and 12 weeks after quit day , while participants r and omised to patches will be told to use them daily for the same period . All participants will be offered behavioural support to quit from the NZ Quitline . Primary outcome : Biochemically verified ( exhaled carbon monoxide ) continuous abstinence at six months after quit day . Sample size : 657 people ( 292 in both the nicotine e-cigarette and nicotine patch groups and 73 in the placebo e-cigarettes group ) will provide 80 % power at p = 0.05 to detect an absolute difference of 10 % in abstinence between the nicotine e-cigarette and nicotine patch groups , and 15 % between the nicotine and placebo e-cigarette groups . Discussion This trial will inform international debate and policy on the regulation and availability of e-cigarettes . If shown to be efficacious and safe , these devices could help many smokers as an alternative smoking cessation aid to st and ard nicotine products . Trial registration Australian NZ Clinical Trials Registry ( ACTRN12610000866000 ) Abstract Background Smoking is Australia ’s leading preventable cause of premature mortality and a major contributor to the national disease burden . If quit rates do not dramatically improve , then smoking will continue to be a major public health issue for decades to come . Harm-reduction approaches using novel nicotine products like e-cigarettes as long term replacements for smoking have the potential to improve quit rates . However , little research has assessed such approaches . Methods / Design Design : Three-arm parallel-group pragmatic r and omised controlled trial . Participants : People living in Australia who are at least 18 years old , smoke five or more cigarettes per day and are willing to try a sample of nicotine products . Intervention : Participants are r and omised to receive st and ard quit advice and medicinal nicotine ( Condition A ) ; quit or substitute advice and medicinal nicotine ( Condition B ) ; or quit or substitute advice and medicinal nicotine and e-cigarettes ( Condition C ) . Participants choose which ( if any ) nicotine products to receive to try in a free sample pack followed by a two to three week free supply of their favourite product(s ) and the option to purchase more at a discounted price . Follow-up surveys will assess nicotine product use and smoking . Primary outcome : Continuous abstinence for at least 6 months . Target sample size : 1600 people ( Condition A : 340 ; Condition B : 630 ; Condition C : 630 ) provides at least 80 % power at p = 0.05 to detect a 5 % difference in abstinence rates between each condition . Discussion This trial will provide data on tobacco harm-reduction approaches and in particular the use of e-cigarettes as a replacement for smoking . Trial registration Australian and New Zeal and Clinical Trials Registry : ACTRN12612001210864 . Date of registration : 15/11/2012 In a clinical study , changes in 14 biomarkers of exposures ( BOEs ) from 10 tobacco smoke constituents and mutagens detected by the urine mutagenicity test were investigated using a non-combustion inhaler type of tobacco product ( NCIT ) by switching from a conventional cigarette . This study was conducted in 80 Japanese healthy adult males with a 4-week residential , controlled , open-label , parallel group design . After r and omization , 40 smokers used NCIT with approximately 750 aspirations , other 20 smokers smoked approximately 20 pieces of an assigned 1-mg ISO tar conventional cigarette ( CC1 ) every day . Twenty non-smokers ( NS ) did not use any tobacco product . Under this study condition , switching from cigarette to NCIT showed significant reduction in all BOEs measured . On day 29 , the levels of these BOEs were almost the same as those in the NS group , except BOEs of nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone ( NNK ) . This suggested that the exposure to 8 constituents and mutagens in the NCIT group was similar to that in the NS group , while the exposure to nicotine was higher . Although the precise exposure level to NNK was not estimated because of the long half-life of its BOE , it would be substantially lower in the NCIT group than in the CC1 group Background While electronic cigarettes are forbidden in several countries , their sales are exploding in many others . Although e-cigarettes have been proposed as long-term substitutes for traditional smoking or as a tool for smoking cessation , very scarce data are available on their efficacy and safety . We describe the protocol of a 5-year multicentric prospect i ve study aim ed to evaluate short- and long-term adherence to e-cigarette smoking and the efficacy of e-cigarettes in reducing and /or quitting traditional cigarette smoking . The study will also compare the health effects of electronic vs traditional vs mixed cigarette smoking . Methods / design From June to December 2013 , we will enroll adult smokers of : ( EC ) e-cigarettes ( self-reported inhaling ≥ 50 puffs per week since ≥ 6 months ) ; ( TC ) traditional cigarettes ( ≥ 1 per day since ≥ 6 m ) ; ( Mixed ) both electronic and traditional cigarettes ( ≥1 per day since ≥ 6 m ) . Eligible subjects will be requested participation through newspaper advertisements and direct contact at the shops . Each subject will have to compile a structured question naire at enrolment and after 6 , 12 , 24 , 36 and 60 months . The level of carbon monoxide in expired after breath will be evaluated in all subjects declaring no traditional cigarette smoking in any follow-up phase , using portable carbon monoxide analyzers . The primary outcomes are traditional smoking cessation rates and number of smoked cigarettes . Secondary outcomes include adherence to e-cigarettes , self-reported adverse events , quality of life , and time to hospital admission for one among cardiovascular diseases , chronic obstructive pulmonary diseases , cancer of the lung , esophagus , larynx , oral cavity , bladder , pancreas , kidney , stomach , cervix , and myeloid leukemia . Admissions will be checked using official discharge data of the Abruzzo Region . A minimum of 500 subjects in each group will be enrolled , for a total of 1500 participants . Cox proportional hazards analysis will be used to calculate adjusted relative hazards of smoking cessation by each variable . Discussion Data on long-term efficacy and safety of e-cigarettes will be of utmost importance to form the basis for guidelines and regulatory decisions on e-cigarettes . Trial registration The protocol has been registered ( NCT01785537 ) and approved by the Ethics Committee of the University of Chieti ( Record n. 6 ; 25 - 03 - 2013 ) Background and Aims Electronic cigarettes ( e-cigarettes ) are rapidly increasing in popularity . Two r and omized controlled trials have suggested that e-cigarettes can aid smoking cessation , but there are many factors that could influence their real-world effectiveness . This study aim ed to assess , using an established methodology , the effectiveness of e-cigarettes when used to aid smoking cessation compared with nicotine replacement therapy ( NRT ) bought over-the-counter and with unaided quitting in the general population . Design and Setting A large cross-sectional survey of a representative sample of the English population . Participants The study included 5863 adults who had smoked within the previous 12 months and made at least one quit attempt during that period with either an e-cigarette only ( n = 464 ) , NRT bought over-the-counter only ( n = 1922 ) or no aid in their most recent quit attempt ( n = 3477 ) . Measurements The primary outcome was self-reported abstinence up to the time of the survey , adjusted for key potential confounders including nicotine dependence . Findings E-cigarette users were more likely to report abstinence than either those who used NRT bought over-the-counter [ odds ratio ( OR ) = 2.23 , 95 % confidence interval ( CI ) = 1.70–2.93 , 20.0 versus 10.1 % ] or no aid ( OR = 1.38 , 95 % CI = 1.08–1.76 , 20.0 versus 15.4 % ) . The adjusted odds of non-smoking in users of e-cigarettes were 1.63 ( 95 % CI = 1.17–2.27 ) times higher compared with users of NRT bought over-the-counter and 1.61 ( 95 % CI = 1.19–2.18 ) times higher compared with those using no aid . Conclusions Among smokers who have attempted to stop without professional support , those who use e-cigarettes are more likely to report continued abstinence than those who used a licensed NRT product bought over-the-counter or no aid to cessation . This difference persists after adjusting for a range of smoker characteristics such as nicotine dependence Smoking cessation treatment is now integrated into many health-care systems and a major research effort is under way to improve current success rates . Until now results from r and omized clinical trials have been reported in many different ways , leading to problems of interpretation . We propose six st and ard criteria comprising the ' Russell St and ard ' ( RS ) . These criteria are applicable to trials of cessation aids where participants have a defined target quit date and there is face-to-face contact with research ers or clinic staff , as follows . ( 1 ) Follow-up for 6 months ( RS6 ) or 12 months ( RS12 ) from the target quit date or the end of a predefined ' grace period ' ; ( 2 ) self-report of smoking abstinence over the whole follow-up period allowing up to five cigarettes in total ; ( 3 ) biochemical verification of abstinence at least at the 6-month or 12-month follow-up point ; ( 4 ) use of an ' intention-to-treat ' approach in which data from all r and omized smokers are included in the analysis unless they have died or moved to an untraceable address ( participants who are included in the analysis are counted as smokers if their smoking status at the final follow-up can not be determined ) ; ( 5 ) following-up ' protocol violators ' and using their true smoking status in the analysis ; and ( 6 ) collecting follow-up data blind to smokers ' allocation to trial group . We believe that these criteria provide the best compromise between practicability and surrogacy for long-term cessation and will enable meaningful comparison between studies . There may be good reasons why other outcome criteria would also be reported , and studies that involve interventions with special groups or where there is no design ated target quit date or face to face contact would need to adapt these criteria accordingly Background Electronic cigarettes ( e-cigarettes ) are becoming increasingly popular with smokers worldwide . Users report buying them to help quit smoking , to reduce cigarette consumption , to relieve tobacco withdrawal symptoms , and to continue having a ‘ smoking ’ experience , but with reduced health risks . Research on e-cigarettes is urgently needed in order to ensure that the decisions of regulators , healthcare providers and consumers are based on science . Methods ECLAT is a prospect i ve 12-month r and omized , controlled trial that evaluates smoking reduction/abstinence in 300 smokers not intending to quit experimenting two different nicotine strengths of a popular e-cigarette model ( ‘ Categoria ’ ; Arbi Group Srl , Italy ) compared to its non-nicotine choice . GroupA ( n = 100 ) received 7.2 mg nicotine cartridges for 12 weeks ; GroupB ( n = 100 ) , a 6-week 7.2 mg nicotine cartridges followed by a further 6-week 5.4 mg nicotine cartridges ; GroupC ( n = 100 ) received no-nicotine cartridges for 12 weeks . The study consisted of nine visits during which cig/day use and exhaled carbon monoxide ( eCO ) levels were measured . Smoking reduction and abstinence rates were calculated . Adverse events and product preferences were also review ed . Results Declines in cig/day use and eCO levels were observed at each study visits in all three study groups ( p<0.001 vs baseline ) , with no consistent differences among study groups . Smoking reduction was documented in 22.3 % and 10.3 % at week-12 and week-52 respectively . Complete abstinence from tobacco smoking was documented in 10.7 % and 8.7 % at week-12 and week-52 respectively . A substantial decrease in adverse events from baseline was observed and withdrawal symptoms were infrequently reported during the study . Participants ’ perception and acceptance of the product under investigation was satisfactory . Conclusion In smokers not intending to quit , the use of e-cigarettes , with or without nicotine , decreased cigarette consumption and elicited enduring tobacco abstinence without causing significant side effects . Trial Registration Clinical Trials.gov NCT01164072 Background : Smoking reduction remains a pivotal issue in public health policy , but quit rates obtained with traditional quit-smoking therapies remain disappointingly low . Tobacco Harm Reduction ( THR ) , aim ing at less harmful ways of consuming nicotine , may provide a more effective alternative . One promising c and i date for THR are electronic cigarettes ( e-cigs ) . The aim of this study was to investigate the efficacy of second-generation e-cigs both in terms of acute craving-reduction in the lab and in terms of smoking reduction and experienced benefits /complaints in an eight-month R and omized Controlled Trial ( RCT ) . Design : RCT with three arms . Methods : Participants ( N = 48 ) unwilling to quit smoking were r and omized into two e-cig groups and one control group . During three lab sessions ( over two months ) participants , who had been abstinent for four hours , vaped/smoked for five minutes , after which we monitored the effect on craving and withdrawal symptoms . eCO and saliva cotinine levels were also measured . In between lab sessions , participants in the e-cig groups could use e-cigs or smoke ad libitum , whereas the control group could only smoke . After the lab sessions , the control group also received an e-cig . The RCT included several question naires , which repeatedly monitored the effect of ad libitum e-cig use on the use of tobacco cigarettes and the experienced benefits /complaints up to six months after the last lab session . Results : From the first lab session on , e-cig use after four hours of abstinence result ed in a reduction in cigarette craving which was of the same magnitude as when a cigarette was smoked , while eCO was unaffected . After two months , we observed that 34 % of the e-cig groups had stopped smoking tobacco cigarettes , versus 0 % of the control group ( difference p < 0.01 ) . After five months , the e-cig groups demonstrated a total quit-rate of 37 % , whereas the control group showed a quit rate of 38 % three months after initiating e-cig use . At the end of the eight-month study , 19 % of the e-cig groups and 25 % of the control group were totally abstinent from smoking , while an overall reduction of 60 % in the number of cigarettes smoked per day was observed ( compared to intake ) . eCO levels decreased , whereas cotinine levels were the same in all groups at each moment of measurement . Reported benefits far outweighed the reported complaints . Conclusion : In a series of controlled lab sessions with e-cig naïve tobacco smokers , second generation e-cigs were shown to be immediately and highly effective in reducing abstinence induced cigarette craving and withdrawal symptoms , while not result ing in increases in eCO . Remarkable ( > 50 pc ) eight-month reductions in , or complete abstinence from tobacco smoking was achieved with the e-cig in almost half ( 44 % ) of the participants The objective of this study was to compare the short-term respiratory effects due to the inhalation of electronic and conventional tobacco cigarette-generated mainstream aerosols through the measurement of the exhaled nitric oxide ( eNO ) . To this purpose , twenty-five smokers were asked to smoke a conventional cigarette and to vape an electronic cigarette ( with and without nicotine ) , and an electronic cigarette without liquid ( control session ) . Electronic and tobacco cigarette mainstream aerosols were characterized in terms of total particle number concentrations and size distributions . On the basis of the measured total particle number concentrations and size distributions , the average particle doses deposited in alveolar and tracheobronchial regions of the lungs for a single 2-s puff were also estimated considering a subject performing resting ( sitting ) activity . Total particle number concentrations in the mainstream result ed equal to 3.5±0.4 × 10(9 ) , 5.1±0.1 × 10(9 ) , and 3.1±0.6 × 10(9 ) part . cm(-3 ) for electronic cigarettes without nicotine , with nicotine , and for conventional cigarettes , respectively . The corresponding alveolar doses for a resting subject were estimated equal to 3.8 × 10(10 ) , 5.2 × 10(10 ) and 2.3 × 10(10 ) particles . The mean eNO variations measured after each smoking/vaping session were equal to 3.2ppb , 2.7ppb and 2.8ppb for electronic cigarettes without nicotine , with nicotine , and for conventional cigarettes , respectively ; whereas , negligible eNO changes were measured in the control session . Statistical tests performed on eNO data showed statistically significant differences between smoking/vaping sessions and the control session , thus confirming a similar effect on human airways whatever the cigarette smoked/vaped , the nicotine content , and the particle dose received AIM To determine the combined effect of very low nicotine content ( VLNC ) cigarettes and usual Quitline care [ nicotine replacement therapy ( NRT ) and behavioural support ] on smoking abstinence , in smokers motivated to quit . DESIGN Single-blind , parallel r and omized trial . SETTING New Zeal and . PARTICIPANTS Smokers who called the Quitline for quitting support were r and omized to either VLNC cigarettes to use whenever they had an urge to smoke for up to 6 weeks after their quit date , in combination with usual Quitline care ( 8 weeks of NRT patches and /or gum or lozenges , plus behavioural support ) or to usual Quitline care alone . MEASUREMENTS The primary outcome was 7-day point-prevalence smoking abstinence 6 months after quit day . Secondary outcomes included continuous abstinence , cigarette consumption , withdrawal , self-efficacy , alcohol use , serious adverse events and views on the use of the VLNC cigarettes at 3 and 6 weeks and 3 and 6 months . FINDINGS A total of 1410 participants were r and omized ( 705 in each arm ) , with a 24 % loss to follow-up at 6 months . Participants in the intervention group were more likely to have quit smoking at 6 months compared to the usual care group [ 7-day point-prevalence abstinence 33 versus 28 % , relative risk ( RR ) = 1.18 , 95 % confidence interval ( CI ) : 1.01 , 1.39 , P = 0.037 ; continuous abstinence 23 versus 15 % , RR = 1.50 , 95 % CI : 1.20 , 1.87 , P = 0.0003 ] . The median time to relapse in the intervention group was 2 months compared to 2 weeks in the usual care group ( P < 0.0001 ) . CONCLUSIONS Addition of very low nicotine content cigarettes to st and ard Quitline smoking cessation support may help some smokers to become abstinent Abstract Context : Electronic cigarettes ( e-cigarettes ) are becoming increasingly popular yet their effects on health remain unknown . Objective : To conduct the first comprehensive and st and ardized assessment of the acute impact of active and passive e-cigarette smoking on serum cotinine and lung function , as compared to active and passive tobacco cigarette smoking . Material s and methods : Fifteen smokers ( ≥15 cigarettes/day ; seven females ; eight males ) and 15 never-smokers ( seven females ; eight males ) completed this repeated- measures controlled study . Smokers underwent a control session , an active tobacco cigarette ( their favorite br and ) smoking session and an active e-cigarette smoking session . Never-smokers underwent a control session , a passive tobacco cigarette smoking session and a passive e-cigarette smoking session . Serum cotinine , lung function , exhaled carbon monoxide and nitric oxide were assessed . The level of significance was set at p ≤ 0.001 to adjust for multiple comparisons . Results : e-Cigarettes and tobacco cigarettes generated similar ( p > 0.001 ) effects on serum cotinine levels after active ( 60.6 ± 34.3 versus 61.3 ± 36.6 ng/ml ) and passive ( 2.4 ± 0.9 versus 2.6 ± 0.6 ng/ml ) smoking . Neither a brief session of active e-cigarette smoking ( indicative : 3 % reduction in FEV1/FVC ) nor a 1 h passive e-cigarette smoking ( indicative : 2.3 % reduction in FEV1/FVC ) significantly affected the lung function ( p > 0.001 ) . In contrast , active ( indicative : 7.2 % reduction in FEV1/FVC ; p < 0.001 ) but not passive ( indicative : 3.4 % reduction in FEV1/FVC ; p = 0.005 ) tobacco cigarette smoking undermined lung function . Conclusion : Regarding short-term usage , the studied e-cigarettes generate smaller changes in lung function but similar nicotinergic impact to tobacco cigarettes . Future research should target the health effects of long-term e-cigarette usage , including the effects of nicotine dosage Background People with mental illness have higher rates of smoking than the general population and are at greater risk of smoking-related death and disability . In smokers from the general population , electronic cigarettes ( e-cigarettes ) have been shown to have a similar effect on quit rates as nicotine replacement therapy , but little is known about their effect in smokers with mental illness . Methods Secondary analysis of data from the ASCEND trial involving 657 dependent adult smokers motivated to quit , r and omised to 16 mg nicotine e-cigarette , 21 mg nicotine patch , or 0 mg nicotine e-cigarette , with minimal behavioural support . Using self-reported medication use and the Anatomical Therapeutic Chemical Classification System , we identified 86 participants with mental illness and analysed their cessation and smoking reduction outcomes . Results For e-cigarettes alone , and all interventions pooled , there was no statistically significant difference in biochemically verified quit rates at six months between participants with and without mental illness , nor in smoking reduction , adverse events , treatment compliance , or acceptability . Rates of relapse to smoking were higher in participants with mental illness . Among this group , differences between treatments were not statistically significant for cessation ( patch 14 % [ 5/35 ] , 16 mg e-cigarette 5 % [ 2/39 ] , 0 mg e-cigarette 0 % [ 0/12 ] , p = 0.245 ) , adverse events or relapse rates . However , e-cigarette users had higher levels of smoking reduction , treatment compliance , and acceptability . Conclusions The use of e-cigarettes for quitting appears to be equally effective , safe , and acceptable for people with and without mental illness . For people with mental illness , e-cigarettes may be as effective and safe as patches , yet more acceptable , and associated with greater smoking reduction . Trial registration Australian New Zeal and Clinical trials Registry , number : ACTRN12610000866000 BACKGROUND Electronic cigarettes ( e-cigarettes ) can deliver nicotine and mitigate tobacco withdrawal and are used by many smokers to assist quit attempts . We investigated whether e-cigarettes are more effective than nicotine patches at helping smokers to quit . METHODS We did this pragmatic r and omised-controlled superiority trial in Auckl and , New Zeal and , between Sept 6 , 2011 , and July 5 , 2013 . Adult ( ≥18 years ) smokers wanting to quit were r and omised ( with computerised block r and omisation , block size nine , stratified by ethnicity [ Māori ; Pacific ; or non-Māori , non-Pacific ] , sex [ men or women ] , and level of nicotine dependence [ > 5 or ≤5 Fagerström test for nicotine dependence ] ) in a 4:4:1 ratio to 16 mg nicotine e-cigarettes , nicotine patches ( 21 mg patch , one daily ) , or placebo e-cigarettes ( no nicotine ) , from 1 week before until 12 weeks after quit day , with low intensity behavioural support via voluntary telephone counselling . The primary outcome was biochemically verified continuous abstinence at 6 months ( exhaled breath carbon monoxide measurement < 10 ppm ) . Primary analysis was by intention to treat . This trial is registered with the Australian New Zeal and Clinical Trials Registry , number ACTRN12610000866000 . FINDINGS 657 people were r and omised ( 289 to nicotine e-cigarettes , 295 to patches , and 73 to placebo e-cigarettes ) and were included in the intention-to-treat analysis . At 6 months , verified abstinence was 7·3 % ( 21 of 289 ) with nicotine e-cigarettes , 5·8 % ( 17 of 295 ) with patches , and 4·1 % ( three of 73 ) with placebo e-cigarettes ( risk difference for nicotine e-cigarette vs patches 1·51 [ 95 % CI -2·49 to 5·51 ] ; for nicotine e-cigarettes vs placebo e-cigarettes 3·16 [ 95 % CI -2·29 to 8·61 ] ) . Achievement of abstinence was substantially lower than we anticipated for the power calculation , thus we had insufficient statistical power to conclude superiority of nicotine e-cigarettes to patches or to placebo e-cigarettes . We identified no significant differences in adverse events , with 137 events in the nicotine e-cigarettes group , 119 events in the patches group , and 36 events in the placebo e-cigarettes group . We noted no evidence of an association between adverse events and study product . INTERPRETATION E-cigarettes , with or without nicotine , were modestly effective at helping smokers to quit , with similar achievement of abstinence as with nicotine patches , and few adverse events . Uncertainty exists about the place of e-cigarettes in tobacco control , and more research is urgently needed to clearly establish their overall benefits and harms at both individual and population levels . FUNDING Health Research Council of New Zeal and Objective To evaluate the safety and efficacy as a tool of smoking cessation of electronic cigarettes ( e-cigarettes ) , directly comparing users of e-cigarettes only , smokers of tobacco cigarettes only , and smokers of both . Design Prospect i ve cohort study . Final results are expected in 2019 , but given the urgency of data to support policies on electronic smoking , we report the results of the 12-month follow-up . Data Sources Direct contact and structured question naires by phone or via internet . Methods Adults ( 30–75 years ) were included if they were smokers of ≥1 tobacco cigarette/day ( tobacco smokers ) , users of any type of e-cigarettes , inhaling ≥50 puffs weekly ( e-smokers ) , or smokers of both tobacco and e-cigarettes ( dual smokers ) . Carbon monoxide levels were tested in a sample of those declaring tobacco smoking abstinence . Main Outcome Measures Sustained smoking abstinence from tobacco smoking at 12 months , reduction in the number of tobacco cigarettes smoked daily . Data Synthesis We used linear and logistic regression , with region as cluster unit . Results Follow-up data were available for 236 e-smokers , 491 tobacco smokers , and 232 dual smokers ( overall response rate 70.8 % ) . All e-smokers were tobacco ex-smokers . At 12 months , 61.9 % of the e-smokers were still abstinent from tobacco smoking ; 20.6 % of the tobacco smokers and 22.0 % of the dual smokers achieved tobacco abstinence . Adjusting for potential confounders , tobacco smoking abstinence or cessation remained significantly more likely among e-smokers ( adjusted OR 5.19 ; 95 % CI : 3.35–8.02 ) , whereas adding e-cigarettes to tobacco smoking did not enhance the likelihood of quitting tobacco and did not reduce tobacco cigarette consumption . E-smokers showed a minimal but significantly higher increase in self-rated health than other smokers . Non significant differences were found in self-reported serious adverse events ( eleven overall ) . Conclusions Adding e-cigarettes to tobacco smoking did not facilitate smoking cessation or reduction . If e-cigarette safety will be confirmed , however , the use of e-cigarettes alone may facilitate quitters remaining so . Registration Number NCT01785537 INTRODUCTION This study examined changes in smokers ' readiness and confidence to quit smoking , smoking behavior , nicotine withdrawal symptoms , and tobacco product preference following electronic cigarette ( EC ) experimentation and 1 week of ad libitum use . METHODS Current cigarette smokers , with no prior use of ECs and uninterested in quitting , completed 3 study phases : baseline assessment ( N = 20 ) , experimentation ( N = 19 ) , and ad libitum use ( N = 16 ) . Baseline assessment consisted of completion of assessment measures and exhaled carbon monoxide measurements . Experimentation phases consisted of four , 75-min sessions in which participants completed assessment measures and sample d 3 EC br and s and their own br and of cigarette ( OBC ) . Ad libitum use included participants selecting and being provided their preferred EC br and from the experimentation phase to be used " as you want " for 1 week . Outcome measures included readiness and confidence to quit smoking , nicotine withdrawal symptoms , product preference/satisfaction , and smoking behavior items . RESULTS Readiness and confidence to quit increased significantly during the experimentation period and continued to increase during ad libitum use . There were no significant differences in reported effectiveness in reducing smoking urges and cravings between OBC and EC though OBC were rated as more enjoyable and satisfying . During ad libitum use , regular cigarette smoking decreased by approximately 44 % from baseline levels with overall tobacco use ( EC + OBC ) remaining the same . CONCLUSIONS Among a small convenience sample of unmotivated cigarette smokers , EC experimentation and 1 week of ad libitum use increased readiness and confidence to quit regular cigarettes and reduced regular cigarette smoking Stop smoking it is often associated to weight gain that is one of the most important causes for relapse . This is the first study to describe long-term changes in body weight in smokers invited to quit or reduce smoking by switching to ECs . Conventional cigarettes consumption and body weight were measured prospect ively in a r and omized controlled trial of smokers invited to switch to ECs . Post cessation weight changes from baseline at week-12 , -24 and -52 were compared among 1 ) high , medium and zero nicotine strength products and 2 ) pooled continuous smoking failure , smoking reduction and abstinence phenotypes . Saliva cotinine levels and appetite levels were also measured . No significant changes in body weight were observed among high , medium and zero nicotine strength products . Differences among continuous smoking phenotypes were significant only at week-12 ( p = 0.010 ) and week-24 ( p = 0.012 ) with quitters gaining 2.4{plus minus}4.3 Kg and 2.9{plus minus}4.4 Kg respectively . However , weight gain at week-52 ( 1.5{plus minus}5.0 Kg ) was no longer significant compared to Failures and Reducers . No confounding factors could explain the significant changes in body weight . Smokers who quit smoking by switching to ECs may limit their post-cessation weight gain , with substantial reversal in weight gain being manifest at late time points Rationale It is well established that nicotine improves , and deprivation impairs , cognitive performance and mood in smokers . Prospect i ve memory ( PM ) , remembering to execute a delayed intention at a given time point , is under-explored in smokers . Whilst a h and ful of studies have shown improved PM with nicotine , the effects of nicotine delivered via the electronic cigarette ( e-cigarette ) have not been investigated . Objective This study explores whether , by comparison with placebo , nicotine delivered via the e-cigarette can improve PM , tobacco withdrawal symptoms and desire to smoke in abstinent smokers . Methods Twenty smokers , abstinent for 8–10 h , each completed two experimental sessions under nicotine ( 18 mg ) and placebo ( 0 mg ) e-cigarette conditions . Participants completed a single-item desire-to-smoke scale and the Mood and Physical Symptoms Scale . PM was measured using the Cambridge Prospect i ve Memory Test . Results Compared with placebo , the nicotine e-cigarette reduced the desire to smoke and tobacco withdrawal symptoms , and improved time-based but not event-based PM . There was a moderate , marginally significant negative correlation between PM performance during abstinence and nicotine dependence . Conclusions This is the first study to show that nicotine derived via e-cigarette can improve PM in abstinent smokers , suggesting efficient nicotine delivery . The finding that the effect of nicotine was restricted to time-based rather than event-based PM is consistent with the view that nicotine acts to improve performance on strategic ( effortful ) rather than automatic processing . These findings add to the growing body of evidence that the e-cigarette can replace some of the effects of nicotine derived from tobacco smoking , thus highlighting its potential for smoking cessation Background It is well established in studies across several countries that tobacco smoking is more prevalent among schizophrenic patients than the general population . Electronic cigarettes are becoming increasingly popular with smokers worldwide . To date there are no large r and omized trials of electronic cigarettes in schizophrenic smokers . A well- design ed trial is needed to compare efficacy and safety of these products in this special population . Methods / Design Intervention : We have design ed a r and omized controlled trial investigating the efficacy and safety of electronic cigarette . The trial will take the form of a prospect i ve 12-month r and omized clinical study to evaluate smoking reduction , smoking abstinence and adverse events in schizophrenic smokers not intending to quit . We will also monitor quality of life , neurocognitive functioning and measure participants ’ perception and satisfaction of the product . Outcome measures : A ≥50 % reduction in the number of cigarettes/day from baseline , will be calculated at each study visit ( “ reducers ” ) . Abstinence from smoking will be calculated at each study visit ( “ quitters ” ) . Smokers who leave the study protocol before its completion and will carry out the Early Termination Visit or who will not satisfy the criteria of “ reducers ” and “ quitters ” will be defined “ non responders”.Statistical analysis : The differences of continuous variables between the three groups will be evaluated with the Kruskal-Wallis Test , followed by the Dunn multiple comparison test . The differences between the three groups for normally distributed data will be evaluated with ANOVA test one way , followed by the Newman-Keuls multiple comparison test . The normality of the distribution will be evaluated with the Kolmogorov-Smirnov test . Any correlations between the variables under evaluation will be assessed by Spearman r correlation . To compare qualitative data will be used the Chi-square test . Discussion The main strengths of the SCARIS study are the following : it ’s the first large RCT on schizophrenic patient , involving in and outpatient , evaluating the effect of a three-arm study design , and a long term of follow-up (52-weeks).The goal is to propose an effective intervention to reduce the risk of tobacco smoking , as a complementary tool to treat tobacco addiction in schizophrenia . Trial registration Clinical Trials.gov , NCT01979796 BACKGROUND Smoking acutely relieves negative affect ( NA ) due to smoking abstinence but may not relieve NA from other sources , such as stressors . METHODS Dependent smokers ( n = 104 ) r and omly assigned to one of three smoking conditions ( nicotine or denicotinized cigarettes , or no smoking ) completed four negative mood induction procedures ( one per session ) : 1 ) overnight smoking abstinence , 2 ) challenging computer task , 3 ) public speech preparation , and 4 ) watching negative mood slides . A fifth session involved a neutral mood control . The two smoking groups took four puffs on their assigned cigarette and then smoked those same cigarettes ad libitum during continued mood induction . All subjects rated their level of NA and positive affect on several measures ( Mood Form , Positive and Negative Affect Scale , Stress-Arousal Checklist , and State-Trait Anxiety Inventory-state ) . They also rated craving and withdrawal . RESULTS Negative affect relief from smoking depended on the NA source ( i.e. , mood induction procedure ) and the affect measure . Smoking robustly relieved NA due to abstinence on all four measures but only modestly relieved NA due to the other sources and typically on only some measures . Smoking 's effects on positive affect and withdrawal were similar to effects on NA , but relief of craving depended less on NA source . Smoking reinforcement only partly matched the pattern of NA relief . Few responses differed between the nicotine and denicotinized smoking groups . CONCLUSIONS Acute NA relief from smoking depends on the situation and the affect measure used but may not depend on nicotine intake . These results challenge the common assumption that smoking , and nicotine in particular , broadly alleviates NA Previous studies have suggested that sensory cues associated with cigarette smoking can suppress certain smoking withdrawal symptoms , including craving for cigarettes . In this study we investigated the subjective effects of a cigarette substitute delivering a vapor of black pepper essential oil . Forty-eight cigarette smokers participated in a 3-h session conducted after overnight deprivation from smoking . Subjects were r and omly assigned to one of three conditions : one group of smokers puffed on a device that delivered a vapor from essential oil of black pepper ; a second group puffed on the device with a mint/menthol cartridge , and a third group used a device containing an empty cartridge . Subjects puffed and inhaled ad libitum from the device throughout the session during which no smoking was allowed . Reported craving for cigarettes was significantly reduced in the pepper condition relative to each of the two control conditions . In addition , negative affect and somatic symptoms of anxiety were alleviated in the pepper condition relative to the unflavored placebo . The intensity of sensations in the chest was also significantly higher for the pepper condition . These results support the view that respiratory tract sensations are important in alleviating smoking withdrawal symptoms . Cigarette substitutes delivering pepper constituents may prove useful in smoking cessation treatment Rationale Electronic cigarettes are becoming increasingly popular among smokers worldwide . Commonly reported reasons for use include the following : to quit smoking , to avoid relapse , to reduce urge to smoke , or as a perceived lower-risk alternative to smoking . Few studies , however , have explored whether electronic cigarettes ( e-cigarettes ) deliver measurable levels of nicotine to the blood . Objective This study aims to explore in experienced users the effect of using an 18-mg/ml nicotine first-generation e-cigarette on blood nicotine , tobacco withdrawal symptoms , and urge to smoke . Methods Fourteen regular e-cigarette users ( three females ) , who are abstinent from smoking and e-cigarette use for 12 h , each completed a 2.5 h testing session . Blood was sample d , and question naires were completed ( tobacco-related withdrawal symptoms , urge to smoke , positive and negative subjective effects ) at four stages : baseline , 10 puffs , 60 min of ad lib use and a 60-min rest period . Results Complete sets of blood were obtained from seven participants . Plasma nicotine concentration rose significantly from a mean of 0.74 ng/ml at baseline to 6.77 ng/ml 10 min after 10 puffs , reaching a mean maximum of 13.91 ng/ml by the end of the ad lib puffing period . Tobacco-related withdrawal symptoms and urge to smoke were significantly reduced ; direct positive effects were strongly endorsed , and there was very low reporting of adverse effects . Conclusions These findings demonstrate reliable blood nicotine delivery after the acute use of this br and /model of e-cigarette in a sample of regular users . Future studies might usefully quantify nicotine delivery in relation to inhalation technique and the relationship with successful smoking cessation/harm reduction Background Electronic cigarettes ( e-Cigs ) are an attractive long-term alternative nicotine source to conventional cigarettes . Although they may assist smokers to remain abstinent during their quit attempt , studies using first generation e-Cigs report low success rates . Second generation devices ( personal vaporisers - PVs ) may result in much higher quit rates , but their efficacy and safety in smoking cessation and /or reduction in clinical trials is unreported . Method We conducted a prospect i ve proof-of-concept study monitoring modifications in smoking behaviour of 50 smokers ( unwilling to quit ) switched onto PVs . Participants attended five study visits : baseline , week-4 , week-8 , week-12 and week-24 . Number of cigarettes/day ( cigs/day ) and exhaled carbon monoxide ( eCO ) levels were noted at each visit . Smoking reduction/abstinence rates , product usage , adverse events and subjective opinions of these products were also review ed . Results Sustained 50 % and 80 % reduction in cigs/day at week-24 was reported in 15/50 ( 30 % ) and 7/50 ( 14 % ) participants with a reduction from 25cigs/day to 6cigs/day ( p < 0.001 ) and 3cigs/day ( p < 0.001 ) , respectively . Smoking abstinence ( self-reported abstinence from cigarette smoking verified by an eCO ≤10 ppm ) at week-24 was observed in 18/50 ( 36 % ) participants , with 15/18 ( 83.3 % ) still using their PVs at the end of the study . Combined 50 % reduction and smoking abstinence was shown in 33/50 ( 66 % ) participants . Throat/mouth irritation ( 35.6 % ) , dry throat/mouth ( 28.9 % ) , headache ( 26.7 % ) and dry cough ( 22.2 % ) were frequently reported early in the study , but waned substantially by week-24 . Participants ’ perception and acceptance of the products was very good . Conclusion The use of second generation PVs substantially decreased cigarette consumption without causing significant adverse effects in smokers not intending to quit . Trial registration ( Clinical Trials.gov Identifier : NCT02124200 Background Electronic cigarettes have been developed and marketed in recent years as smoking substitutes . However , no studies have evaluated their effects on the cardiovascular system . The purpose of this study was to examine the immediate effects of electronic cigarette use on left ventricular ( LV ) function , compared to the well-documented acute adverse effects of smoking . Methods Echocardiographic examinations were performed in 36 healthy heavy smokers ( SM , age 36 ± 5 years ) before and after smoking 1 cigarette and in 40 electronic cigarette users ( ECIG , age 35 ± 5 years ) before and after using the device with “ medium-strength ” nicotine concentration ( 11 mg/ml ) for 7 minutes . Mitral flow diastolic velocities ( E , A ) , their ratio ( E/A ) , deceleration time ( DT ) , isovolumetric relaxation time ( IVRT ) and corrected-to-heart rate IVRT ( IVRTc ) were measured . Mitral annulus systolic ( Sm ) , and diastolic ( Em , Am ) velocities were estimated . Myocardial performance index was calculated from Doppler flow ( MPI ) and tissue Doppler ( MPIt ) . Longitudinal deformation measurements of global strain ( GS ) , systolic ( SRs ) and diastolic ( SRe , SRa ) strain rate were also performed . Results Baseline measurements were similar in both groups . In SM , IVRT and IVRTc were prolonged , Em and SRe were decreased , and both MPI and MPIt were elevated after smoking . In ECIG , no differences were observed after device use . Comparing after-use measurements , ECIG had higher Em ( P = 0.032 ) and SRe ( P = 0.022 ) , and lower IVRTc ( P = 0.011 ) , MPI ( P = 0.001 ) and MPIt ( P = 0.019 ) . The observed differences were significant even after adjusting for changes in heart rate and blood pressure . Conclusions Although acute smoking causes a delay in myocardial relaxation , electronic cigarette use has no immediate effects . Electronic cigarettes ’ role in tobacco harm reduction should be studied intensively in order to determine whether switching to electronic cigarette use may have long-term beneficial effects on smokers ’ health . Trial registration Current Controlled Trials IS RCT Electronic cigarettes ( e-cigarettes ) are battery operated devices that deliver nicotine via inhaled vapour . Few studies have evaluated acute effects on craving and mood , and none have explored effects on cognition . This study aim ed to explore the effects of the White Super e-cigarette on desire to smoke , nicotine withdrawal symptoms , attention and working memory . Eighty-six smokers were r and omly allocated to either : 18 mg nicotine e-cigarette ( nicotine ) , 0 mg e-cigarette ( placebo ) , or just hold the e-cigarette ( just hold ) conditions . Participants rated their desire to smoke and withdrawal symptoms at baseline ( T1 ) , and five ( T2 ) and twenty ( T3 ) minutes after using the e-cigarette ad libitum for 5 min . A subset of participants completed the Letter Cancellation and Brown-Peterson Working Memory Tasks . After 20 min , compared with the just hold group , desire to smoke and some aspects of nicotine withdrawal were significantly reduced in the nicotine and placebo group ; the nicotine e-cigarette was superior to placebo in males but not in females . The nicotine e-cigarette also improved working memory performance compared with placebo at the longer interference intervals . There was no effect of nicotine on Letter Cancellation performance . To conclude , the White Super e-cigarette alleviated desire to smoke and withdrawal symptoms 20 min after use although the nicotine content was more important for males . This study also demonstrated for the first time that the nicotine e-cigarette can enhance working memory performance . Further evaluation of the cognitive effects of the e-cigarette and its efficacy as a cessation tool is merited Background : Cigarette smoking is a tough addiction to break . This dependence is the most common dual diagnosis for individuals with schizophrenia . Currently three effective drugs are approved for smoking cessation : nicotine replacement therapy ( NRT ) , varenicline and bupropion . However , some serious side effects of varenicline have been reported , including depression , suicidal thoughts , and suicide . The use of bupropion also has side effects . It should not be used by people who have epilepsy or any condition that lowers the seizure threshold , nor by people who take a specific class of drugs called monoamine oxidase inhibitors . Hence , there are pharmacodynamic reason to believe they could precipitate or exacerbate psychosis . For its capacity to deliver nicotine and provide a coping mechanism for conditioned smoking cues by replacing some of the rituals associated with smoking gestures , electronic-cigarettes may reduce nicotine withdrawal symptoms without serious side effects . Our recent work with ECs in healthy smokers not intending to quit consistently show surprisingly high success rates . We hypothesised that these positive findings could be replicated in difficult patients with schizophrenia This tool may help smokers with schizophrenia remain abstinent during their quitting attempts or to reduce cigarette consumption . Efficacy and safety of these devices in long-term smoking cessation and /or smoking reduction studies have never been investigated for this special population . Methods : In this study we monitored possible modifications in smoking habits of 14 smokers ( not intending to quit ) with schizophrenia experimenting with the “ Categoria ” e-Cigarette with a focus on smoking reduction and smoking abstinence . Study participants were invited to attend six study visits : at baseline , week-4 , week-8 , week-12 week-24 and week 52 . Product use , number of cigarettes smoked , carbon monoxide in exhaled breath ( eCO ) and positive and negative symptoms of schizophrenia levels were measured at each visit . Smoking reduction and abstinence rates were calculated . Adverse events were also review ed . Results : Sustained 50 % reduction in the number of cig/day at week-52 was shown in 7/14 ( 50 % ) participants ; their median of 30 cig/day decreasing significantly to 15 cig/day ( p = 0.018 ) . Sustained smoking abstinence at week-52 was observed in 2/14 ( 14.3 % ) participants . Combined sustained 50 % reduction and smoking abstinence was shown in 9/14 ( 64.3 % ) participants . Nausea was observed in 2/14 ( 14.4 % ) of participants , throat irritation in 2/14 ( 14.4 % ) of participants , headache in 2/14 ( 14.4 % ) of participants , and dry cough in 4/14 ( 28.6 % ) of participants . However , these adverse events diminished substantially by week-24 . Overall , one to two cartridges/day were used throughout the study . Positive and negative symptoms of schizophrenia are not increased after smoking reduction/cessation in patients using e-cigarettes . Conclusions : We have shown for the first time that the use of e-cigarette substantially decreased cigarette consumption without causing significant side effects in chronic schizophrenic patients who smoke not intending to quit . This was achieved without negative impacts on the symptoms of schizophrenia as assessed by SAPS and SANS symptoms scales Background Smoking is a global public health problem . For this reason , experts have called smoking dependence a global epidemic . Over the past 5 years , sales of electronic cigarettes , or e-cigarettes , have been growing strongly in many countries . Yet there is only partial evidence that e-cigarettes are beneficial for smoking cessation . In particular , although it has been proven that nicotine replacement devices may help individuals stop smoking and tolerate withdrawal symptoms , e-cigarettes ’ power to increase the quitting success rate is still limited , ranging from 5 % to 20 % dependent on smokers ’ baseline conditions as shown by a recent Cochrane review . Consequently , it is urgent to know if e-cigarettes may have a higher success rate than other nicotine replacement methods and under what conditions . Furthermore , the effects of the therapeutic setting and the relationship between individual characteristics and the success rate have not been tested . This protocol is particularly innovative , because it aims to test the effectiveness of electronic devices in a screening program ( the COSMOS II lung cancer prevention program at the European Institute of Oncology ) , where tobacco reduction is needed to lower individuals ’ lung cancer risks . Objective This protocol was design ed with the primary aim of investigating the role of tobacco-free cigarettes in helping smokers improve lung health and either quit smoking or reduce their tobacco consumption . In particular , we aim to investigate the impact of a 3-month e-cigarettes program to reduce smoking-related respiratory symptoms ( eg , dry cough , shortness of breath , mouth irritation , and phlegm ) through reduced consumption of tobacco cigarettes . Furthermore , we evaluate the behavioral and psychological ( eg , well-being , mood , and quality of life ) effects of the treatment . Methods This is a prospect i ve , r and omized , placebo-controlled , double-blind , three-parallel group study . The study is organized as a nested r and omized controlled study with 3 branches : a nicotine e-cigarettes group , a nicotine-free e-cigarettes group , and a control group . The study is nested in a screening program for early lung cancer detection in heavy smokers . Results The study is open and is still recruiting . Conclusions Stopping or reducing tobacco consumption should be a main goal of any health organization . However , traditional antismoking programs are expensive and not always effective . Therefore , favoring a partial or complete shift to e-cigarettes in heavy smokers ( eg , persons at high risk for a number of diseases ) could be considered a moral imperative . However , before following this path , sound and reliable data on large sample s and in a variety of context s are required . Trial Registration Clinical trials.gov NCT02422914 ; https:// clinical trials.gov/ct2/show/NCT02422914 ( Archived by WebCite at http://www.webcitation.org/6etwz1bPL An Electronic Vapour Product ( EVP ) has been evaluated for short-term safety parameters and subjective effects in a 2-part study , in smokers . Part 1 compared the EVP with unflavoured ( UF ) and flavoured ( FL ) e-liquid at 2.0 % nicotine to a conventional cigarette ( CC ; JPS Silver King Size , 0.6 mg ) and a licensed nicotine inhalator ( Nicorette ( ® ) , 15 mg ) . Part 2 assessed the effect of increasing concentrations of nicotine in the e-liquid used with the EVP ( 0 % , 0.4 % , 0.9 % , 2.0 % ) . The study was design ed as a r and omised , controlled , crossover trial . Outcomes included adverse events ( AEs ) , vital signs , exhaled carbon monoxide ( CO ) , clinical laboratory parameters , smoking urges and withdrawal symptoms . In both study parts , only mild non-serious AEs were reported . No major differences were observed in AEs between the EVPs and Nicorette ( ® ) . Exhaled CO levels only increased for CC . All products appeared to decrease smoking urges and nicotine withdrawal symptom scores to a similar extent . The EVP had a similar short-term safety profile to Nicorette ( ® ) and relieved smoking urges and nicotine withdrawal symptoms to a similar extent as Nicorette ( ® ) and CC . Unlike nicotine replacement therapies , the EVP may offer an alternative for those finding it difficult to quit the behavioural and sensorial aspects of smoking INTRODUCTION Electronic cigarettes ( e-cigarettes ) have gained popularity rapidly in the Western world but data in the East are scarce . We examined the awareness and ever use of e-cigarettes , and reasons for e-cigarette use in a probability sample of adults in Hong Kong . METHODS Cross-sectional data were collected in 2014 from Chinese adults aged 15 - 65 in Hong Kong ( 819 never smokers , 800 former smokers , 800 current smokers ) via computer-assisted telephone interviews ( response rate : 73.8 % ) . Analysis was limited to a subset of 809 respondents ( i.e. , 357 never smokers , 269 former smokers , 183 current smokers ) who were r and omly selected to answer questions on e-cigarettes . Chi-square analyses compared e-cigarette awareness and ever use by gender , age , education , and cigarette smoking status . Multivariable logistic regression examined if e-cigarette awareness was associated with demographic variables and cigarette smoking status . RESULTS 75.4 % of adults had heard of e-cigarettes , and 2.3 % reported having used e-cigarettes . Greater awareness was associated with male gender and higher education . Ever use of e-cigarettes was higher among males ( 3.6 % , p=.03 ) , younger adults ( aged 15 - 29 , 5.2 % , p=.002 ) , and current cigarette smokers ( 11.8 % , p<.001 ) . Common reasons for using e-cigarettes were curiosity ( 47.4 % ) , the stylish product design ( 25.8 % ) , and quitting smoking ( 13.6 % ) . CONCLUSIONS Awareness of e-cigarettes was widespread in Hong Kong . Although the use of e-cigarettes was low , its relation with younger age and current smoking is of concern . Health surveillance of e-cigarette use is needed . Interventions should target young adults and cigarette smokers , and address the marketing messages , especially the effect of e-cigarettes on smoking cessation INTRODUCTION St and ard treatments ( STs ) for smoking cessation typically combine pharmacotherapy and behavioral support but do not address the sensory and behavioral aspects of smoking which may play a role in maintaining smoking behavior . Replacing such sensations temporarily after cessation may enhance treatment efficacy . We hypothesized that denicotinized cigarettes ( DNCs ) , which have a very low nicotine content but provide these sensory and behavioral stimuli , could help alleviate urges to smoke and tobacco withdrawal symptoms and in turn enhance the efficacy of ST . METHODS Two hundred smokers seeking treatment received nine weekly behavioral support sessions and pharmacotherapy ( 100 used varenicline , 100 used nicotine replacement therapy ) . They were r and omized on the target quit day to receive 280 DNCs ( used ad libitum over 2 weeks in addition to ST ) or ST alone . RESULTS Urge-to-smoke frequency ( 2.61 vs. 2.96 , P = .03 ) but not strength ( 2.85 vs. 3.10 , P = .20 ) in the first week of abstinence was significantly lower in DNC users versus ST alone . There were no differences in composite withdrawal scores between groups . Abstinence was significantly higher among DNC users versus ST alone at 1 ( OR = 2.07 ; 95 % CI : 1.63 % to 3.70 % ) and 4 weeks ( OR = 1.83 ; 95 % CI : 1.05 % to 3.21 % ) , but not at 12 weeks ( OR = 1.42 ; 95 % CI : 0.79 % to 2.55 % ) . DNC use was a significant predictor of abstinence at 1 and 4 weeks ( OR = 2.63 ; 95 % CI : 1.40 % to 4.93 % and OR = 2.38 ; 95 % CI : 1.26 % to 4.46 % ) , but not at 12 weeks . CONCLUSIONS Adding DNCs to ST has the potential to assist smokers early in their quit attempt , but research is needed to determine how best to utilize DNCs in treatment BACKGROUND There are several nicotine replacement products on the market , and physicians are likely to be asked with increasing frequency about which of these products their patients should use . OBJECTIVE To provide a basis for rational advice by comparing nicotine polacrilex ( gum ) , a transdermal patch , nasal spray , and an inhaler . DESIGN R and omized trial with assessment s at the quit date and 1 , 4 , and 12 weeks later . SETTING Hospital smokers ' clinic . PATIENTS Male and female community volunteers ( N = 504 ) smoking 10 or more cigarettes per day and seeking help to stop smoking . INTERVENTIONS Patients were given brief advice , and purchased their nicotine replacement treatment at approximately half the regular retail price . MAIN OUTCOME MEASURES Nicotine replacement treatment use , ratings of withdrawal symptoms , ratings of product characteristics and helpfulness , and biochemically vali date d continuous lapse-free abstinence . RESULTS The products did not differ in their effects on withdrawal discomfort , urges to smoke , or rates of abstinence . The continuous vali date d 12-week abstinence rates were 20 % , 21 % , 24 % , and 24 % in the gum , patch , spray , and inhaler groups , respectively . Compliance with recommended nicotine replacement treatment use was high for the patch , low for gum , and very low for the spray and the inhaler . The spray was underused because of adverse effects more often than the other products . In the subjects using the spray , the level of use among abstainers at week 1 predicted outcome at week 12 . The inhaler was rated as more embarrassing to use than the other products , but provided at least as much nicotine as the gum . CONCLUSION When asked about nicotine replacement treatment products available , physicians should note that , despite low compliance with the recommended dose of the spray and inhaler and differences in product ratings , overall , there are no notable differences between the products in their effects on withdrawal discomfort , perceived helpfulness , or general efficacy Aims : Here , we present results from a prospect i ve pilot study that was aim ed at surveying changes in daily cigarette consumption in smokers making their first purchase at vape shops . Modifications in products purchase were also noted . Design : Participants were instructed how to charge , fill , activate and use their e-cigarettes ( e-cigs ) . Participants were encouraged to use these products in the anticipation of reducing the number of cig/day smoked . Setting s : Staff from LIAF contacted 10 vape shops in the province of the city of Catania ( Italy ) that acted as sponsors to the 2013 No Tobacco Day . Participants : 71 adult smokers ( ≥18 years old ) making their first purchase at local participating vape shops were asked by professional retail staff to complete a form . Measurements : Their cigarette consumption was followed-up prospect ively at 6 and 12 months . Details of products purchase ( i.e. , e-cigs hardware , e-liquid nicotine strengths and flavours ) were also noted . Findings : Retention rate was elevated , with 69 % of participants attending their final follow-up visit . At 12 month , 40.8 % subjects could be classified as quitters , 25.4 % as reducers and 33.8 % as failures . Switching from st and ard refillables ( initial choice ) to more advanced devices ( MODs ) was observed in this study ( from 8.5 % at baseline to 18.4 % at 12 month ) as well as a trend in decreasing the e-liquid nicotine strength , with more participants adopting low nicotine strength ( from 49.3 % at baseline to 57.1 % at 12 month ) . Conclusions : We have found that smokers purchasing e-cigarettes from vape shops with professional advice and support can achieve high success rates Sensory aspects of cigarette smoke are important for providing smoking satisfaction . In previous studies , we have found that substitution of the sensory cues of smoking with a citric acid aerosol significantly reduces craving for cigarettes and enhances smoking reduction and cessation with people trying to quit smoking cigarettes . In the current study , we conducted two clinical smoking cessation trials using an ascorbic acid aerosol as a sensory substitute . The cigarette substitute consisted of a cigarette-sized tube which delivered a fine aerosol of ascorbic acid ( approx . 1 mg/puff , up to a maximum of 300 mg/day ) . Study 1 examined the overall effectiveness of the ascorbic acid smoking substitute device . One group of subjects which used the device and received clinical counseling was compared with another group which received only clinical counseling . The group using the device showed significantly greater abstinence rates at 3 weeks post-cessation . After the subjects stopped using the device , no difference in abstinence was detected . Study 2 was conducted to focus specifically on the role of tracheobronchial sensations in relieving craving for cigarettes . Two closely matched ascorbic acid delivery systems were compared . One device delivered fine particles of ascorbic acid that were targeted to reach the trachea , while the other delivered coarser particles of ascorbic acid that were not expected to reach the trachea or lower airways . An initial enhancement in smoking reduction was found for subjects using the fine particle device relative to those using the coarse particle device . However , by the end of treatment ( 5 weeks ) both groups showed similar degrees of smoking reduction . For those who were abstinent from smoking at the end of treatment , craving for cigarettes and negative mood were both significantly lower for those using the fine particle device . Also , hunger for food was significantly lower in the fine particle device group . These results suggest that ascorbic acid delivered from a cigarette substitute may be effective in reducing smoking and promoting smoking abstinence The pharmacokinetic ( PK ) profile of nicotine delivered by an Electronic Vapour Product ( EVP ) was characterised in a 2-part study in smokers . The study was design ed as a r and omised , controlled , four-way crossover trial . Part 1 compared an unflavoured e-liquid ( UF2.0 % ) and a flavoured e-liquid ( FL2.0 % ) to a conventional cigarette ( CC ; JPS Silver King Size , 0.6 mg ) and a licensed nicotine inhalator ( Nicorette ( ® ) ; 15 mg ) . Part 2 compared e-liquids with increasing nicotine concentrations ( 0 % , 0.4 % , 0.9 % , 2.0 % ) . Subjects used each different product for a daily use session . In Part 1 , maximum plasma nicotine concentration ( Cmax ) for UF2.0 % , FL2.0 % , Nicorette ( ® ) and CC was 3.6 , 2.5 , 2.5 and 21.2 ng/mL , respectively . The time to maximum plasma nicotine concentration ( Tmax ) was longer for the EVP ( UF2.0 % , 9.0 min ; FL2.0 % , 10.0 min ) and the nicotine inhalator ( 13.0 min ) compared to CC ( 3.0 min ) . In Part 2 , EVP with 0 % , 0.4 % , 0.9 % and 2.0 % nicotine produced Cmax values of 0.6 , 1.0 , 1.9 and 3.6 ng/mL , respectively . At the maximum nicotine concentration of 2 % as prescribed by the European Tobacco Directive , the EVP achieved nicotine delivery that was comparable to the inhalator . EVPs thus offer a potential alternative to nicotine inhalator devices for those finding it difficult to quit smoking Although electronic cigarettes ( e-cigarettes ) are aggressively promoted as smoking cessation aids,1 studies of their effectiveness for cessation have been unconvincing.2 , 3 One r and omized trial comparing e-cigarettes with and without nicotine , and nicotine patch found no differences in 6-month quit rates.2 Population -based , longitudinal studies have also not shown associations between e-cigarette use and quitting.4 , 5 A longitudinal , international study found that , although 85 % of smokers who used e-cigarettes reported using them to quit , e-cigarette users did not quit more frequently than non-users (p=.516).4 Among US quitline callers , e-cigarette users were less likely to have quit at 7 months than non-users.5 We employed a longitudinal analysis of a national sample of current US smokers to determine whether e-cigarette use predicted successful quitting , or reduced cigarette consumption STUDY OBJECTIVE This study was conducted to determine if the combination of airway sensory replacement and nicotine replacement improves 10-week smoking abstinence rates over nicotine replacement alone . DESIGN Double-blind , r and omized , placebo-controlled trial . SETTING Outpatient research clinic . PARTICIPANTS One hundred healthy volunteers who smoked at least one pack of cigarettes per day and desired to quit smoking . INTERVENTIONS Subjects received either citric acid ( n = 41 ) or lactose placebo ( n = 59 ) inhalers to cope with smoking urges for 10 weeks . All subjects received self-help material s and nicotine patches for 6 weeks . Return visits were at weeks 1 , 4 , 6 , and 10 . Abstinence was defined as zero cigarettes smoked since the quit date verified by exhaled carbon monoxide < or = 8 ppm at all return visits . Inhaler effects were measured by a st and ardized question naire . MEASUREMENTS AND RESULTS The primary outcome of continuous abstinence at the end of the 10-week treatment period was 19.5 % ( 95 % confidence interval [ CI ] = 7.4 to 31.6 % ) for the citric acid group vs 6.8 % ( 95 % CI = 0.4 to 13.2 % ) for the lactose group ( p = 0.05 ) . Relief from craving and short-term abstinence increased as airway sensations from the inhaler also increased . Abstinence at 10 weeks for subjects receiving strong airway sensations from the inhalers was 33.3 % ( 95 % CI = 14.5 to 52.1 % ) . At 6 months , there was no difference in abstinence between the treatment groups ( 0 % vs 5.1 % , p = 0.20 ) . CONCLUSIONS When combined with the nicotine patch , the citric acid inhaler improved 10-week smoking abstinence over lactose inhaler . The combination of airway sensory replacement and nicotine replacement may prove beneficial for smoking cessation AIMS Cardiac remodelling might be an important mechanism for aldosterone-mediated cardiovascular ( CV ) morbidity and mortality . Previous studies relating aldosterone to left ventricular ( LV ) structure however revealed conflicting results . METHODS AND RESULTS We aim ed to evaluate the relationship of serum aldosterone concentration ( SAC ) and aldosterone-to-renin ratio ( ARR ) with echocardiographic parameters of LV remodelling in CV risk patients with preserved left ventricular ejection fraction ( LVEF ) . We studied 1575 participants ( 54.1 % female ) with CV risk factors and LVEF > 50 % ( 61.7 ± 6.1 % ) . Of the total , 94.7 % of patients had no overt heart failure . All patients underwent measurement of SAC , ARR , and comprehensive echocardiographic analysis . Overall , multivariate adjusted analysis of covariance ( ANCOVA ) showed a significant increase in LV mass ( P= 0.001 ) , LV mass index ( P= 0.001 ) , relative wall thickness ( P= 0.011 ) , and LV posterior wall thickness ( P < 0.001 ) with increasing SAC . This overall association of SAC and LV remodelling was driven by a statistic significant effect exclusively in women . In multivariate logistic regression analysis higher SAC levels were independently related to concentric LV hypertrophy [ odds ratio ( OR ; with 95 % CI ) by comparing SAC levels in the third gender-specific tertile with the first tertile : 1.87 ; 95 % CI : 1.31 - 2.68 ; P= 0.001 ] . Higher SAC levels were positively related to concentric LVH in either sex . We observed no significant associations between the ARR and echocardiographic parameters of LV remodelling . CONCLUSION Circulating aldosterone but not ARR levels are independently related to echocardiographic parameters of LV structure , particularly in women . Higher SAC however was related to concentric LVH in either sex . Our findings in a large CV risk cohort with preserved LVEF indicate aldosterone-mediated pro-hypertrophic effects as a potential pathway for structural alterations of the left ventricular myocardium Sensorimotor smoking stimuli are important determinants of cigarette use . The present study aim ed to determine whether denicotinized cigarettes lose their reinforcing and /or subjective effects over a 9-day outpatient period when they are smoked with or without concurrent transdermal nicotine . After a preferred br and baseline , 68 participants were r and omized into one of four conditions based on the dose ( mg ) of transdermal nicotine and the type of cigarettes ( dose/cigarette ) : 0/nicotine , 0/denicotinized , 7/denicotinized , and 21/denicotinized . Under placebo patch conditions , participants smoked a similar number of nicotine and denicotinized cigarettes and no group differences emerged over repeated testing . The total volume of smoke inhaled was lower in the denicotinized group , although this decrease dissipated over time . Denicotinized cigarettes were rated as having low positive and high negative subjective effects . Compared to placebo , transdermal nicotine decreased the number of denicotinized cigarette smoked , produced a lasting decrease in the total volume of denicotinized cigarette smoke inhaled , but had little effect on the subjective effects of denicotinized cigarettes . Transdermal nicotine attenuated withdrawal during initial smoking abstinence ; however , once participants were allowed to smoke withdrawal symptoms were relatively low regardless of patch condition . The persistent use of denicotinized cigarettes may result from the presence of nicotine withdrawal and /or the degree to which smoking becomes somewhat independent of the outcome of the behavior ( i.e. , habit learning ) . Additional studies would be useful to determine what factors drive continued use of denicotinized cigarettes , whether their use subsides as withdrawal dissipates , and whether they address motives for smoking distinct from current pharmacotherapy AIMS To provide an initial abuse liability assessment of an electronic cigarette ( EC ) in current tobacco cigarette smokers . DESIGN The first of four within-subject sessions was an EC sampling session that involved six , 10-puff bouts ( 30 seconds inter-puff interval ) , each bout separated by 30 minutes . In the remaining three sessions participants made choices between 10 EC puffs and varying amounts of money , 10 EC puffs and a varying number of own br and cigarette ( OB ) puffs , or 10 OB puffs and varying amounts of money using the multiple-choice procedure ( MCP ) . The MCP was completed six times at 30-minute intervals , and one choice was reinforced r and omly at each trial . SETTING Clinical laboratory . PARTICIPANTS Twenty current tobacco cigarette smokers . MEASUREMENTS Sampling session outcome measures included plasma nicotine , cardiovascular response and subjective effects . Choice session outcome was the cross-over value on the MCP . FINDINGS EC use result ed in significant nicotine delivery , tobacco abstinence symptom suppression and increased product acceptability ratings . On the MCP , participants chose to receive 10 EC puffs over an average of $ 1.06 or three OB puffs and chose 10 OB puffs over an average of $ 1.50 ( P < 0.003 ) . CONCLUSIONS Electronic cigarettes can deliver clinical ly significant amounts of nicotine and reduce cigarette abstinence symptoms and appear to have lower potential for abuse relative to traditional tobacco cigarettes , at least under certain laboratory conditions One of the latest findings from the Office of the Surgeon General is clear : Even people diagnosed with cancer should benefit from quitting smoking . According to the 2014 report The Health Consequences of Smoking—50 Years of Progress , enough evidence exists to infer “ a causal relationship between cigarette smoking and adverse health outcomes ” and that “ quitting smoking improves the prognosis of cancer patients . ” The question for cancer patients then becomes , “ Fine , but how do I quit since I have n’t been able before ? ” It ’s no wonder , then , that electronic cigarettes ( e-cigarettes ) might appeal to cancer patients whose doctors have advised to quit smoking . The devices are marketed as a relatively benign alternative , although there is not yet adequate information to support this perception . They supply nicotine without the tar , carbon monoxide , and other harmful ingredients suggesting they may represent a stepping-stone to quitting . Plus , e-cigarettes produce only vapor , not smoke , thus eliminating the stigma . E-cigarettes also look like their tobacco-laden cousin and offer the same h and -to-mouth sensory experience . Despite their allure , an observational study found that e-cigarettes are not an effective tool for cancer patients to quit smoking . “ Our study did not find evidence that there were benefits or differences in their quitting outcomes ” from using e-cigarettes , said study coauthor Jamie S. Ostroff , Ph.D. She is chief of the Behavioral Sciences Service and director of the Tobacco Treatment Program at New York ’s Memorial Sloan – Kettering Cancer Center . Ostroff added that they did not assess how people perceived the risk of using e-cigarettes . Even so , their findings suggested that although patients with cancer may perceive the devices to be less harmful than combustible cigarettes , that did not necessarily lead to quitting . E-cigarettes were invented in China in 2003 and introduced in the U.S. in 2007 . These battery-powered devices convert liquid nicotine into a vaporthat the user inhales ( known as “ vaping ” ) , similar to a regular cigarette . Propylene glycol , the primary ingredient in antifreeze , and glycerin are the main ingredients of the liquid . The vapor delivers nicotine to the lungs . The user then exhales vapor that resembles a cloud of smoke . E-liquids come in flavors , adding to their appeal . In Ostroff ’s study ( Cancer 2014;120:3527–35 ) , 1,074 smoking cancer patients enrolled in a 2012–2013 tobacco treatment program at Memorial Sloan– Kettering . At enrollment , mean age was 56 years ( range , 18–87 years ) ; 607 ( 56.5 % ) were female and 467 ( 43.5 % ) were male . Of the participants , 698 ( 64.9 % ) had already tried quitting at least twice . Between 6 and 12 months after enrollment , research ers collected data on attempts to quit . Approximately one-fourth ( 26.5 % ) reported having used within 30 days , and most e-cigarette users ( 92 % ) reported having also used traditional cigarettes . Between 2012 and 2013 , the number of people using e-cigarettes during 30 days also increased from 10.6 % to 38.5 % . Meanwhile , e-cigarette users and nonusers had similar 7-day abstinence rates ( 44.4 % and 43.1 % , respectively ) . Compared with nonusers , e-cigarette users had higher nicotine dependence , smoked more cigarettes per day , and were more likely to be diagnosed with either thoracic or head and neck cancer ( even though both groups were demographically and clinical ly similar in many respects ) . “ These cancers are widely associated with cigarette smoking , ” Ostroff said . E-cigarette users were also twice as likely to be chronic tobacco smokers , and fewer users of the product reported abstaining from cigarettes for 24 hours during the observation period . “ That may actually have averted or delayed quit attempts , ” Ostroff said . Although e-cigarettes may appeal to patients seeking to reduce smoking ’s harms , Ostroff added , the findings do not support oncologists ’ recommending them to cancer patients advised to quit smoking . Ostroff said that to the best of her knowledge , this study presents the first data on e-cigarette use among cancer patients . Regardless of the mechanism , together the studies suggesting NSAIDs can prevent cancer are thought provoking , said Gregory A. Masters , M.D. , chair of the American Society of Clinical Oncology Communications Committee . But “ you have to be cautious looking at retrospective analyses , ” he added . “ The individual studies are not convincing . ” Until more data on the benefits and risks are available , “ we are n’t ready for any broad recommendations , ” he said . “ The risk of bleeding is not insignificant , ” said Wendy Y. Chen , M.D. , M.P.H. , assistant professor of medicine at Harvard Medical School in Boston . “ I would not feel comfortable telling my patients to take NSAIDs for cancer prevention alone . ” A prospect i ve r and omized trial looking at NSAIDs ’ ability to prevent cancer or metastases would provide the necessary evidence . Such a study would require monitoring thous and s of participants for 5–10 years . But according to one of the study ’s authors , Pierre P. Massion , M.D. , professor of medicine and cancer biology at V and erbilt , such a study would not appeal to industry financially because NSAIDs are generic drugs . Drugs that selectively inhibit COX-2 carry a lower risk of gastrointestinal side effects . But risk of cardiovascular side effects has vastly limited their use , making the pharmaceutical industry leery of study ing them to prevent cancer , DuBois said . Also , industry may not see a huge market in cancer prevention , Chen added . The UK and Singapore are planning clinical trials to study whether taking regular aspirin after treating early-stage cancer can prevent the cancer from returning . But these results are years away . Although taking aspirin to prevent cancer or metastases after diagnosis “ is not yet ready for clinical implementation , ” Massion said , at the very least , “ there is going to be renewed interest in this . This study examined the subjective and cardiovascular effects of two of the components of cigarette smoking when given separately : nicotine and airway sensations . Using a within-subjects design , six healthy volunteer smokers , age 18 - 45 years , who smoked at least 20 cigarettes per day were given six conditions in a r and omized , counterbalanced order . The effects of IV nicotine , IV saline , and denicotinized cigarettes were compared to a st and ard 1-mg cigarette . The st and ard cigarette produced more of a calming effect and more irritability reduction than either the nicotine or airway sensations alone . The denicotinized cigarette was similar to the st and ard cigarette condition , except the cigarette condition was associated with higher feelings of " exhilaration . " Many of the positive subjective effects from a denicotinized cigarette were comparable to that of a st and ard cigarette . These data support the hypothesis that replacement of the sensory cues of smoking with " airway sensory replacement " may be useful for smoking cessation Background This study is a systematic evaluation of a novel tobacco product , electronic cigarettes ( ECIGs ) using a two-site , four-arm , 6-month , parallel-group r and omized controlled trial ( RCT ) with a follow-up to 9 months . Virginia Commonwealth University is the primary site and Penn State University is the secondary site . This RCT design is important because it is informed by analytical work , clinical laboratory results , and qualitative/quantitative findings regarding the specific ECIG products used . Methods Participants ( N = 520 ) will be r and omized across sites and must be healthy smokers of > 9 cigarettes for at least one year , who have not had a quit attempt in the prior month , are not planning to quit in the next 6 months , and are interested in reducing cigarette intake . Participants will be r and omized into one of four 24-week conditions : a cigarette substitute that does not produce an inhalable aerosol ; or one of three ECIG conditions that differ by nicotine concentration 0 , 8 , or 36 mg/ml . Blocked r and omization will be accomplished with a 1:1:1:1 ratio of condition assignments at each site . Specific aims are to : characterize ECIG influence on toxicants , biomarkers , health indicators , and disease risk ; determine tobacco abstinence symptom and adverse event profile associated with real-world ECIG use ; and examine the influence of ECIG use on conventional tobacco product use . Liquid nicotine concentration-related differences on these study outcomes are predicted . Participants and research staff in contact with participants will be blinded to the nicotine concentration in the ECIG conditions . Discussion Results from this study will inform knowledge concerning ECIG use as well as demonstrate a model that may be applied to other novel tobacco products . The model of using prior empirical testing of ECIG devices should be considered in other RCT evaluations . Trial registration TRN : NCT02342795 , registered December 16 , 2014 Objectives To measure the short-term effects of an electronic nicotine delivery device ( “ e cigarette ” , ENDD ) on desire to smoke , withdrawal symptoms , acceptability , pharmacokinetic properties and adverse effects . Design Single blind r and omised repeated measures cross-over trial of the Ruyan V8 ENDD . Setting University research centre in Auckl and , New Zeal and . Participants 40 adult dependent smokers of 10 or more cigarettes per day . Interventions Participants were r and omised to use ENDDs containing 16 mg nicotine or 0 mg capsules , Nicorette nicotine inhalator or their usual cigarette on each of four study days 3 days apart , with overnight smoking abstinence before use of each product . Main outcome measures The primary outcome was change in desire to smoke , measured as “ area under the curve ” on an 11-point visual analogue scale before and at intervals over 1 h of use . Secondary outcomes included withdrawal symptoms , acceptability and adverse events . In nine participants , serum nicotine levels were also measured . Results Over 60 min , participants using 16 mg ENDD recorded 0.82 units less desire to smoke than the placebo ENDD ( p=0.006 ) . No difference in desire to smoke was found between 16 mg ENDD and inhalator . ENDDs were more pleasant to use than inhalator ( p=0.016 ) and produced less irritation of mouth and throat ( p<0.001 ) . On average , the ENDD increased serum nicotine to a peak of 1.3 mg/ml in 19.6 min , the inhalator to 2.1 ng/ml in 32 min and cigarettes to 13.4 ng/ml in 14.3 min . Conclusions The 16 mg Ruyan V8 ENDD alleviated desire to smoke after overnight abstinence , was well tolerated and had a pharmacokinetic profile more like the Nicorette inhalator than a tobacco cigarette . Evaluation of the ENDD for longer-term safety , potential for long-term use and efficacy as a cessation aid is needed . Trial registration No.12607000587404 , Australia and New Zeal and Clinical Trials Despite the recent popularity of e-cigarettes , to date only limited data is available on their safety for both users and secondh and smokers . The present study reports a comprehensive inner and outer exposure assessment of e-cigarette emissions in terms of particulate matter ( PM ) , particle number concentrations ( PNC ) , volatile organic compounds ( VOC ) , polycyclic aromatic hydrocarbons ( PAH ) , carbonyls , and metals . In six vaping sessions nine volunteers consumed e-cigarettes with and without nicotine in a thoroughly ventilated room for two hours . We analyzed the levels of e-cigarette pollutants in indoor air and monitored effects on FeNO release and urinary metabolite profile of the subjects . For comparison , the components of the e-cigarette solutions ( liquids ) were additionally analyzed . During the vaping sessions substantial amounts of 1,2-propanediol , glycerine and nicotine were found in the gas-phase , as well as high concentrations of PM2.5 ( mean 197 μg/m(3 ) ) . The concentration of putative carcinogenic PAH in indoor air increased by 20 % to 147 ng/m(3 ) , and aluminum showed a 2.4-fold increase . PNC ranged from 48,620 to 88,386 particles/cm(3 ) ( median ) , with peaks at diameters 24 - 36 nm . FeNO increased in 7 of 9 individuals . The nicotine content of the liquids varied and was 1.2-fold higher than cl aim ed by the manufacturer . Our data confirm that e-cigarettes are not emission-free and their pollutants could be of health concern for users and secondh and smokers . In particular , ultrafine particles formed from supersaturated 1,2-propanediol vapor can be deposited in the lung , and aerosolized nicotine seems capable of increasing the release of the inflammatory signaling molecule NO upon inhalation . In view of consumer safety , e-cigarettes and nicotine liquids should be officially regulated and labeled with appropriate warnings of potential health effects , particularly of toxicity risk in children AIMS Sensorimotor stimuli associated with tobacco smoking influence smoking behavior ; however , current research has focused almost exclusively on the effects of brief , laboratory-based exposure to smoking-related stimuli . The purpose of this experiment was to characterize the effects of smoking stimuli delivered in the absence of nicotine over an extended ( 11-day ) exposure . DESIGN , SETTING AND PARTICIPANTS Thirty adult regular smokers participated in an in-patient study . After assessing preferred br and smoking , participants were assigned r and omly to one of three groups corresponding to subsequent smoking conditions : nicotine-containing cigarettes , de-nicotinized cigarettes or no smoking . MEASUREMENTS Measures of smoking reinforcement , subjective effects , physiological effects , withdrawal/craving and puff topography were taken repeatedly during both periods of free access and controlled assessment s during abstinence . FINDINGS Daily de-nicotinized cigarette use declined immediately by 1.7 cigarettes/day compared to the preferred br and baseline and declined by another 3.5 cigarettes over time ; participants smoking de-nicotinized cigarettes also demonstrated a 31 % decline in the number of puffs earned on a progressive ratio , a measure of the motivation to smoke , during the study . Subjective ratings of smoking were largely negative throughout the study in the de-nicotinized group , while the nicotine-containing condition reported increasingly positive subjective effects with repeated exposure . Acute craving suppression following smoking remained evident throughout the study regardless of nicotine content . CONCLUSIONS These effects highlight the importance of non-nicotine sensorimotor stimuli as determinants of the maintenance of smoking behavior and suggests that extinction of conditioned reinforcement in the absence of nicotine progresses slowly INTRODUCTION Electronic cigarettes ( ECs ) are marketed as nicotine delivery devices . Two studies with EC-naïve participants suggest that ECs deliver little or no nicotine . In those studies , st and ard-sized ECs were used , though experienced EC users often use larger devices that house higher voltage and /or longer lasting batteries . Whether user experience and device characteristics influence EC nicotine delivery is uncertain . The purpose of the present study was to examine the effects of ECs in experienced users who were using their preferred devices . METHODS Eight EC users ( 3 women ) who had been using ECs for at least 3 months , completed one 5-hr session using devices they provided and the flavor/strength nicotine cartridges they selected . Sessions consisted of 4 phases : baseline , 10 puffs ( 30-s interpuff interval ) from the device , 1-hr ad lib puffing period , and a 2-hr rest period ( no puffing ) . Outcome measures in each phase included plasma nicotine concentration , heart rate , and subjective ratings of nicotine/product effects and abstinence symptoms . RESULTS Relative to baseline , plasma nicotine and heart rate increased significantly within 5 min of the first puff and remained elevated throughout the ad lib puffing period . Increases in ratings of direct effects of nicotine and product were observed as well as decreases in abstinence symptoms . CONCLUSIONS User experience and /or device characteristics likely influence EC nicotine delivery and other effects . Systematic manipulation of these and other variables could eluci date conditions that produce intended effects INTRODUCTION This study examined overall changes in nicotine concentrations when using a popular e-cigarette and 18 mg/mL nicotine e-Juice , and it further explored effects of sex and flavorings on these concentrations . METHODS We recruited nontreatment-seeking smokers who were willing to try e-cigarettes for 2 weeks and abstain from cigarette smoking . Subjects were r and omized to either menthol tobacco or non-menthol tobacco-flavored e-cigarette use for 7 - 10 days , and the next week they were crossed over to the other condition . On the last day of e-cigarette use of each flavor , subjects completed a laboratory session in which they used the e-cigarette for 5 min ad libitum . Nicotine concentrations were obtained 5 min before and 5 , 10 , 15 , 20 , and 30 min after the onset of e-cigarette use . RESULTS Twenty subjects completed at least 1 monitoring session . Nicotine concentrations significantly increased from baseline to 5 min by 4 ng/mL at the first laboratory session ( p < .01 ) and by 5.1 ng/mL at the second laboratory session ( p < .01 ) . Combining sessions , there were no main effects of sex or preferred flavor ( based on smoking history ) on changes in nicotine concentrations . After adding preferred flavor , sex , and visit order to the model , there was a significant preferred flavor by sex interaction ( p < .01 ) , such that women who received nonpreferred flavors had lower nicotine concentrations and rated their e-cigarette as less likeable ( p < .01 ) . CONCLUSION We found nicotine concentrations significantly increase after e-cigarette use for 5 min , and flavor may impact nicotine concentrations with e-cigarette use in women BACKGROUND Previous cross-sectional studies found that positive beliefs about electronic nicotine delivery systems ( commonly known as electronic cigarettes or e-cigarettes ) were associated with use of these products . However , the prospect i ve association between these beliefs and subsequent use of e-cigarettes is unclear . PURPOSE To identify the beliefs predicting subsequent use of e-cigarettes . METHODS A total of 1379 young adults ( mean age=24.1 years ) from the Minnesota Adolescent Community Cohort who reported never using e-cigarettes at baseline ( collected Oct 2010-Mar 2011 ) and completed follow-up data collection ( during Oct 2011-Mar 2012 ) were included in this analysis . Participants ' beliefs about e-cigarettes ( potential as quit aids , harmfulness and addictiveness relative to cigarettes ) were asked at baseline ( yes/no ) . At follow-up , participants were asked if they had ever used e-cigarettes . Logistic regression models were used to assess the associations between beliefs about e-cigarettes and subsequent experimentation . Analysis was conducted in 2012 . RESULTS At follow-up , 7.4 % of the sample reported ever using e-cigarettes ( 21.6 % among baseline current smokers , 11.9 % among baseline former smokers , and 2.9 % among baseline nonsmokers ) . Participants who believed e-cigarettes can help people quit smoking and perceived e-cigarettes to be less harmful than cigarettes at baseline were more likely to report experimenting with e-cigarettes at follow-up ( p<0.05 ) . These associations did not differ by smoking status . CONCLUSIONS Given that young adults are still developing their tobacco use behaviors , informing them about the lack of evidence to support e-cigarettes as quit aids and the unknown health risk of e-cigarettes may deter young adults from trying these products The effects of the acute administration of nicotine [ through nicotine inhalers ( NI ) and placebo inhalers ( PI ) ] , nicotine-containing tobacco ( NT ) , and denicotinized tobacco ( DT ) , on smokers ' subjective responses and motivation to smoke were examined in 22 smokers ( 12 male , 10 female ; 11 low dependent , 11 high dependent ) . During four r and omized blinded sessions , participants self-administered NI , PI , NT , or DT , and assessed their effects using Visual Analogue Scales and the Brief Question naire of Smoking Urges . They could then self-administer their preferred br and of cigarettes using a progressive ratio task . NT and DT were each associated with increased satisfaction and relaxation as well as decreased craving relative to the inhalers and NT increased ratings of stimulation relative to each of the other products . Both NT and DT delayed the onset of preferred tobacco self-administration relative to NI and PI but only NT reduced the total amount self-administered . Sex differences were evident in the effects of DT on withdrawal-related cravings with women experiencing greater DT-induced craving relief than men . Findings suggest that DT is effective in acutely reducing many smoking abstinence symptoms , especially in women , but a combination of nicotine and non-nicotine tobacco ingredients may be necessary to suppress smoking behavior The development of electronic cigarettes ( e-cigs ) has the potential to offer a less harmful alternative for tobacco users . This clinical study was design ed to characterize e-cig users ' exposure to nicotine , and to investigate the acute effects of e-cigs on the hemodynamic measurements ( blood pressure and heart rate ) in comparison with the effects of regular smoking . Five e-cigs and one Marlboro ® cigarette were r and omized for twenty-three participants under two exposure scenarios from Day 1 to Day 11 : half-hour controlled administration and one hour ad lib use . The nicotine plasma concentrations after 1.5h of product use ( C90 ) were significantly lower in the users of e-cigs than of Marlboro ® cigarettes . The combination of glycerin and propylene glycol as the vehicle facilitated delivery of more nicotine than glycerin alone . The heart rate , systolic and diastolic blood pressure were significantly elevated after use of Marlboro ® cigarettes , but the elevation was less after use of most of the e-cigs . Use of e-cigs had no impact on the exhaled CO levels , whereas the Marlboro ® cigarette significantly increased the exhaled CO more than 8 times above the baseline . In conclusion , e-cigs could be a less harmful alternative for tobacco users |
13,603 | 15,846,672 | Outcomes evaluated in these studies were heterogeneous , there was a variety of adherence measurement instruments .
Nurse led interventions , home aids , diabetes education , pharmacy led interventions , adaptation of dosing and frequency of medication taking showed a small effect on a variety of outcomes including HbA1c .
Current efforts to improve or to facilitate adherence of people with type 2 diabetes to treatment recommendations do not show significant effects nor harms . | BACKGROUND Research suggests adherence to treatment recommendations is low .
In type 2 diabetes , which is a chronic condition slowly leading to serious vascular , nephrologic , neurologic and ophthalmological complications , it can be assumed that enhancing adherence to treatment recommendations may lead to a reduction of complications .
Treatment regimens in type 2 diabetes are complicated , encompassing life-style adaptations and medication intake .
OBJECTIVES To assess the effects of interventions for improving adherence to treatment recommendations in people with type 2 diabetes mellitus . | OBJECTIVE : To compare adherence data from an electronic medication-event monitoring device ( MEMS , Aprex ) with pill counts in assisting pharmacists in making recommendations regarding diabetes therapy . DESIGN : Two-month , double-blind , r and omized , controlled trial . SETTING : Veterans Affairs Medical Center ambulatory care clinics . PATIENTS : Forty-seven patients with poor to fair metabolic control of diabetes mellitus were enrolled . Patients were excluded if they were receiving insulin , had a concurrent infection , required child-resistant caps or medication reminder devices , or could not return for follow-up visits . Twenty patients were r and omized to the MEMS and 27 to the control group ( pill counts ) . Fasting plasma glucose concentrations were measured monthly and glycohemoglobin concentrations were measured at baseline and 60 days . Thirty-two patients were evaluable : 15 using MEMS and 17 using pill counts . INTERVENTION : Investigators made pharmacologic or educational recommendations to the patient 's healthcare provider based on both laboratory data and MEMS readings in the treatment group or laboratory data and pill counts in the control group . MAIN OUTCOME MEASURE : Quantities and types of recommendations regarding diabetes therapy made by pharmacists using adherence data from the two methods were tabulated . RESULTS : In the MEMS group , 47 percent of the recommendations related to patient education compared with 12 percent in the control group ( p=0.028 ) . MEMS data would have changed four recommendations in the control group to involve patient education . CONCLUSIONS : MEMS data result ed in different numbers and types of recommendations than pill counts . Pharmacists then could make specific recommendations regarding patient education before resorting to pharmacologic manipulations Medication compliance may be a problem in the management of patients with diabetes . Some physicians initially treat patients having non-insulin-dependent diabetes with oral sulfonylureas because they fear greater compliance problems with insulin therapy . We compared compliance with insulin and chlorpropamide in patients newly beginning medication for NIDDM . Seventy-seven adults with hyperglycemia despite diet therapy were r and omly assigned to chlorpropamide or insulin . Compliance was measured four times over 24 wk . Patients then crossed over to the other medication and were followed for 24 additional weeks . Overall , there were no differences in compliance with the two medications in terms of percent of prescription used , proportion taking at least 80 % of prescribed medication , self-report of medication or diet compliance , or protocol dropout rates . However , treatment satisfaction was higher with chlorpropamide , and most patients preferred chlorpropamide to insulin ( P < 0.0001 ) . While such differences in satisfaction may affect long-term compliance , physicians should not assume that their patients will be less compliant with insulin than with oral sulfonylureas Abstract OBJECTIVE : To examine the impact of a nurse-coordinated intervention delivered to patients with non-insulin-dependent diabetes mellitus between office visits to primary care physicians . DESIGN : R and omized , controlled trial . SETTING : Veterans Affairs general medical clinic . PATIENTS : 275 veterans who had NIDDM and were receiving primary care from general internists . INTERVENTION : Nurse-initiated contacts were made by telephone at least monthly to provide patient education ( with special emphasis on regimens and significant signs and symptoms of hyperglycemia and hypoglycemia ) , reinforce compliance with regimens , monitor patients ’ health status , facilitate resolution of identified problems , and facilitate access to primary care . MEASUREMENTS : Glycemic control was assessed using glycosylated hemoglobin ( GHb ) and fasting blood sugar ( FBS ) levels . Health-related quality of life ( HRQOL ) was measured with the Medical Outcomes Study SF-36 , and diabetes-related symptoms were assessed using patients ’ self-reports of signs and symptoms of hyper- and hypoglycemia during the previous month . MAIN RESULTS : At one year , between-group differences favored intervention patients for FBS ( 174.1 mg/dL vs 193.1 mg/dL , p=0.011 ) and GHb ( 10.5 % vs 11.1 % , p=0.046 ) . Statistically significant differences were not observed for either SF-36 scores ( p=0.66 ) or diabetes-related symptoms ( p=0.23 ) . CONCLUSIONS : The intervention , design ed to be a pragmatic , low-intensity adjunct to care delivered by physicians , modestly improved glycemic control but not HRQOL or diabetes-related symptoms PURPOSE Few culturally competent health programs have been design ed for Mexican Americans , a group that bears a disproportionate burden of Type 2 diabetes . In Starr County , a Texas-Mexico border community , investigators design ed and tested a culturally competent intervention aim ed at improving the health of this target population . The purpose of this article is to describe the development process of this diabetes education and support group intervention . METHODS The development stages were ( 1 ) community assessment , ( 2 ) intervention design , ( 3 ) selection or development of outcomes , ( 4 ) pilot testing , and ( 5 ) a r and omized clinical investigation . RESULTS Focus group participants identified knowledge deficits regarding diabetes and self-management strategies , and suggested characteristics of an effective intervention for Mexican Americans . Outcome measures included metabolic control indicators , a newly developed knowledge instrument , and an existing health belief instrument . Preliminary analyses indicated that the intervention was successful in significantly improving metabolic control in the target population . CONCLUSIONS Developing successful diabetes interventions for minority groups requires a number of stages , careful planning , assessment of cultural characteristics of the target population , and a systematic approach to implementation An intervention package was examined to determine its effectiveness in increasing office visits and in reducing the incidence of nonelective hospitalizations ( those for urgent or emergent reasons ) . The intervention included mailings of information , appointment reminders , and intense follow-up by telephone of visit failures for rescheduling . Eight hundred fifty-four patients receiving drug therapy for diabetes mellitus were stratified by risk of nonelective hospitalization and r and omly assigned to the control group or the intervention group . After two years , the intervention group averaged 9.1 per cent more kept scheduled visits per month than the control group ( 0.371 vs. 0.340 , p=0.02 ) . However , the mean incidence of nonelective hospitalizations per month was not significantly different between intervention and control groups ( 0.040 vs. 0.041 , p=0.9 ) , nor was there a difference in nonelective hospital days per month ( 0.443 vs. 0.425 , p=0.7 ) . The authors conclude that while mailings and telephone calls can increase office visits , the intervention is not sufficient to reduce morbidity necessitating nonelective hospitalizations of diabetic patients OBJECTIVES In type 2 diabetes , the primary and secondary prevention of long-term micro- and macrovascular complications requires a control of blood glucose levels 24 hours a day . The present study was undertaken to assess the effect of a new formulation of gliclazide administered once daily , gliclazide modified release , on plasma glucose levels over 24 hours . MATERIAL AND METHODS In 21 type 2 diabetic patients previously treated by diet alone or oral antidiabetic agents , glycemic profile ( 8 am , 10 am , 12 am , 2 pm , 5 pm , 8 pm , 10 pm , 3 am and 8 am ) , overall glycemic control , acceptability , and compliance with treatment were assessed before and after a 10-week treatment with gliclazide modified release , ( 30 - 60 mg ) , given once daily at breakfast . RESULTS The results indicate a significant decrease in plasma glucose levels at all points of the cycle . Mean plasma glucose levels over 24 hours and mean plasma glucose levels during the fasting and the postpr and ial periods were significantly improved after treatment . In previous drug-naive patients , decrease in HbA1C was observed ( 1.0 + /- 1.1 % , P=0.022 ) . The acceptability was good , with no hypoglycemic events , and a high compliance with treatment was also observed . CONCLUSION We can therefore conclude that gliclazide modified release , given once daily at breakfast , is effective over 24 hours in reducing plasma glucose levels in type 2 diabetes . This once-daily administration should lead to an optimal patient compliance with treatment The goal of this study was to compare the relative efficacy and cost of self-monitoring of blood glucose ( SMBG ) with routine urine testing in the management of patients with type II ( non-insulin-dependent ) diabetes mellitus not treated with insulin . Fifty-four patients with type II diabetes mellitus , not treated with insulin , who had inadequate glucose control on diet aloneor diet and oral hypoglycemic agents were studied . Patients performed SMBG or urine glucose testing as part of a st and ardized treatment program that also included diet and exercise counseling . During the 6-mo study , both the urine-testing and SMBG groups showed similar improvement in glycemic control ; within each group , there were significant improvements in fasting plasma glucose ( reduction of 1.4 ± 3.2 mM , P < 0.03 ) and glycosylated hemoglobin ( reduction of 2.0 ± 3.4 % , P < 0.01 ) levels . Seventeen ( 31 % ) of54 patients actually normalized their glycosylated hemoglobin values , 9 in the urine-testing group and 8 in the SMBG group . Comparisons between the urine-testing and SMBG groups showed no significant differences in mean fasting plasma glucose ( P > 0.86 ) , glycosylated hemoglobin ( P > 0.95 ) , or weight ( P < 0.19 ) . In patients with type II diabetes mellitus not treated with insulin , SMBG is no more effective , but is 8–12 times more expensive , thanurine testing in facilitating improved glycemic control . Our results do not support widespread use of SMBG in diabetic patients not treated with insulin An estimated 20 million Americans suffer from diabetes . Patients with non-insulin-dependent diabetes mellitus ( NIDDM ) comprise approximately 90 % of the diabetic population . An estimated 10 - 30 % of patients with NIDDM withdraw from their prescribed regimen within 1 year of diagnosis , and of the remainder , nearly 20 % administer insufficient medication to facilitate an adequate reduction in blood glucose . A r and omized trial was undertaken to discern the effect of pharmacy-based value-added utilities on prescription-refill compliance with sulfonylurea therapy and health service utilization . The subjects were 258 Medicaid beneficiaries from the state of South Carolina , previously untreated for NIDDM , prescribed 5 mg of the second-generation sulfonylurea glyburide twice daily , and monitored with regard to prescription-refill compliance and health service utilization for 1 year . Subjects provided informed consent and were r and omly assigned to one of four experimental groups : ( i ) the control cohort received st and ard pharmaceutical care with each dispensing of glyburide ; ( ii ) the second cohort received st and ard pharmaceutical care and was mailed a medication-refill reminder 10 days prior to each sequential refill date ; ( iii ) the third cohort received st and ard pharmaceutical care and was provided unit-of-use packaging with each prescription-refill request ; ( iv ) the fourth cohort received st and ard pharmaceutical care , mailed medication-refill reminders , and unit-of-use packaging . Analysis of variance ( ANOVA ) procedures revealed that patients receiving mailed prescription-refill reminders , unit-of-use packaging , or a combination of both interventions achieved a significant ( P < or = 0.05 ) increase in the Medication Possession Ratio ( MPR ) for sulfonylurea therapy relative to controls . ( ABSTRACT TRUNCATED AT 250 WORDS By use of an interview , return tablet count , and a pharmacologic indicator ( low‐dose phenobarbital ) , we compared compliance with tablets prescribed to be taken once , twice , or three times daily . One hundred seventy‐nine patients with type II diabetes were r and omly allocated to take one 2 mg phenobarbital tablet once , twice , or three times daily for 28 days . Phenobarbital level/dose ratios indicated that compliance was similar with once‐ and twice‐daily regimens , and both were better than thrice‐daily dosing . Mean return tablet counts suggested that compliance was best with the once‐daily regimen ; both twice‐ and thrice‐daily regimens were similarly inferior . This difference between the techniques may be explained by the inadequacies of the residual tablet count , which identified only 13 % of cases identified by phenobarbital . We conclude that compliance with the once‐daily regimen was best , but that compliance with a twice‐daily regimen was very similar , and both were superior to dosing three times a day OBJECTIVE To demonstrate improvements in diabetes care stimulated by comprehensive evaluation of community-based diabetic patients with feedback to the patients and their physicians . RESEARCH DESIGN AND METHODS A comprehensive evaluation of community-based diabetic patients with annotated reporting of results to both patients and their physicians ( universal intervention ) was followed by r and om assignment of 50 % of patients to individual counseling ( r and omized intervention ) . In four communities , two large and two small , 55 type 1 and 376 type 2 diabetic patients were recruited , evaluated , and reassessed at 1 year . Outcome measures were HbA1c , serum cholesterol , and systolic and diastolic blood pressure . RESULTS There were significant improvements in all outcome measures for type 2 diabetic patients r and omized to individual counseling ( P = 0.03 ; follow-up rate 84 % ) and significant improvements in all outcome measures for all high-risk type 2 patients ( highest P value = 0.004 ; follow-up rate 85 % ) . CONCLUSIONS Comprehensive evaluation of diabetic patients at the community level with annotated reporting of results to the patients and their physicians was associated with improvement of mean HbA1c , cholesterol , and systolic and diastolic blood pressure , particularly in patients in high-risk status for these outcome variables . Individual counseling of 50 % of patients , r and omly selected , enhanced these results OBJECTIVE A controlled trial with 15-month follow-up was conducted in two outpatient clinics to study the effects of using the problem-based learning technique to implement a diabetes clinical practice guideline . RESEARCH DESIGN AND METHODS A total of 144 patients with type 2 diabetes aged 25 - 65 years in two internal medicine outpatient clinics were enrolled in the study . African-Americans and Hispanics made up > 75 % of the patients . Doctors and staff in one of the clinics were trained in the use of a clinical practice guideline based on Staged Diabetes Management . A problem-based learning educational program was instituted to reach consensus on a stepped intensification scheme for glycemic control and to determine the st and ards of care used in the clinic . HbA1c was obtained at baseline and at 9 and 15 months after enrollment . RESULTS At 9 months , there was a mean -0.90 % within-subject change in HbA1c in the intervention group , with no significant changes in the control group . The 15-month mean within-subject change in HbA1c of -0.62 % in the intervention group was also significant . Among intervention patients , those with the poorest glycemic control at baseline realized the greatest benefit in improvement of HbA1c . The intervention group also exhibited significant changes in physician adherence with American Diabetes Association st and ards of care . CONCLUSIONS Clinical practice guidelines are an effective way of improving the processes and outcomes of care for patients with diabetes . Problem-based learning is a useful strategy to gain physician support for clinical practice guidelines . More intensive interventions are needed to maintain treatment gains The aim of this study was to evaluate the effect of a structured teaching/treatment programme on the clinical and metabolic control of non-insulin-dependent ( type 2 ) diabetic patients . The programme was aim ed at improving the overall treatment quality in these patients through measures involving self-care , diet , exercise and weight reduction . Four theoretical-practical teaching units were given once a week to group of 5–8 ambulatory patients by previously trained general practitioners . Clinical and biochemical parameters were recorded at the beginning of the course and 1 year after its completion in 40 patients attending the programme and in 39 patients of similar clinical characteristics under conventional diabetes treatment , but receiving no structured teaching before or during the survey period ( control group ) . The drop-out percentage in the intervention group ( 25 % ) was significantly lower than in the control group (45%),P<0.05 , suggesting an incentive toward greater compliance in the former . At the end of the 1-year follow-up , the mean differences observed in the control and in the intervention groups were : body weight loss −2.4±0.5 kg vs −0.4±0.5 ( P<0.001 ) ; haemoglobin HbA1 −0.2%±0.4 % vs + 0.8±0.4 % ( NS ) ; number of daily oral hypoglycaemic agent intake −1.4±0.2 vs + 0.9±0.2 tablets ( P<0.001 ) . Our results strongly suggest that this programme , applied through family doctors , may constitute an efficient tool to improve the compliance and clinico-metabolic control of type 2 patients at the primary health care level The modern management of diabetes relies heavily on self-monitoring of blood glucose ( SMBG ) , and therefore SMBG records are an important source of clinical data for management decision making . The development of a memory Glucometer has provided the opportunity to verify the validity of glucose records thus generated and observe the effects of different educational approaches on compliance with SMBG . Thirty-four patients without previous experience of SMBG were r and omized into one of the following experimental groups differing in the model of diabetes care : mutual decision making , didactic , and authoritarian . Patients , unaware of the memory capacity of the glucose meter , were required to perform four glucose measurements per day over a 14-day observation period . Patient-generated blood glucose records were then compared with objective records stored in the glucose-meter memory . Patients with gestational diabetes mellitus recorded a lower proportion of correct results ( 63 vs. 79 % , P = .049 ) and exhibited a tendency to invent results with lower blood glucose levels ( 5.3 vs. 7.5 mM , P < .0001 ) than the results omitted compared with patients with non-insulin-dependent diabetes mellitus . Predictors of greater validity of records were perceived intelligence of the subject ( χ2 = 4.56 , P < .02 ) and private health-insurance status ( χ2 = 4.52 , P < .04 ) , whereas the experimental group assignment was not significant . These findings reflect potential motivational and sociodemographic limitations in the validity of SMBG recordings within the management and education of patients with gestational and nongestational diabetes A diabetes protocol characterized by self-monitoring of blood glucose was introduced in four general practice s with the aim of making the frequency of consultations dependent on the metabolic regulation and emphasizing body weight reduction . The feasibility of the programme was investigated and the results after 1 year were compared with those of conventional care in four control practice s. In the experimental practice s , 13 patients switched from a medical specialist 's to a general practitioner 's supervision , 20 remained under supervision of their GP and 33 started self-monitoring . The self-monitoring rate , the consultation frequency according to protocol , the low number of dropouts and inadequate referrals and adherence to the therapeutic scheme showed that the protocol was feasible for both the GPs and the patients . At the initial assessment , the regulation of the diabetes was worse in patients of the experimental group , compared with those of the control group ( mean HbA1 9.7 % vs 8.9 % ; p less than 0.05 ) . On average , patients in the experimental group ( n = 56 ) lost 0.4 kg of body weight , whereas those in the control group ( n = 73 ) gained 0.1 kg ( n.s . ) . The mean change in HbA1 , adjusted for the initial value , was -0.4 % in the experimental and + 0.5 % in the control group ( p less than 0.05 ) . The results of the protocol can be attributed to a combination of greater participation of the patient , the individualized consultation frequency and the prescription of oral hypoglycaemic agents according to body weight development OBJECTIVE We evaluated automated telephone disease management ( ATDM ) with telephone nurse follow-up as a strategy for improving diabetes treatment processes and outcomes in Department of Veterans Affairs ( VA ) clinics . We also compared the results with those of a prior ATDM trial conducted in a county health care system . RESEARCH DESIGN AND METHODS A total of 272 VA patients with diabetes using hypoglycemic medications were r and omized . During the 1-year study period , intervention patients received biweekly ATDM health assessment and self-care education calls , and a nurse educator followed up with patients based on their ATDM assessment reports . Telephone surveys were used to measure patients ' self-care , symptoms , and satisfaction with care . Outpatient service use was evaluated using electronic data bases and self-reports , and glycemic control was measured by HbA1c and serum glucose testing . RESULTS At 12 months , intervention patients reported more frequent glucose self-monitoring and foot inspections than patients receiving usual care and were more likely to be seen in podiatry and diabetes specialty clinics . Intervention patients also were more likely than control patients to have had a cholesterol test . Among patients with baseline HbA1c levels > or = 8 % , mean end-point values were lower among intervention patients than control patients ( 8.7 vs. 9.2 % , respectively ; P = 0.04 ) . Among intervention and control patients with baseline values > or = 9 % , mean end-point values were 9.1 and 10.2 % , respectively ( P = 0.04 ) . At follow-up , intervention patients reported fewer symptoms of poor glycemic control than control patients and greater satisfaction with their health care . CONCLUSIONS This intervention improved the quality of VA diabetes care . Intervention effects for most end points replicated findings from the prior county clinic trial , although intervention-control differences in the current study were smaller because of the relatively good self-care and health status among the current study 's enrollees Patients who fail to show for scheduled visits or who fail to contact their provider when warning symptoms occur pose important problems for the primary care physician . A group of interventions was examined to determine the effectiveness in increasing the number of prescribed office visits in patients with diabetes mellitus . This group of interventions included mailed packets with information on how to use the clinic , providers ' names and phone numbers , after-hours phone numbers , a list of early warning signs , and a booklet on managing diabetes mellitus ; mailed appointment reminders ; and intense followup of visit failures for prompt rescheduling . Eight hundred fifty-nine patients on drug therapy for diabetes mellitus were stratified by risk of hospitalization and r and omly assigned within strata to control and intervention groups . The intervention group received all interventions . After 1 year , the intervention group averaged 12 % more total contacts than the control group ( 5.8 vs. 5.2 , P = 0.01 ) , due largely to an increase in kept scheduled visits ( 4.1 vs. 3.6 , P = 0.006 ) . These effects were greatest in those patients at higher risk of hospitalization . Also , visit failures were reduced only in high-risk patients . The effect of the interventions did not diminish during the year of study . This systematic and repetitive intervention appears effective in increasing prescribed office visits and is especially effective in patients requiring more frequent care Home health aides were offered to half of a group of 227 low-income diabetic clinic patients ; in the group offered aides , fasting blood sugar ( FBS ) declined when compared to control group ( 10.1 mg/dl vs an increase of 5.1 mg/dl ) , and missed clinic appointments and emergency room use also decreased . The group of 44 , who , upon offer of an aide actually accepted one , showed a significant increase in eye clinic appointments as well as the greatest decline in FBS ( 13.9 mg/dl ) The effects of a new integrated system of diabetes care with an enhanced role of the diabetes specialist nurse based in a purpose d design diabetes centre , on diabetes control , attendance and cancellation rates , and admission for diabetic emergencies have been review ed . Glycaemic control was examined in : ( a ) a cohort of 163 insulin-treated and 47 non-insulin treated diabetic subjects ( age < 65 years ) studied prospect ively before and 3 years following the introduction of a new system of care ; ( b ) a second cohort of more elderly patients aged greater than 65 years studied for the 3 years after the change over ; ( c ) a cross-sectional study of the clinic population ( n = 700 ) the year before and 3 years after the changeover ; ( d ) a group of patients attending st and ard unaltered clinics in the same district ( n = 157 ) . Significant and sustained falls in HbA1 were observed in all groups of subjects attending the centre , with the means for those aged less than 65 falling from 11.9 + /- 2.3 % to 9.9 + /- 1.9 % and for those aged over 65 from a mean of 11.7 + /- 2.0 % to 10.3 + /- 2.3 % , 3 years later . The cross-sectional study provided similar results with a mean HbA1 of 12.2 + /- 3.0 % prior to changeover and 10.4 + /- 4.4 % , 3 years later . Smaller but significant changes were observed in patients continuing to attend the routine clinic ( from 12.2 + /- 2.3 % to 11.3 + /- 2.6 % ) over a similar period . Yearly admission rates for ketoacidosis and hypoglycaemia fell from 44 and 23 , to 33 and 5 per annum , respectively . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE To evaluate the effectiveness of a nurse-managed smoking cessation intervention in diabetic patients . RESEARCH DESIGN AND METHODS This r and omized controlled clinical trial involved 280 diabetic smokers ( age range 17 - 84 years ) who were r and omized either into control ( n = 133 ) or intervention ( n = 147 ) groups at 12 primary care centers and 2 hospitals located in Navarre , Spain . The intervention consisted of a 40-min nurse visit that included counseling , education , and contracting information ( a negotiated cessation date ) . The follow-up consisted of telephone calls , letters , and visits . The control group received the usual care for diabetic smokers . Baseline and 6-month follow-up measurements included smoking status ( self-reported cessation was verified by urine cotinine concentrations ) , mean number of cigarettes smoked per day , and stage of change . RESULTS At the 6-month follow-up , the smoking cessation incidence was 17.0 % in the intervention group compared with 2.3 % in the usual care group , which was a 14.7 % difference ( 95 % CI 8.2 - 21.3 % ) . Among participants who continued smoking , a significant reduction was evident in the average cigarette consumption at the 6-month follow-up . The mean number of cigarettes per day decreased from 20.0 at baseline to 15.5 at 6 months for the experimental group versus from 19.7 to 18.1 for the control group ( P < 0.01 ) . CONCLUSIONS A structured intervention managed by a single nurse was shown to be effective in changing the smoking behavior of diabetic patients In this r and omized trial patients with non-insulin-dependent diabetes were allocated to one of four programs : a minimal instruction program ( n=59 ) . an education program of individual visits ( n=57 ) , an education program incorporating a group education course ( n=66 ) , and a behavioral program ( n=59 ) . Individual and group education programs had higher attrition rates than the behavioral and minimal programs . The four programs , which involved different amounts of patient contact time , delivery format , and instructional strategies . all produced reductions in HbA atid BMI , with no significant differences between the programs . There were no differences between groups over three time periods in total cholesterol , HDL cholesterol , systolic blood pressure , or proportion of patients consulting an ophthalmologist . The behavioral program ploduced a greater reduction in diastolic blood pressure over 12 months that the education programs and a greater reduction in the cholesterol risk ratio over 3 months than the other programs . The behavioral program patients were more likely to have visited a podiatrist after 6 months and reported higher satisfaction A structured treatment and teaching programme for non-insulin-treated non-insulin-dependent ( type 2 ) diabetes was evaluated prospect ively in general practice . The four group sessions were mainly conducted by paramedical personnel . 65 patients from five general practice s were assessed at the start of the programme and 50 ( mean age 65 years , diabetes duration 7 years ) completed the 1 year follow-up ( intervention group ) . The control group consisted of 49 patients ( mean age 63 years , diabetes duration 7 years ) from three other general practice s without the programme . In the intervention group the percentage of patients receiving sulfonylureas fell from 68 % at the start of the study to 38 % after 1 year ( mean difference 30 % , 95 % confidence interval [ CI ] 16 - 44 % ) ; the mean weight loss was 2.7 kg ( 95 % CI 1.6 - 3.8 kg ) , and non-fasting triglycerides were reduced by 0.77 mmol/1 ( 95 % CI 0.35 - 1.19 mmol/l ) ; and glycosylated haemoglobin remained unchanged ( 7.1 % of total haemoglobin ) . In the control group none of these indices was changed during the study year , and 10 % of patients started insulin treatment . The structured treatment and teaching programme improved the overall quality of patient care in elderly non-insulin-dependent diabetic patients treated by general practitioners BACKGROUND This study was done to determine the efficacy and ease of administration of education/behavior modification classes , provided by a nurse and a dietitian in a primary care clinic for improving control of type 2 diabetes mellitus . METHODS Patients were divided r and omly into two groups . Eighteen patients completed 6 months of structured , office-based classes , and 20 similar patients served as control subjects . All were patients of the same group practice and had their usual office visits . Glycemic control , lipid levels , body weight , knowledge about diabetes , medication requirements , and symptoms were monitored during the 6 months , with follow-up at 12 months . RESULTS At the end of 6 months , the intervention group had significant reductions in mean fasting blood glucose , glycosylated hemoglobin , total cholesterol , and low-density lipoprotein cholesterol ( LDL-C ) values . Their mean body weight was significantly reduced at 12 months , and their knowledge of diabetes was improved . Control patients had significant improvement only in glycosylated hemoglobin and body weight at 6 months . Minimal physician time was required . CONCLUSION The education/behavior modification program was clinical ly worthwhile , and it was easy to administer Structured diabetes teaching and treatment programmes ( STTP ) are increasingly offered for patients with diabetes to improve metabolic control . We prospect ively studied the long term-effect of STTP on metabolic control and knowledge of diabetes in patients with type 2 diabetes . In addition , differences in the mode of follow-up by a university diabetes centre ( UDC ) versus general practitioner ( GP ) were assessed . Of the 64 patients with type 2 diabetes ( 61 + /- 10 years old , diabetes duration 11 + /- 7 years ) included in the study 52 could be reevaluated after 2 years . Of those , 31 were followed up by the UDC and 21 by their GPs who received detailed follow-up instructions from the UDC . In all patients , HbA1c decreased from 9.1 + /- 0.3 % before the programme to 8.3 + /- 0.3 % 2 years after the programme ( P = 0.004 ) , whereas body mass index increased from 28.8 + /- 0.8 to 30.3 + /- 0.9 kg/m2 ( P < 0.001 ) . Patients had a significantly better knowledge of diabetes and diet 2 years after the programme . For all parameters tested , none of the changes differed between patients managed by the UDC versus those managed by their GP . However , patients who chose follow-up by the UDC were more obese and had a better knowledge of diabetes . In conclusion , the STTP for patients with type 2 diabetes was effective in improving the long-term glycaemic control and knowledge of diabetes . Moreover , with precise therapeutic goals and follow-up instructions given to patient and GP this improvement was independent of the mode of outpatient follow-up To study if self-monitoring of glucose , urinary or capillary , could help them to improve their metabolic control through better compliance to diet and /or hypoglycaemic agents , 208 non-insulin-treated poorly controlled diabetic patients were r and omized to : group A -- regular HbA1c determinations but no self-monitoring , group B -- self-urine glucose monitoring , twice every other day , group C -- self blood glucose monitoring , twice every other day , and followed six months . At the end of the study period , the decrease of HbA1c over six months -- main endpoint -- was not significantly different between the three groups ( mean + /- SEM ; group A : -0.5 + /- 0.2 % ; group B : -0.1 + /- 0.3 % ; group C : -0.4 + /- 0.3 % ) . However , the degree of compliance to blood glucose self-monitoring in group C appeared to relate to the outcome : a significant correlation was found between the number of blood glucose strips used and the decrease of HbA1c ( r = .36 , p less than .02 ) . We conclude that regular self-monitoring has no definite advantage over the usual management for improving metabolic control in non-insulin-treated diabetic patients , though it may possibly help patients ready to comply with its use Self-monitoring of blood glucose ( SBGM ) is widely recommended for both type 1 and type 2 diabetic patients despite the lack of evidence of benefit in glucose control or as an aid in weight loss in type 2 subjects . This study tested the hypothesis that combined use of SMBG and dietary carbohydrate ( CHO ) counting , using the blood monitoring results to shape dietary CHO quotas , is beneficial in managing type 2 diabetes . Twenty-three over-weight ( body mass index , BMI 27.5–44 kg/m2 ) patients aged 40–75 participated in a 28-week behavioral weight control program . Baseline hemoglobin HbA 1c ranged between 9.5 % and 13.5 % ( normal range 5.5%–7.7 % ) . Subjects were matched for weight , sex , and HbAlc and assigned to small ( 4–8 participants ) groups which met weekly for 12 weeks and then monthly for 16 weeks . After 8 weeks , the group were r and omized either to continue the behavioral program or to have SMBG and dietary CHO counting . Glucose monitoring was performed 6 times daily ( pre- and 2h postpr and ially ) for the first month , focusing on the meal increment and correlating this to dietary CHO intake . Weight loss was identical in both groups during the year of follow-up . The HbA1c level showed a progressive decline in experimental subjects ( P<0.05 ) , whereas there was no improvement in control subjects After diabetes education , 39 adult diabetic patients were r and omized to either an education group or control group . The two groups received identical medical care and follow-up , except that the education group met with their diabetes educator on at least a quarterly basis . Neither group showed any statistically significant change in their glycosylated hemoglobin values , although the education group did have a 4 % drop after initial education compared to a 6 % rise in the control group . The education group had a lower attrition rate and a better improvement in self-rated dietary compliance . Education remains the cornerstone of diabetes management . Our team identified some trends between the two groups as well as some ideas to improve motivating and developing a stronger and more effective relationship with our patients OBJECTIVE : To assess the effectiveness of a pharmaceutical care model on the management of non-insulin-dependent diabetes mellitus ( NIDDM ) in urban African-American patients . DESIGN : Eligible patients were r and omized to either a pharmacist intervention or control group and followed over a 4-month period . Patients in the intervention group received diabetes education , medication counseling , instructions on dietary regulation , exercise , and home blood glucose monitoring , and evaluation and adjustment of their hypoglycemic regimen . Patients in the control group continued to receive st and ard medical care provided by their physicians . SETTING : A university-affiliated internal medicine outpatient clinic . PARTICIPANTS : The study population consisted of urban African-American patients with NIDDM currently attending the clinic . MAIN OUTCOME MEASURES : Primary outcome measures included fasting plasma glucose and glycated hemoglobin concentrations . Secondary outcome endpoints included blood pressure , serum creatinine , creatinine clearance , microalbumin to creatinine ratio , total cholesterol , triglycerides , high-density lipoprotein , and low-density lipoprotein concentrations . Quality -of-life assessment s were performed in both groups at baseline and at the end of the study . RESULTS : Thirty-nine patients ( 17 intervention , 22 control ) completed the study . The intervention group consisted of 12 women and 5 men with a mean ± SD age of 59 ± 12 years , total body weight ( TBW ) of 93 ± 22 kg , body mass index ( BMI ) of 34 ± 7 kg/m2 , and duration of NIDDM 6.8 ± 6.5 years . The control group consisted of 15 women and 7 men with a mean age of 65 ± 12 years , TBW of 88 ± 19 kg , BMI of 33 ± 7 kg/m2 , and a duration of NIDDM of 6.2 ± 4.8 y. Significant improvement in glycated hemoglobin ( p = 0.003 ) and fasting plasma glucose ( p = 0.015 ) was achieved in the intervention group . No change in glycemia was observed in the control subjects . Statistically significant differences in the final glycated hemoglobin ( p = 0.003 ) and fasting plasma glucose ( p = 0.022 ) concentrations were noted between groups . No significant changes in blood pressure control , lipid profile , renal function parameters , weight , or quality -of-life measures were noted within or between groups . CONCLUSIONS : Our data demonstrate the effectiveness of pharmaceutical care in the reduction of hyperglycemia associated with NIDDM in a group of urban African-American patients A multi-center prospect i ve study was conducted to assess the function and impact of diabetic education programs on diabetic control . A total of 208 subjects with type 2 diabetes were recruited . Diabetes self-care , assessed by question naire , was evaluated before , and 4 months after attending a diabetes education course . A total of 121 subjects who received advanced diabetes education courses were design ated as the experimental group . A second group of 87 cases receiving a basic course served as controls . In addition to basic knowledge , the advanced education programs included dietary control , blood glucose monitoring , management of hypoglycemia , medication compliance , foot care and exercise . Diabetes self-care techniques were significantly improved in the experimental group . The overall score for diabetes self-care techniques improved in both groups at the 4th month over baseline values . The change was significant with the controls ' ( P < 0.001 ) . Multiple regression analysis confirmed the intensity of diabetic education was the only significant variable correlated with the decrease of fasting blood glucose and systolic blood pressure . In conclusion , integrated and intensive diabetes education program in diabetes education centers provides an effective method for improving diabetes self-care techniques and metabolic outcome A r and omized controlled trial was conducted to determine whether an education program specifically design ed for patients with non-insulin-dependent diabetes and limited literacy could improve and sustain glucose and weight control . From a referral clinic , 120 obese ( > 130 per cent of ideal body weight ) diabetic patients who were not taking insulin were recruited . Of these , 55 per cent were female and 49 per cent were black ; the mean age was 53 years . Mean glycosylated hemoglobin ( HbA1 % ) was 10.2 per cent . Each subject was assigned to one of three groups : 1 ) monthly group sessions with videotapes for diabetic persons with low literacy skills ; 2 ) monthly group sessions without videotapes ; or 3 ) no monthly sessions . After seven months , there had been 16 dropouts ( 13 per cent ) . Differences in weight changes between groups were significant ( p<0.05 ) ; group 1 lost a median of 1 kg of weight ( p<0.05 ) compared with a 0.1-kg loss and no change in groups 2 and 3 , respectively . This weight loss was not sustained at 11 months . There was no significant change in HbA1 % . Age , education , and compliance beliefs did not predict outcome . The authors conclude that the patient education programs did not result in sustained glucose or weight control This study tested the hypothesis that follow-up intervention ( by telephone calls and home visit ) affects compliance in patients with non-insulin-dependent diabetes mellitus ( NIDDM ) . Sixty NIDDM patients were r and omly assigned to two groups — a control group , which received the st and ard protocol ( 3-day educational program and a review session 1 month after the program ) ; and an intervention group , which received the st and ard protocol as well as a series offour telephone calls and one home visit by a registered nurse over a 3-month period . Compliance to prescribed regimens was determined by analyzing three sets of data : changes in pre- to post study glycosylated hemoglobin ( HbA1c ) values ; changes in pre- to post study weight ; and frequency with which self-monitoring of blood glucose ( SMBG ) was practice d. Results showed that SMBG practice was significantly better for the intervention group . No significant differences were seen in post study HbA 1c values and weight changes between the two groups . Follow-up inter vention by telephone calls and home visit can enhance patient compliance to certain aspects of the prescribed diabetes management plan AIM Our objective was to evaluate the effect of training in a patient-centred intervention for GPs and practice nurses on outcomes for patients with Type II diabetes . METHODS We carried out a r and omized controlled trial within general practice s as the basis for r and omization and a before- and -after design for measures of patient outcome . A parallel process study examined the use of the method by professionals . The study was carried out in 29 general practice s in South Glamorgan who had participated for at least 2 years in a local scheme of audit and CME in relation to Type II diabetes care . The subjects were 252 Type II diabetic patients recruited by 15 experimental and 14 control practice s. The main outcome measures were changes in glycosylated haemoglobin , patient satisfaction with care and treatment , functional health status and professional ability to apply the intervention . RESULTS Professionals adopted the innovative method with enthusiasm , but after 2 years only 19 % continued to apply the method systematic ally . The trial was , therefore , unable to demonstrate significant biochemical or functional improvements . This highlights the need to underst and the factors associated with professional uptake and subsequent ability to sustain changes in behaviour . CONCLUSIONS The efficacy of this behavioural intervention remains unproved , despite its acceptability to professional staff . Detailed and prolonged development and testing of behavioural interventions is an essential first step before embarking on r and omized controlled trials which involve complex behavioural changes in professionals or patients Aims Intensive management of risk parameters in diabetic patients may retard the progression of both micro‐ and macrovascular complications . Intensified care requires expert staff and is expensive . The aim of the present study was to examine whether sharing the therapeutic responsibility with the patients will improve the outcome OBJECTIVE To examine whether a telephone-delivered intervention ( TDI ) , design ed to improve glycemie control in patients with non-insulin-dependent diabetes mellitus ( N1DDM ) , improved coronary risk factors in high-risk patients . RESEARCH DESIGN AND METHODS This r and omized controlled trial involved 275 veterans with N1DDM followed in a general medical clinic . Intervention ( TDI ) patients were telephoned at least monthly by a nurse . Calls emphasized compliance with the medical regimen ( diet , medications , and exercise ) , encouraged behavioral changes , and facilitated referrals to a dietitian or smoking cessation clinic . Control patients received no such calls . Baseline and 12-month follow-up measurements included fasting lipid profiles , weight , smoking status ( self-reported ; cessation verified by measurement of exhaled CO ) , adherence to diet and exercise ( self-reported ) , appointments , and medications ( hospital computerized data base ) . RESULTS After 12 months , equal numbers of obese patients in the two groups reported adhering to a diabetic diet and exercising , although more obese TDI patients had seen a dietitian ( 30 vs. 7 % , P = 0.003 ) . Weight loss was not seen in either group ( —0.9 ± 5.3 vs. —0.1 ± 3.6 kg , P = 0.202 ) . Hyperlipidemic TDI patients were more likely to see a dietitian ( 31 vs. 6 % , P = 0.003 ) and receive lipid-lowering medications ( 22 vs. 9 % , P = 0.096 ) , but serum cholesterol reduction was similar between groups ( –11.7 ± 33.4 vs. –4.3 ± 32.7 mg/dl , P = 0.270 ) ; comparable results were seen for high-density lipoprotein , low-density lipoprotein , and triglyceride levels . More TDI group smokers reported quitting ( 26 vs. 0 % , P = 0.033 ) , but the difference was not significant for CO-verified abstention ( 10 vs. 0 % , P = 0.231 ) . CONCLUSIONS The TDI improved self-reported adherence to regimens that might reduce coronary risk , but had little effect on objective measures of risk The purpose of our study was to compare the effect on diabetes control of group management with the advice-educational technique traditionally used in managing obese out patients with poorly controlled non-insulin-dependent diabetes mellitus ( NIDDM ) . Forty-one patients were r and omly assigned to these two treatment programs , and 32 patients completed the 6-mo study . Initially , patients were seen for 1-h sessions at 1- and 2-wk intervals and later at 1-mo intervals . Patients were asked to do home blood glucose monitoring , decrease caloric intake , increase exercise , and if they were taking insulin , to adjust the dose to attain approximate euglycemia and to stabilize food and exercise patterns . The combined groups reduced mean ± SD glycohemoglobin from 10.9 ± 3.1 to 9.4 ± 2.4 % ( P < .05 ) . Internal Health Locus of Control Scale was negatively and significantly correlated with initial and subsequent glycohemoglobin values ( the more internal , the lower the glycohemoglobin ) . At the end of the study the patients in the group management program had significantly lower blood glucose levels than those given advice and education , but no significant differences in glycohemoglobin values or percentage overweight were observed . One patient had a normal initial glycohemoglobin , and only 4 patients had values in the normal range of 4–6.8 % at the end of the study . Better management programs need to be developed for treating obese out patients with NIDDM OBJECTIVE : To determine the impact of clinical pharmacists involved in direct patient care on the glycemic control of patients with type 2 diabetes mellitus . DESIGN : Eligible patients included those with type 2 diabetes who received insulin or were initiated on insulin therapy by the pharmacists and were willing to perform self-monitoring of blood glucose . The pharmacists provided diabetes education , medication counseling , monitoring , and insulin initiation and /or adjustments . All initial patient interactions with the pharmacists were face-to-face . Thereafter , patient – pharmacist interactions were either face-to-face or telephone contacts . SETTING : Two primary care clinics in a university-affiliated Veterans Affairs Medical Center . PARTICIPANTS : Study subjects were patients with type 2 diabetes who were referred to the pharmacists by their primary care providers for better glycemic control . OUTCOME MEASURES : Primary outcome variables were changes from baseline in glycosylated hemoglobin , fasting blood glucose , and r and om blood glucose measurements . Secondary outcomes were the number and severity of symptomatic episodes of hypoglycemia , and the number of emergency room visits or hospitalizations related to diabetes . Twenty-three veterans aged 65 ± 9.4 years completed the study . Fifteen ( 65 % ) patients were initiated on insulin by the pharmacists ; 8 ( 35 % ) were already using insulin . Patients were followed for a mean ± SD of 27 ± 10 weeks . Glycosylated hemoglobin , fasting blood glucose concentrations , and r and om blood glucose concentrations significantly decreased from baseline by 2.2 % ( p = 0.00004 ) , 65 mg/dL ( p < 0.01 ) , and 82 mg/dL ( p = 0.00001 ) , respectively . Symptomatic hypoglycemic episodes occurred in 35 % of patients . None of these episodes required physician intervention . CONCLUSIONS : This study demonstrates that pharmacists working as members of interdisciplinary primary care teams can positively impact glycemic control in patients with type 2 diabetes requiring insulin We assessed diabetes education and peer support interventions as facilitators of weight loss and glycemic control in a community sample of 79 elderly persons with noninsulin-dependent diabetes mellitus ( NIDDM ) . Different groups received : education only , education and peer support , and no treatment . Peer support was higher in groups where it was actively facilitated . Weight loss and reduction in level of glycemic control occurred within groups receiving both diabetes education and peer support Effective control of diabetes is known to delay or prevent the end-organ complications of this disease . Can telemedicine improve a patient 's ability to self-manage diabetes ? Twenty-eight patients entered a study comparing home telemedicine consultation with st and ard outpatient care . A nurse case manager contacted the telemedicine group once a week under the direction of a primary care physician , who contacted the telemedicine group once a month . Laboratory studies and total body weight were measured at the beginning and at the end of the 3-month study . The hemoglobin A1c ( HbA1c ) and total body weight improved significantly in the intervention ( telemedicine ) group , as shown by a 16 % reduction in mean HbA1c level ( from 9.5 to 8.2 % ) and a 4 % mean weight reduction ( from 214.3 to 206.7 pounds ) . Based on our experience , we present a functionally based telemedicine classification system to improve the application of electronic medicine in future studies Diabetes care , morbidity , and mortality are usually worse in poor minority population s compared with nonminority ones . This report evaluates evidence -based process and outcome measures of diabetes care in diabetic patients followed in a free medical clinic and compares them to published results . The following process measures compared favorably with measures of the general population : dilated eye and foot exams and measurements of glycated hemoglobin levels ; concentrations of total cholesterol ; fasting triglycerides and low density lipoprotein ( LDL ) cholesterol ; and proteinuria ( by dipstick ) . Process and outcome measures in 89 diabetic patients referred to a Diabetes Management Program in which diabetes care was delivered by pharmacists following detailed algorithms ( experimental group ) were compared with measures in 92 diabetic patients who received diabetes care in the general clinic setting ( control group ) . The patients in the experimental group had a slightly longer duration of diabetes and more microvascular and neuropathic complications , and more diabetic patients were taking insulin than were patients in the control group . All of the process measures listed above were more frequent in the experimental group . Compared with the control group , the initial glycated hemoglobin level ( % ± SE ) in the experimental group was significantly ( P < .001 ) higher ( 8.8 ± 0.2 versus 7.9 ± 0.2 ) but fell significantly ( P < .03 ) more ( -0.8 - 0.2 versus -0.05 ± 0.3 ) . The lack of a greater decrease in the glycated hemoglobin levels in the experimental group was not related to the inability of the pharmacists to follow the algorithms , the patients ' refusal to follow the recommended medication adjustments , or the lack of appropriate self-monitoring of blood glucose in insulin-requiring patients . It was inversely related ( r = -0.36 , P < .03 ) to the number of missed visits , ie , the greater the number of broken appointments , the less the glycated hemoglobin fell . In conclusion , diabetes care for a poor minority population in a free clinic setting can compare favorably to care in the general population . Pharmacists following detailed algorithms can enhance this care further . Administrative and support system changes that minimize the number of missed visits might further improve diabetes care in this population OBJECTIVE To assess the impact of calendar blister pack ( CBP ) use on glycemic and blood pressure control . RESEARCH DESIGN AND METHODS We conducted an 8-month r and omized controlled double-blind study among diabetic patients with poor glucose control ( HbA1c > 9.0 % ) in an urban area of South Auckl and , New Zeal and , with a high proportion of Maori and Pacific Isl and s people . Subjects included 68 consecutive patients , of whom 50 % were prescribed three or more medications per day RESULTS HbA1c was reduced by 0.95+/-0.22 % in the CBP group and 0.15+/-0.25 % in the control group ( P = 0.026 ) . Diastolic blood pressure decreased 5.8+/-1.5 mm Hg in the CBP group and increased 0.1+/-1.9 mm Hg in the control group ( P = 0.0041 ) . Systolic blood pressure did not change significantly CONCLUSIONS CBPs should be considered among diabetic patients with poor glycemic control receiving multiple medications The Diabetes Education Study ( DIABEDS ) was a r and omized , controlled trial of the effects of patient and physician education . This article describes a systematic education program for diabetes patients and its effects on patient knowledge , skills , self-care behaviors , and relevant physiologic outcomes . The original sample consisted of 532 diabetes patients from the general medicine clinic at an urban medical center . Patients were predominantly elderly , black women with non-insulin-dependent diabetes mellitus of long duration . Patients r and omly assigned to experimental groups ( N = 263 ) were offered up to seven modules of patient education . Each content area module contained didactic instruction ( lecture , discussion , audio-visual presentation ) , skill exercises ( demonstration , practice , feedback ) , and behavioral modification techniques ( goal setting , contracting , regular follow-up ) . Two hundred seventy-five patients remained in the study throughout baseline , intervention , and postintervention periods ( August 1978 to July 1982 ) . Despite the requirement that patients demonstrate mastery of educational objectives for each module , postintervention assessment 11–14 mo after instruction showed only rare differences between experimental and control patients in diabetes knowledge . However , statistically significant group differences in self-care skills and compliance behaviors were relatively more numerous . Experimental group patients experienced significantly greater reductions in fasting blood glucose ( −27.5 mg/dl versus −2.8 mg/dl , P < 0.05 ) and glycosylated hemoglobin ( −0.43 % versus + 0.35 % , P < 0.05 ) as compared with control subjects . Patient education also had similar effects on body weight , blood pressure , and serum creatinine . Continued follow-up is planned for DIABEDS patients to determine the longevity of effects and subsequent impact on emergency room visits and hospitalization OBJECTIVE To evaluate a system for improving diabetes care in remote Indigenous communities . DESIGN R and omised , unblinded cluster trial over one year ( 1 March to 29 February 2000 ) . PARTICIPANTS AND SETTING Primary healthcare staff in 21 primary healthcare centres in the Torres Strait and Northern Peninsula Area ( NPA ) Health Service District , north Queensl and , and 678 people with diabetes , mostly Torres Strait Isl and ers . INTERVENTION Diabetes recall system established at eight of the 21 sites , as well as staff training in basic diabetes care , regular phone calls from the project officer , a two-monthly newsletter and a mid-project workshop . MAIN OUTCOME MEASURES Regular checks of weight , blood pressure , eye and foot care , serum lipid levels and glucose monitoring and control , urinary albumin to creatinine ratio and serum creatinine levels , and administration of recommended vaccines ; hospitalisation in the previous 12 months . RESULTS There was improvement in most measures at most sites , except for blood pressure monitoring and control , and vaccination status . Intervention sites showed greater improvement in most indicators than control sites ( combined relative risk [ RR ] , 1.21 ; 95 % CI , 1.03 - 1.43 ) . The intervention group showed a 32 % reduction in hospital admissions for diabetes-related conditions over the study period ( P=0.012 ) . At follow-up , patients in intervention sites were 40 % less likely to be hospitalised for a diabetes-related condition than those in control sites ( RR , 0.60 ; 95 % CI , 0.41 - 0.86 ; P=0.007 ) . CONCLUSION A simple recall system , managed by local healthcare workers and supported by a diabetes outreach service , achieved significant improvements in diabetes care and reduced hospitalisations in a high-risk population OBJECTIVE To determine whether multiple mailed patient reminders can produce an increase in the rate of diabetic retinal examinations ( DRE ) over that seen with a single reminder . RESEARCH DESIGN AND METHODS All diabetic members > or = 18 years who were enrolled in a large network-based health maintenance organization ( HMO ) in California from August 1996 to July 1997 were identified using cl aims and pharmacy data bases . Members who had no record of DRE in the HMO 's cl aims data base were then r and omized into two groups . Both groups received mailed educational material s and a reminder to obtain the examination . Their physician groups also received a letter explaining the program , current guidelines for DRE , and a list of their diabetes patients with their DRE status . The single intervention group received no additional reminders . The multiple intervention group received additional reminders at 3 , 6 , and 9 months after baseline if they continued with no record of service , as determined from the cl aims data base . RESULTS The study cohort comprised 19,523 diabetic members , which were r and omized into single ( n = 9,614 ) and multiple ( n = 9,909 ) intervention groups . There was an increase in monthly DRE rates after the intervention in August 1996 for both intervention groups . After the second reminder was sent to the multiple intervention group , the percentage of diabetic members receiving DRE was higher than the single intervention group . Rates before and after the third intervention were not significantly different , nor were monthly differences found . There was a significant difference in overall annual DRE rates between the groups ( P = 0.023 ) . CONCLUSIONS Multiple patient reminders are more effective than single reminders in improving DRE rates in a managed care setting . However , the improvement noted was clinical ly small and appeared only after the second reminder ; no incremental improvement was seen with additional reminders . Re sources used for multiple reminders aim ed at diabetic retinopathy might better be spent on other approaches to reducing complications of diabetes |
13,604 | 12,137,623 | REVIEW ER 'S CONCLUSIONS Smoking cessation counselling can assist smokers to quit | BACKGROUND Individual counselling from a smoking cessation specialist may help smokers to make a successful attempt to stop smoking .
OBJECTIVES The objective of the review is to determine the effects of individual counselling . | The primary objective of this study was to determine whether health beliefs influenced the outcome of the three alternate modalities of reducing cigarette consumption . The study r and omized volunteers either to a control group or to one of three cessation programs , using behavior modification , health education , or hypnosis . A question naire was used to document health beliefs , demographic characteristics , and smoking history . Blood sample s were taken before and after the completion of intervention programs to measure changes in serum thiocyanate . A follow-up question naire was used to assess smoking behavior after 6 months . Statistically significant decreases in serum thiocyanate levels followed participation in each of the three programs . Factor analysis and reliability tests were used to identify four scales reflecting major variable dimensions in the health belief model . Significant correlations between change in serum thiocyanate and two of the scales ( general health concern and perceived vulnerability ) were found only for the group r and omly assigned to the health education intervention program BACKGROUND This study examined the 1-year effects of a minimal-contact smoking cessation intervention for cardiac in patients . METHODS The multicenter study included cardiac in patients who had smoked prior to hospitalization . A pretest-posttest quasi-experimental design was used . Patients ' experimental condition depended on the hospital they were assigned to . The design was partially r and omized : 4 of the 11 hospitals selected the experimental condition themselves ( 2 experimental , 2 control ) , while the remaining 7 hospitals were r and omly assigned . The experimental group consisted of patients of 5 hospitals ( N = 388 ) . Patients of 6 other hospitals served as the control group ( N = 401 ) . The intervention included stop-smoking advice by the cardiologist , brief counseling by the nurse , the provision of self-help material s , and aftercare by the cardiologist . RESULTS Logistic regression analyses controlling for baseline differences and covariates did not show significant intervention effects on point prevalence and continuous abstinence . The study also showed that the outcomes were not significantly related to the way hospitals were assigned to the experimental condition . CONCLUSIONS While short-term effects were found , the minimal-contact intervention did not result in significant effects after 12 months , at least if patients lost to follow-up were treated as posttest smokers . Efforts should be made to improve the intervention , especially the aftercare Background : Guidelines recommend that smoking cessation interventions are offered in all clinical setting s to all smokers willing to make a quit attempt . Since the effectiveness of routine provision of behavioural counselling and nicotine replacement therapy ( NRT ) to smokers admitted to hospital has not been established , a r and omised controlled trial of these interventions given together compared with counselling alone or minimal intervention was performed in hospital in patients . Methods : Medical and surgical in patients who were current smokers at the time of admission were r and omised to receive either usual care ( no additional advice at admission ) , counselling alone ( 20 minute intervention with written material s ) , or NRT plus counselling ( counselling intervention with a 6 week course of NRT ) . Continuous and point prevalence abstinence from smoking ( vali date d by exhaled carbon monoxide < 10 ppm ) was measured at discharge from hospital and at 3 and 12 months , and self-reported reduction in cigarette consumption in smokers was assessed at 3 and 12 months . Results : 274 inpatient smokers were enrolled . Abstinence was higher in the NRT plus counselling group ( n=91 ) than in the counselling alone ( n=91 ) or usual care ( n=92 ) groups . The difference between the groups was significant for vali date d point prevalence abstinence at discharge ( 55 % , 43 % , 37 % respectively , p=0.045 ) and at 12 months ( 17 % , 6 % , 8 % , p=0.03 ) . The respective differences in continuous vali date d abstinence at 12 months were 11 % , 4 % , 8 % ( p=0.25 ) . There was no significant difference between counselling alone and usual care , or in reduction in cigarette consumption between the treatment groups . Conclusions : NRT given with brief counselling to hospital in patients is an effective routine smoking cessation intervention Objective The purpose of this study was to evaluate the effects of stage-matched repeated individual behavioral counseling as an intervention for the cessation of smoking . Methods We conducted a multisite r and omized controlled trial that enrolled smokers unselected for their readiness to quit . There were 979 smokers with hypertension or hypercholesterolemia recruited from 72 study sites and r and omly allocated to the intervention or control group . Smokers in the intervention group received stage-matched individual counseling consisting of a 40 minute initial session and four 20–30 minute follow-up sessions . Smokers in the control group received individual behavioral counseling for hypertension or hypercholesterolemia . Results The point prevalence abstinence rate at 6 months , vali date d by carbon monoxide testing , in the intervention group ( 13.6 % ) was 5.4 times higher ( p<0.001 ) than that in the control group ( 2.5 % ) . When the data were analyzed based on the baseline stage of change , there were significant differences in the abstinence rates at 6 months in smokers versus controls with each stage of change except in immotives . The odds ratio was 6.4 ( p<0.001 ) in precontemplators , 6.7 ( p<0.001 ) in contemplators , and 6.2 ( p<0.01 ) in preparators . There was a positive , consistent effect of the intervention regardless of study site ( worksite or community ) or the presence of hypertension or hypercholesterolemia . Conclusions We showed the effects of an intervention with repeated individual behavioral counseling on the cessation of smoking in smokers unselected for their readiness to quit . This result suggests that stage-matched individual counseling , based on the transtheoretical model , is effective in smokers with a lower motivation to quit as well as those ready to quit AIMS In an additive design , test the efficacy of cue exposure treatment for smoking relapse prevention as an adjunct to current st and ard cognitive behavioral and pharmacological treatments . DESIGN R and omized , controlled clinical trial . SETTING Outpatient behavioral medicine clinic . PARTICIPANTS One hundred and twenty-nine cigarette smokers recruited through newspaper advertisements . INTERVENTION After receiving an initial counseling session for cessation and setting a quit day , 129 smokers were r and omly assigned to one of four relapse prevention treatment conditions : ( 1 ) brief cognitive behavioral ; ( 2 ) cognitive behavioral and nicorette gum ; ( 3 ) cognitive behavioral and cue exposure ; and ( 4 ) cognitive behavioral and cue exposure with nicorette gum . All smokers met individually with their counselor for six RP sessions . MEASURES Seven-day , point-prevalence abstinence rates ( CO verified ) taken at 1 , 3 , 6 and 12-months post-treatment and time to first slip . FINDINGS All manipulation checks and process measures suggested that the treatments were delivered as intended . There were no significant differences between conditions in point-prevalence abstinence rates or in time to first slip . CONCLUSIONS These results call into question the utility of cue exposure treatment for smoking relapse prevention Many patients attempt to stop smoking during hospitalization , but most relapse after discharge . This study developed and evaluated a brief smoking-cessation and relapse-prevention program for hospitalized smokers . All hospitalized smokers ( n=1,119 ) were identified by question naire at hospital admission and then received either usual care or usual care plus a hospital-based smoking- cessation intervention regardless of interest in stopping smoking . Intervention components included a 20-minute bedside counseling session , a 12-minute videotape , a variety of self-help material s , and a follow-up telephone call . Special attention was given to techniques for preventing relapse after hospital discharge . Defining ex-smokers as those who reported no tobacco use at both 3- and 12-month follow-up assessment s , and counting those lost to follow-up as smokers , the intervention increased the proportion of patients who quit smoking by one half ( 9.2%vs 13.5 % , P<0.05 ) . These results demonstrate the efficacy of a brief in-hospital intervention and suggest that relapse-prevention efforts are needed to convert temporary cessation during hospitalization into longterm abstinence Smoking treatment for newly recovering drug and alcohol-dependent smokers in a residential rehabilitation program was examined . The r and omly assigned conditions ( n = 50 each ) were multicomponent smoking treatment ( MST ) , MST plus generalization training of smoking cessation to drug and alcohol cessation ( MST+G ) , or usual care ( UC ) . Fifty participants who declined smoking treatment ( treatment refusers ) also were studied . Both treatment conditions achieved continuous smoking abstinence rates ( MST : 12 % , MST+G : 10 % , at 12-month follow-up ) that were significantly higher than in the UC condition ( 0 % ) . The MST condition had a continuous drug and alcohol abstinence rate that was significantly higher than that of the MST+G condition ( 40 % vs. 20 % at 12-month follow-up ) although neither differed significantly from that of the UC condition ( 33 % ) . These results support the feasibility of smoking treatment for this population and provide information regarding appropriate treatment components OBJECTIVE To evaluate a peer counseling intervention for pregnant smokers . METHODS One hundred forty-two pregnant , predominantly Hispanic women were assigned to a peer-led smoking cessation program or to usual care . RESULTS Compared with usual care , peer counseling reduced smoking ( −9.1 versus −4.5 cigarettes daily , P = .03 ) , but did not affect absolute quit rates ( 24 % versus 21 % ) at 36 weeks ' gestation . Infant birth weight negatively correlated with cigarettes smoked per day ( r = −0.29 , P < .01 ) and expired carbon monoxide ( r = −0.39 , ( P < .001 ) at delivery . Birth weight for infants born to women who quit smoking averaged 7.2 lb versus 6.8 and 6.3 lb for mothers smoking one to six and more than six cigarettes per day at delivery ( P < .01 ) . CONCLUSION Peer counseling reduced the number of cigarettes smoked daily but did not increase cigarette abstinence rates . Infant birth weight increases with both smoking cessation and smoking reduction , suggesting that peer counseling intervention programs may improve newborn health despite their failure to affect smoking cessation Periodic health examinations are an excellent opportunity to counsel smokers to quit . The impact of a specialized smoking cessation counselor on the smoking behavior of patients having periodic health examinations was studied in a general internal medicine practice . One hundred fifty-five smokers having periodic health examinations were r and omly assigned to a control group who received usual physician advice or an intervention group who received usual physician advice and two counseling sessions with a smoking cessation counselor . The two groups were similar in all demographic variables , smoking-related baseline variables , and baseline levels of motivation and intention to quit smoking . The smoking status of 97 % of the subjects was assessed 6 months later . In the intervention group , 46 % made quit attempts and 19 % quit , compared with 34 % and 12 % , respectively , in the control group . Intervention-group smokers made more quit attempts ( mean + /- SD , 5.0 + /- 2.5 vs 1.8 + /- 0.2 ) and had a greater reduction in daily cigarette use ( 8.4 + /- 1.5 vs 3.5 + /- 1.3 ) . Of the 74 % of smokers with higher levels of motivation to quit smoking , more intervention-group smokers attempted to quit ( 70.8 % vs 45.5 % ) and succeeded in quitting at the 6-month follow-up ( 27.1 % vs 10.9 % ) . Periodic health examinations are an excellent opportunity to counsel smokers to quit , especially those smokers with higher levels of motivation to quit smoking In Japan , the prevalence of smoking among males and females was 56.1 % and 14.2 % , respectively , in 1997 . Male smoking prevalence was exceedingly high as compared to those in other industrialized countries . We conducted a r and omized controlled intervention study on smoking cessation for all smokers in a worksite regardless of their willingness to quit smoking . All of the male smokers in a radiator manufacturing factory ( n=263 ) were r and omly allocated to an intervention group ( n=132 ) or a control group ( n=131 ) . Subjects in the intervention group received individual counseling by a doctor , and those who signed a Smoking Cessation Declaration underwent a five-month intervention . Subjects in the control group received equivalent delayed intervention for four months . The cessation rate after the original intervention was 12.9 % ( 17/132 ) and 3.1 % ( 4/131 ) in the intervention and control groups , respectively ( p=0.003 ) . Among those who once succeeded in quitting , 48.6 % ( 18/37 ) maintained cessation at the long-term survey . Overall , the cessation rate was 8.4 % ( 22/263 ) and the prevalence of smoking among males significantly decreased from 62.9 to 56.7 % ( p=0.038 ) . As a conclusion , intervention in all smokers at a worksite regardless of their willingness to quit is effective and impacts the overall smoking rate Aims : To assess the effectiveness of a smoking cessation intervention at the workplace . The intervention was adapted to smokers ‘ tobacco dependence , and included minimal structured counselling at the first visit ( 5–8 minutes ) , nicotine patches for three months , and three sessions of counselling for reinforcement of abstinence ( 2–3 minutes ) over a three month period . Methods : Open r and omised trial with two groups : the intervention group , and the control group which was subjected to st and ard clinical practice , consisting of short ( 30 seconds to one minute ) sporadic sessions of unstructured medical antismoking advice . The trial was carried out among 217 smokers of both sexes , aged 20–63 years , motivated to quit smoking and without contraindications for nicotine patches , who were employees at a public transport company and at two worksites of an electric company . The main outcome measure was self reported tobacco abstinence confirmed by carbon monoxide in expired air ≤10 ppm . Analysis was performed according to intention-to-treat . Results : The rate of continuous abstinence at 12 months was 20.2 % for the intervention versus 8.7 % for the control group ( OR : 2.58 ; 95 % CI : 1.13 to 5.90 ; p = 0.025 ) . In subgroup analyses , effectiveness of the intervention did not vary substantially with age , tobacco dependence , number of cigarettes smoked per day , number of years of tobacco consumption , degree of desire to quit smoking , time spent with smokers , subjective health , and presence of tobacco related symptoms . Weight gain at 12 months was similar for both groups ( 1.69 kg in the intervention v 2.01 kg in the control group ; p = 0.21 ) . Conclusions : A simple and easily generalisable intervention at the workplace is effective to achieve long term smoking cessation . In a setting similar to ours , nine subjects would have to be treated for three months for one to achieve continuous abstinence for 12 months OBJECTIVE To evaluate the effectiveness of a nurse-managed smoking cessation intervention in diabetic patients . RESEARCH DESIGN AND METHODS This r and omized controlled clinical trial involved 280 diabetic smokers ( age range 17 - 84 years ) who were r and omized either into control ( n = 133 ) or intervention ( n = 147 ) groups at 12 primary care centers and 2 hospitals located in Navarre , Spain . The intervention consisted of a 40-min nurse visit that included counseling , education , and contracting information ( a negotiated cessation date ) . The follow-up consisted of telephone calls , letters , and visits . The control group received the usual care for diabetic smokers . Baseline and 6-month follow-up measurements included smoking status ( self-reported cessation was verified by urine cotinine concentrations ) , mean number of cigarettes smoked per day , and stage of change . RESULTS At the 6-month follow-up , the smoking cessation incidence was 17.0 % in the intervention group compared with 2.3 % in the usual care group , which was a 14.7 % difference ( 95 % CI 8.2 - 21.3 % ) . Among participants who continued smoking , a significant reduction was evident in the average cigarette consumption at the 6-month follow-up . The mean number of cigarettes per day decreased from 20.0 at baseline to 15.5 at 6 months for the experimental group versus from 19.7 to 18.1 for the control group ( P < 0.01 ) . CONCLUSIONS A structured intervention managed by a single nurse was shown to be effective in changing the smoking behavior of diabetic patients OBJECTIVE To compare the efficacy and safety of 22-mg and 44-mg doses of transdermal nicotine therapy when it is paired with minimal , individual , or group counseling to improve smoking cessation rates . DESIGN An 8-week clinical trial ( 4 weeks double-blind followed by 4 weeks open label ) using r and om assignment of participants to both dose ( 22 or 44 mg ) and counseling ( minimal , individual , or group ) conditions . PARTICIPANTS Daily cigarette smokers ( > or = 15 cigarettes per day for at least 1 year ) who volunteered to participate in a study of smoking cessation treatment . A total of 504 participants were enrolled at two sites . INTERVENTION Four weeks of 22- or 44-mg transdermal nicotine therapy followed by 4 weeks of dosage reduction ( 2 weeks of 22 mg followed by 2 weeks of 11 mg ) . Counseling consisted of a self-help pamphlet ( minimal ) ; a self-help pamphlet , a brief physician motivational message , and three brief ( < 15 minutes ) follow-up visits with a nurse ( individual ) ; or the pamphlet , the motivational message , and eight weekly 1-hour group smoking cessation counseling visits ( group ) . All participants returned weekly to turn in question naires and for assessment of their smoking status . MAIN OUTCOME MEASURES Abstinence from smoking was based on self-report , confirmed by an expired carbon monoxide concentration lower than 10 ppm . Withdrawal severity was assessed by means of an eight-item self-report question naire completed daily . RESULTS Smoking cessation rates for the two nicotine patch doses and three levels of counseling did not differ significantly at either 8 weeks or 26 weeks following the quit date . Among those receiving minimal contact , the 44-mg dose produced greater abstinence at 4 weeks than did the 22-mg dose ( 68 % vs 45 % ; P < .01 ) . Participants receiving minimal-contact adjuvant treatment were less likely to be abstinent at the end of 4 weeks than those receiving individual or group counseling ( 56 % vs 67 % ; P < .05 ) . The 44-mg dose decreased desire to smoke more than the 22-mg dose , but this effect was not related to success in quitting smoking . Transdermal nicotine therapy at doses of 44 mg produced a significantly greater frequency of nausea ( 28 % ) , vomiting ( 10 % ) , and erythema with edema at the patch site ( 30 % ) than did a 22-mg dose ( 10 % , 2 % , and 13 % , respectively ; P < .01 for each adverse effect ) . Three serious adverse events occurred during use of the 44-mg patch dose . CONCLUSIONS There does not appear to be any general , sustained benefit of initiating transdermal nicotine therapy with a 44-mg patch dose or of providing intense adjuvant smoking cessation treatment . The two doses and all adjuvant treatments produced equivalent effects at the 26-week follow-up , and the higher patch dose produced more adverse effects . Higher-dose ( 44-mg ) nicotine replacement does not appear to be indicated for general clinical population s , although it may provide short-term benefit to some smokers attempting to quit with minimal adjuvant treatment AIMS To assess the effects of a smoking cessation program for recovering alcoholics on use of alcohol , tobacco and illicit drugs after discharge from residential treatment . DESIGN AND SETTING A r and omized community intervention trial design was employed in which 12 residential drug treatment centers in Iowa , Kansas and Nebraska were matched and then r and omly assigned to the intervention or control condition . PARTICIPANTS Approximately 50 adult residents ( in patients ) from each site were followed for 12 months after treatment discharge . INTERVENTION Participating residents in the six intervention centers received a 4-part , individually tailored , smoking cessation program while those in the six control sites received usual care . FINDINGS Both moderate and heavy drinking rates were reduced in the intervention group . Intervention site participants were significantly more likely than controls to report alcohol abstinence at both the 6-month ( OR = 1.59 , 95%CI : 1.09 - 2.35 ) and 12-month assessment ( OR = 1.84 , 95%CI : 1.28 - 2.92 ) . Illicit drug use rates were comparable . Effect of the intervention on tobacco quit rates was not statistically significant . CONCLUSIONS Counseling alcoholics in treatment to quit smoking does not jeopardize the alcohol recovery process . However , low-intensity tobacco interventions are unlikely to yield high tobacco quit rates Background —Although men hospitalized with cardiovascular disease ( CVD ) show high smoking-cessation rates , similar data for women are lacking . We tested the efficacy of smoking-cessation intervention in women hospitalized for CVD . Methods and Results —In this r and omized controlled trial conducted from 1996 to 2001 , 277 women diagnosed with CVD ( mean age 61±10 years ) were r and omly assigned within 1 of 12 San Francisco Bay Area hospitals to a usual-care group ( UG ; n=135 ) or intervention group ( IG ; n=142 ) . Baseline histories were obtained , and interviews to ascertain self-reported smoking status occurred at 6 , 12 , 24 , and 30 months after hospitalization . The UG received strong physician ’s advice , a self-help pamphlet , and a list of community re sources . The IG received strong physician ’s advice and a nurse-managed cognitive behavioral relapse-prevention intervention at bedside , with telephone contact at intervals after discharge . The groups were similar demographically and had smoked cigarettes for a median of 38 ( IG ) or 40 ( UG ) years . Time to resumption of continuous smoking was assessed by Kaplan-Meier analysis , and risk differences between groups were determined . Time smoke-free was significantly greater for the IG than the UG ( P = 0.038 ) . Point prevalence for nonsmoking at the interviews was somewhat greater for the IG than the UG ( P > 0.15 at all times ) . Conclusions —Cognitive behavioral intervention result ed in longer average times to resumption of smoking , but in these 2 groups of older women with limited social and financial re sources , long-term success rates were similar . Systematic identification of smokers and even the brief intervention afforded the UG yielded a high smoking-cessation rate over time BACKGROUND Formal efforts to recruit smokers into cessation programs have failed to reach large segments of the smoking population . Telephone intervention may represent a viable strategy to promote smoking cessation . An even more promising approach may be a combination of brief telephone support and outreach to identified smokers . METHODS Telephone support for smoking cessation was provided to four identified smoker population s in Bloomington , Minn , one of three Minnesota Heart Health Program education communities . Smokers were r and omly assigned to an intervention consisting of two 15-minute telephone calls approximately 1 to 3 weeks apart or to a nonintervention control . RESULTS At the 6-month follow-up , a significant overall effect was found in favor of the intervention condition for both self-reported and cotinine-vali date d quitting . Differences between intervention and control conditions were no longer significant at 18 months . CONCLUSIONS Smokers ' receptivity to telephone intervention was at least moderately encouraging . The cost of intervention could be relatively low if trained volunteers initiated telephone calls . However , more intensive telephone intervention and support may be needed to produce lasting changes in smoking prevalence OBJECTIVES Previous research has documented that hospital-based smoking-cessation counseling is efficacious and cost-effective when delivered by research staff . This study evaluated the implementation and effectiveness of this intervention program when delivered by respiratory therapists chosen from the regular hospital staff . METHODS A total of 1,173 hospitalized smokers were r and omly assigned to either usual care or a stage-based bedside counseling program supplemented with a videotape , self-help material s , and a follow-up telephone call . RESULTS Using an intent-to-treat analysis and counting those lost to follow-up as smokers , we did not find a significant difference in outcome between intervention ( 14.2 % reported being abstinent for > or = 6 months at the 1-year follow-up ) and usual care conditions ( 13.6 % abstinence ) . Process analyses revealed that these results were due to a combination of failure to reach many patients and reduced effectiveness of respiratory therapist interventionists compared with experienced professional counselors in a previous study conducted in the same hospitals . CONCLUSIONS We recommend implementation of hospital-based smoking-cessation counseling by professional counselors whose primary responsibility is to deliver the intervention . Recommendations for future research and for innovative ways to reach hospitalized smokers who are not receiving intervention are discussed Seventy-four cigarette-smoking patients admitted with COPD to the Chest Unit of a 600-bed teaching hospital served as subjects for a r and omized trial of smoking cessation counseling . All patients were advised to quit smoking and smoking in the unit was not allowed . One-half of the patients were , in addition , provided with a self-help manual and three to eight 15- to 20-min counseling sessions on alternate days while in hospital . Self-reports of smoking status were obtained at 3 and 6 months , a sample of which were vali date d with serum COHb . The results were disappointing . Differences between the counseled group and the controls both in rates of cessation at 6 months ( 33.3 % vs 21.4 % ) and , for patients still smoking , reductions in amount smoked would have lacked practical significance even if statistical significance had been obtained . Some alternative treatment approaches are suggested for this group of patients Predictors of smoking behavior change were examined in a r and omized controlled trial of individualized smoking cessation counseling delivered by a smoking cessation counselor during periodic health examination . Self-reports of not smoking at 6 and 18 months and attempts to quit were greater , but not significantly so , in the intervention group compared with the usual care group . There was no difference between the intervention group and the usual care group in reported continuous abstinence . Multivariate analysis showed that longer periods of abstinence in the past and having smoking identified as the main problem were important predictors of subsequent quitting . Having fewer other smokers in the household , stronger intentions to stop smoking in the next month , and being in the intervention group were also significant predictors of abstinence at 6 months , but not at 18 months . Those who had tried to quit by 6 months and 18 months were more likely to be in the intervention group , to have greater motivation to stop smoking , and to have more problems of daily living . Supplementing physician 's advice with individualized smoking cessation counseling during health maintenance examinations was associated with a greater short-term quit rate and more quit attempts over 18 months than physician advice alone , but did not influence continuous abstinence from cigarettes over this time BACKGROUND Hospitalization may be an opportune time to change smoking behavior because it requires smokers to abstain from tobacco at the same time that illness can motivate them to quit . A hospital-based intervention may promote smoking cessation after discharge . METHODS We tested the efficacy of a brief bedside smoking counseling program in a r and omized controlled trial at Massachusetts General Hospital , Boston . The 650 adult smokers admitted to the medical and surgical services were r and omly assigned to receive usual care or a hospital-based smoking intervention consisting of ( 1 ) a 15-minute bedside counseling session , ( 2 ) written self-help material , ( 3 ) a chart prompt reminding physicians to advise smoking cessation , and ( 4 ) up to 3 weekly counseling telephone calls after discharge . Smoking status was assessed 1 and 6 months after hospital discharge by self-report and vali date d at 6 months by measurement of saliva cotinine levels . RESULTS One month after discharge , more intervention than control patients were not smoking ( 28.9 % vs 18.9 % ; P=.003 ) . The effect persisted after multiple logistic regression analyses adjusted for baseline group differences , length of stay , postdischarge smoking treatment , and hospital readmission ( adjusted odds ratio , 2.19 ; 95 % confidence interval , 1.34 - 3.57 ) . At 6 months , the intervention and control groups did not differ in smoking cessation rate by self-report ( 17.3 % vs 14.0 % ; P=.26 ) or biochemical validation ( 8.1 % vs 8.7 % ; P=.72 ) , although the program appeared to be effective among the 167 patients who had not previously tried to quit smoking ( 15.3 % vs 3.7 % ; P=.01 ) . CONCLUSIONS A low-intensity , hospital-based smoking cessation program increased smoking cessation rates for 1 month after discharge but did not lead to long-term tobacco abstinence . A longer period of telephone contact after discharge might build on this initial success to produce permanent smoking cessation among hospitalized smokers Hospitalization represents a teachable moment for quitting . The current study examined predictors of quitting among hospitalized smokers . Patients reported smoking history and demographic characteristics during in-hospital baseline interviews . Discharge diagnosis also was collected . Smoking status was ascertained in interviews at 7 days and at 12 months after discharge . A total of 2,350 patients in four Minneapolis and St. Paul ( Twin Cities ) , Minnesota , area hospitals participated in the study ; 1,477 patients who provided data at both follow-ups and whose 12-month self-report of quitting was corroborated by cotinine analysis of saliva sample s were included in the current analyses . Predictors of both short- and long-term abstinence in the multivariate analysis included smoking-related illness , age ( those who were older were more likely to be abstinent ) , stage of change ( precontemplators were least likely to quit , and those initially in action were most likely to quit ) , and time to first cigarette ( those who reported smoking within 5 min of awakening were least likely to quit ) . The predictors presented few surprises ; the most important finding may have been that the experience of hospitalization itself led to substantial long-term quitting for virtually all categories of hospitalized smokers Background : Many believe that smoking cessation programmes for Latinos should be tailored to the values and beliefs of the culture . However , r and omised studies of culturally appropriate smoking cessation interventions with Latinos are rare . Methods : Latino smokers ( n = 313 ) were r and omised to an intervention condition or a comparison group . The intervention was a three month programme based on social cognitive constructs and delivered in the smoker ’s home by trained lay health advisors , or promotores . Comparison group participants were referred to the California Smoker ’s Helpline in Spanish . Predictors of abstinence among all participants also were examined . Results : About one week post-intervention , vali date d ( carbon monoxide ) past week abstinence rates were more than twice as high in the intervention group ( 20.5 % ) than in the comparison ( 8.7 % ) ( p ≤ 0.005 ) . The pattern of results held for self reported abstinence , and after recoding dropouts to non-abstinence . The primary predictor of abstinence was number of cigarettes smoked per day at baseline , a common measure of addiction . Conclusions : The culturally appropriate intervention facilitated abstinence in Latino smokers , at least in the short term . Strengths and weaknesses of the study are discussed The purpose of this study was to determine the efficacy of hypnosis , health education , and behaviour modification programs for cigarette smoking cessation . A r and omized clinical trial comparing these three programs and a control group was conducted in 168 volunteers . Follow-up data three weeks after completion was available in 140 subjects . Each program showed significant reductions in reported cigarette consumption and serum thiocyanate levels , an indicator of long-term cigarette consumption , compared to entry and to the control group . However , there were no significant differences between the hypnosis , health education , or behaviour modification groups with respect to the proportion who reported quitting smoking , the number cigarettes smoked or change in serum thiocyanate levels . Reported cigarette consumption ascertained six months later again showed no significant differences between these three approaches . Factors such as subject age , age at starting cigarette smoking , educational level , marital status , spouse or partners smoking did not identify subgroups with differences between treatment responses . Thus , hypnosis , health education , and behaviour modification are each effective programs for changing cigarette smoking and each is equally effective in this regard A 2 × 2 r and omized , factorial pretest/posttest group design was used to evaluate the effectiveness of self-help smoking cessation methods at the worksite . The study investigated the effect of a multicomponent health education and skill intervention versus the effect of a monetary incentive to the employee for quitting . All employees received , in addition , a st and ardized self-help smoking cessation manual and maintenance manual . Following agreement to participate and a baseline smoking history , all participants were followed for 6 weeks , 6 months , and 12 months . Saliva was obtained for thiocyanate ( SCN ) analysis of smoking status . Of the estimated 2000 smokers at the site , 387 smokers were recruited . Employees were r and omly assigned to one of four groups . Results of this r and om trial indicate that those employees receiving a multicomponent program were most successful in quitting and remaining abstinent . The monetary incentive appears to have no effect on quit rate Several studies have tested the effectiveness of telephone counseling as a smoking cessation intervention , but few have addressed its application with the special population of smokers who are also problem drinkers or recovering alcoholics . Two hundred and eighty-eight male and female subjects were recruited from six residential alcohol treatment programs in Nebraska , Iowa , and Kansas to receive three postreatment telephone calls based on the stages of change model . Most subjects ( 71 % ) participated in at least one telephone counseling session , but only 38 % participated in all three . Those who completed of session were significantly ( p < .01 ) more likely to have advanced one stage of change in their readiness to quit smoking and to report having quit smoking for at least 24 hours since leaving treatment ( p < .01 ) . Stage-based telephone counseling appears to be a feasible approach to addressing smoking cessation among recovering alcoholics , with a modest positive effect on subsequent tobacco use OBJECTIVE Passive smoke exposure among children is widespread in the United States ; estimates suggest that almost 40 % of children who are younger than 5 years live with a smoker . Few r and omized studies of passive smoke exposure reduction among children have been conducted , and the impact of interventions that have been evaluated has been limited . The objective of this study was to determine whether a motivational intervention for smoking parents of young children will lead to reduced household passive smoke exposure . METHODS Project KISS ( Keeping Infants Safe From Smoke ) , a theory-driven exposure reduction intervention targeting low-income families with young children , was a r and omized controlled study in which participants -smoking parents/caregivers ( N = 291 ) who had children who were younger than 3 years and who were recruited through primary care setting s-were r and omly assigned to either the motivational intervention ( MI ) or a self-help ( SH ) comparison condition was used . Follow-up assessment s were conducted at 3 and 6 months . The MI condition consisted of a 30- to 45-minute motivational interviewing session at the participant 's home with a trained health educator and 4 follow-up telephone counseling calls . Feedback from baseline household air nicotine assessment s and assessment of the participant 's carbon monoxide level was provided as part of the intervention . Participants in the SH group received a copy of the smoking cessation manual , the passive smoke reduction tip sheet , and the re source guide in the mail . Household nicotine levels were measured by a passive diffusion monitor . RESULTS The 6-month nicotine levels were significantly lower in MI households . Repeated measures analysis of variance across baseline , 3-month , and 6-month time points showed a significant time-by-treatment interaction , whereby nicotine levels for the MI group decreased significantly and nicotine levels for the SH group increased but were not significantly different from baseline . CONCLUSIONS This study targeted a large sample of racially and ethnically diverse low-income families , in whom both exposure and disease burden is likely to be significant . This is the first study to our knowledge that has been effective in reducing objective measures of passive smoke exposure in households with healthy children . These findings have important implication s for pediatric health care providers , who play an important role in working with parents to protect children 's health . Providers can help parents work toward reducing household passive smoke exposure using motivational strategies and providing a menu of approaches regardless of whether the parents are ready to quit The authors evaluated whether completing a multi-item assessment of smoking craving ( the Question naire of Smoking Urges [ QSU ] ) promoted increases in smoking craving . A sample of 39 regular smokers was r and omly assigned to 1 of 3 manipulations ( each of 3 min duration ): ( a ) complete the QSU-Brief ( 10 items ) , ( b ) complete a noncraving question naire that was structurally identical to the QSU-Brief ( scale-based control ) , and ( c ) a time-based control . Participants responded to an oral question assessing their degree of craving immediately before and after the manipulations . Results indicated that the QSU did not promote increases in craving compared to the 2 control conditions . Despite continuing debate over the most appropriate self-report measure of craving , investigators who use the QSU-Brief can be reasonably sure that the scores that result are not biased due to reactivity effects The authors compared 9- , 16- , 26- , and 52-week outcomes for two r and omly assigned groups of nicotine-dependent subjects : 1 ) nicotine patch plus four smoking cessation sessions with a nurse-practitioner giving advice and instruction ( n = 36 ; moderate-intensity condition , MI ) ; or 2 ) the foregoing treatments plus 16 weekly individual cognitive/ behavioral relapse-prevention therapy sessions ( n = 33 ; high-intensity condition , HI ) . Patch completion rates were 69.7 % in the HI group and 55.6 % in the MI group ( NS ) . Self-reported abstinence rates at the four follow-up points were comparable for the two treatment groups ; HI : 39 % , 36 % , 36 % , and 36 % ; MI : 44 % , 28 % , 25 % , and 28 % , respectively . There was some indication that MI patients with high nicotine dependence had lower abstinence rates than highly dependent HI patients PURPOSE To determine whether an intensive cognitive-behavioral intervention begun during hospitalization when combined with transdermal nicotine replacement therapy is more effective than a minimal counseling intervention combined with transdermal nicotine replacement therapy in helping in patients to quit smoking . METHODS A total of 223 patients who smoked were enrolled in a hospital-based r and omized smoking cessation trial at the San Francisco Veterans Affairs Medical Center . One hundred and seven participants ( 48 % ) received intensive counseling and outpatient telephone follow-up ; 116 participants ( 52 % ) received minimal counseling . All study participants received 2 months of transdermal nicotine replacement therapy . We determined 6-month quit rates by self-report and measured saliva cotinine levels or obtained proxy reports to confirm self-reported smoking cessation at 12 months . Analyses adjusted for baseline differences in the distribution of coronary disease . RESULTS At 6 months , 35 % ( 36/103 ) of the intensive intervention group reported quitting , compared with 21 % ( 23/109 ) of the comparison group ( relative risk [ RR ] = 1.7 ; 95 % confidence interval [ CI ] : 1.1 to 2.7 ) . At 12 months , the self-reported quit rate was 33 % ( 33/99 ) in the intensive intervention group versus 20 % ( 21/103 ) in the comparison group ( RR = 1.7 ; 95 % CI : 1.1 to 2.7 ) . Based on biochemical or proxy confirmation , 29 % ( 30/102 ) in the intensive intervention group versus 20 % ( 21/107 ) in the comparison group quit smoking at 12 months ( RR = 1.6 ; 95 % CI : 0.96 to 2.5 ) . CONCLUSION Hospital-initiated smoking cessation interventions that include transdermal nicotine replacement therapy can improve long-term quit rates A r and omized clinical trial assessed the effectiveness of control , low-intensity , and high-intensity stop-smoking treatments in a Department of Veterans Affairs outpatient setting . The study actively recruited male cigarette smokers attending outpatient clinics at a university-affiliated Veterans Affairs medical center . Subjects in the control group received an informational leaflet on smoking . Subjects in the low-intensity treatment group received a self-help booklet and a 20- to 30-minute session with a trained counselor . Subjects in the high-intensity group received the low-level treatments and individually tailored follow-up treatments provided in person , over the telephone , and through the mail . At least 6 months after r and omization or last treatment , biochemically verified 1-month quit-smoking rates were 1.2 % in 173 control subjects , 6.3 % in 143 low-intensity treated subjects , and 6.0 % in 150 high-intensity treated subjects . When rigorously defined , quit rates in each of the treated groups differed significantly from the control rate , but not from each other . The results demonstrated the effectiveness of moderately intensive stop-smoking treatments in a clinical setting of considerable interest , but not the incremental effectiveness of progressively more intensive treatments OBJECTIVES This study evaluated the cost-effectiveness of a smoking cessation and relapse-prevention program for hospitalized adult smokers from the perspective of an implementing hospital . It is an economic analysis of a two-group , controlled clinical trial in two acute care hospitals owned by a large group-model health maintenance organization . The intervention included a 20-minute bedside counseling session with an experienced health counselor , a 12-minute video , self-help material s , and one or two follow-up calls . METHODS Outcome measures were incremental cost ( above usual care ) per quit attributable to the intervention and incremental cost per discounted life-year saved attributable to the intervention . RESULTS Cost of the research intervention was $ 159 per smoker , and incremental cost per incremental quit was $ 3,697 . Incremental cost per incremental discounted life-year saved ranged between $ 1,691 and $ 7,444 , much less than most other routine medical procedures . Replication scenarios suggest that , with realistic implementation assumptions , total intervention costs would decline significantly and incremental cost per incremental discounted life-year saved would be reduced by more than 90 % , to approximately $ 380 . CONCLUSIONS Providing brief smoking cessation advice to hospitalized smokers is relatively inexpensive , cost-effective , and should become a part of the st and ard of inpatient care OBJECTIVES The purpose of this study was to evaluate a brief smoking cessation intervention for women 15 to 35 years of age attending Planned Parenthood clinics . METHODS Female smokers ( n = 1154 ) were r and omly assigned either to advice only or to a brief intervention that involved a 9-minute video , 12 to 15 minutes of behavioral counseling , clinician advice to quit , and follow-up telephone calls . RESULTS Seventy-six percent of those eligible participated . Results revealed a clear , short-term intervention effect at the 6-week follow-up ( 7-day self-reported abstinence : 10.2 % vs 6.9 % for advice only , P < .05 ) and a more ambiguous effect at 6 months ( 30-day biochemically vali date d abstinence : 6.4 % vs 3.8 % , NS ) . CONCLUSIONS This brief , clinic-based intervention appears to be effective in reaching and enhancing cessation among female smokers , a traditionally underserved population The impact of a smoking cessation program on substance abuse in patients was investigated . Thirty-nine male veterans were r and omly assigned to stop-smoking ( n = 19 ) or wait-list conditions ( n = 20 ) , and followed up 3- and 6-months postdischarge . Compared to wait-list subjects , stop-smoking subjects were more likely to continue inpatient treatment at least 30 days following study enrollment and reported greater posttreatment reductions in cigarette nicotine delivery . Importantly , assessment s of postdischarge substance use and hospital readmission rates did not reveal any adverse effects from participation in the stop-smoking program This study tested the feasibility and efficacy of a brief smoking intervention for adolescents in a hospital setting . Forty adolescent patients were r and omized to receive either brief advice or a motivational interview , a nonconfrontational therapeutic intervention . Feasibility of brief smoking interventions with teen patients was supported by high rates of recruitment , retention , and quit attempts , and long periods of continuous abstinence . Although between-groups differences on smoking measures were not significant at 3-month follow-up , an effect size of h = .28 was noted . The sample showed significant decreases in smoking dependence and number of days smoked . Baseline stage of change , smoking rate , and depression were significant prospect i ve predictors of smoking outcome . Implication s for smoking intervention research with adolescents are discussed BACKGROUND Smoking cessation after myocardial infa rct ion ( MI ) has been associated with a 50 % reduction in mortality but in-hospital smoking cessation interventions are rarely part of routine clinical practice . METHODS One hundred cigarette smokers consecutively admitted during 1996 with MI were assigned to minimal care or to a hospital-based smoking cessation program . Intervention consisted of bedside cessation counseling followed by seven telephone calls over the 6 months following discharge . Primary outcomes were abstinence rates measured at 6 months and 1 year post-discharge . RESULTS At follow-up , 43 and 34 % of participants in minimal care and 67 and 55 % of participants in intervention were abstinent at 6 and 12 months . respectively ( P<0.05 ) . Abstinence rates were calculated assuming that participants lost to attrition were smokers at follow-up . Intervention and self-efficacy were independent predictors of smoking status at follow-up . Low self-efficacy combined with no intervention result ed in a 93 % relapse rate by 1 year ( P<0.01 ) . CONCLUSIONS A hospital-based smoking cessation program consisting of inpatient counseling and telephone follow-up substantially increases smoking abstinence 1 year after discharge in patients post-MI . Patients with low self-efficacy are almost certain to relapse without intervention . Such smoking cessation programs should be part of the management of patients with MI This gender-specific research study compares the relative effectiveness of two theory-based interventions targeting women who smoke . Women with coronary artery disease ( CAD ; n = 53 ) or CAD risk factors ( n = 107 ) were r and omly assigned to either coping-skills Relapse Prevention ( RP ) treatment or an educational/supportive treatment based on Health Belief Model ( HBM ) principles . RP was comparable , but not superior to HBM treatment , as indicated by the lack of differential smoking outcomes at 3 and 6 months . RP was more effective than HBM for women with low self-efficacy , as predicted . The presence of a smoking-related disease had a substantial effect on smoking status , in that the odds of being abstinent at 6 months were 2.2 times greater for non-diagnosed women when compared with CAD women . These findings indicate that more potent relapse prevention interventions are needed to increase cessation rates in women who smoke , especially those with established heart disease BACKGROUND Lack of interest has been cited as a reason not to offer cessation assistance to smokers , but research suggests that smokers accept treatments offered proactively . This study assessed acceptability , utilization , and effectiveness of free smoking cessation treatment among diverse primary care patients . METHOD Medical assistants invited 4174 adult smokers to participate . Enrollees ( 1869 ) self-selected or were assigned to receive free nicotine patch therapy alone or in combination with the Committed Quitters(R ) program , and for some , individual counseling . RESULTS In nearly 68 % of cases , patients accepted a treatment invitation ; 77 % of eligible smokers enrolled ; 85 % of these picked up free patches . Given a choice of treatments , 75 % of participants elected a psychosocial treatment in addition to patch therapy . Thirteen percent of treatment initiators achieved biochemically confirmed 7-day point-prevalence abstinence at 1 year , with no significant treatment effects . Minority patients showed greater initial interest but less utilization did than White patients . CONCLUSIONS Free , readily accessible smoking cessation treatment offered in primary care setting s was accepted and used by the majority of unselected smokers of diverse racial/ethnic origins . Psychosocial treatment components did not significantly increase abstinence rates . Barriers , rather than lack of interest , may keep minority smokers from using cessation treatments Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value , and for many such patients mortality reductions of about 25 % can be achieved . No important differences are clearly apparent among the benefits of different beta blockers , although some are more convenient than others ( or have slightly fewer side effects ) , and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit . If monitored , the side effects of long-term therapy are not a major problem , as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment . By contrast , although very early IV short-term beta blockade can definitely limit infa rct size , more reliable information about the effects of such treatment on mortality will not be available until a large trial ( ISIS ) reports later this year , with data on some thous and s of patients entered within less than 4 hours of the onset of pain . Our aim has been not only to review the 65-odd r and omized beta blocker trials but also to demonstrate that when many r and omized trials have all applied one general approach to treatment , it is often not appropriate to base inference on individual trial results . Although there will usually be important differences from one trial to another ( in eligibility , treatment , end-point assessment , and so on ) , physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related r and omized trials and not just a few particular trial results . Although most trials are too small to be individually reliable , this defect of size may be rectified by an overview of many trials , as long as appropriate statistical methods are used . Fortunately , robust statistical methods exist -- based on direct , unweighted summation of one O-E value from each trial -- that are simple for physicians to use and underst and yet provide full statistical sensitivity . These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another . ( Moreover , they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust . ) Their robustness , sensitivity , and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews BACKGROUND Cigarette smoking is the greatest cause of preventable mortality in the United States . Because most smokers would like to quit and most hospitals are smoke free , surgical admissions represent a window of opportunity for tobacco cessation interventions . METHODS A total of 324 patients ( 98 % men ) , aged 25 to 82 years , who were current smokers and who underwent noncardiac surgery were enrolled in a r and omized controlled trial at the Veterans Affairs Medical Center , San Francisco , Calif. One hundred sixty-eight participants ( 52 % ) received a multicomponent intervention design ed to increase self-efficacy and coping skills that included face-to-face in-hospital counseling , viewing a smoking cessation videotape , self-help literature , nicotine replacement therapy , and 3 months of telephone follow-up . One hundred fifty-six participants ( 48 % ) received self-help literature and brief counseling lasting 10 minutes . Serum or saliva cotinine levels were measured to confirm self-reported smoking cessation . RESULTS At 12 months of follow-up , the self-reported quit rate was 27 % among the intervention group and 13 % among the comparison group ( relative risk , 2.1 ; 95 % confidence interval , 1.2 - 3.5 ; P < .01 ) . Based on biochemical confirmation , 15 % of the intervention group , compared with 8 % of the comparison group , quit smoking at 12 months ( relative risk , 2.0 ; 95 % confidence interval , 1.0 - 3.9 ; P = .04 ) . CONCLUSIONS A smoking cessation intervention targeted at smokers hospitalized for noncardiac surgery can increase long-term quit rates . Surgical hospitalizations provide an opportunity to reach smokers who want to quit smoking |
13,605 | 18,458,282 | Clearly , factors other than low bone mass are important in identifying patients at elevated risk for osteoporotic fracture .
An increased risk for falling may explain why some factors are identified as risk factors for osteoporotic fractures independent of bone mineral density ( BMD ) ( for example , tricyclic antidepressants ) ( 6 ) .
Although imperfect , a strong and grade d relationship exists between DXA-determined BMD and future osteoporotic fracture in women and men ( 7 , 8) .
Additional important high-risk factors are physical inactivity , corticosteroid use , and | Osteoporosis in men is substantially underdiagnosed and undertreated in the United States and worldwide ( 1 ) .
Looker and colleagues ( 2 ) , evaluating the Third National Health and Nutrition Examination Survey data base in 1997 , estimated that between 300000 and 2 million Americans older than age 50 years have osteoporosis and up to 13 million may have low bone mass .
A 60-year-old white man has a 25 % lifetime risk for an osteoporotic fracture ( 3 ) , and the consequences of the fracture can be severe .
The 1-year mortality rate in men after hip fracture is twice that in women ( 1 ) .
Diagnostic evaluation and treatment of men at high risk for fracture remains low , despite the prevalence of this condition in men ( 1 , 4 ) .
Dual-energy x-ray absorptiometry ( DXA ) is the current gold st and ard test for diagnosing osteoporosis in people without a known osteoporotic fracture .
It is , however , an imperfect test , identifying less than one half of the people who progress to have an osteoporotic fracture .
The Rotterdam Study ( 7 ) reported that the incidence of vertebral and hip fracture approximately doubled for every SD decrease in BMD at the lumbar spine and femoral neck , respectively .
Furthermore , pharmacologic treatment of men with low DXA-determined BMD has been shown to decrease the risk for subsequent fractures ( 9 ) .
Some organizations have called for universal screening of older men with DXA testing ( 5 , 10 ) .
Although these universal DXA screening strategies would probably increase the diagnosis rate of undetected male osteoporosis , such strategies may not be cost-effective in all men .
In addition , DXA is not portable , requires a special technician , and is not readily available in many locales ( 5 , 1013 ) , and efforts to find a non-DXA test that is suitable for widespread use have not succeeded to date .
Our aims were to determine the risk factors for low BMDmediated osteoporotic fracture in men that could be used to help select patients for BMD testing and whether non-DXA screening tests could be reliably used to diagnose DXA-defined osteoporosis . | Previous epidemiological study has suggested that depression might be associated with low bone mass in Caucasian women . This has not been studied in Asian men . Mr. Os ( Hong Kong ) is the first , large , cohort study on osteoporosis in Asian men , and the current analysis deals with the association between depression and bone mass in this group . Data from the baseline examination of Mr. Os ( Hong Kong ) were used . Two thous and Hong Kong men aged 65 to 92 years were recruited from the community . Depression was diagnosed by face-to-face interview , using a vali date d Chinese version of the Geriatric Depression Scale ( GDS ) , with depression being defined as a cut-off score of 8 or more . Bone mineral density ( BMD ) of the lumbar spine , total hip and total body was measured by dual X-ray densitometry ( DEXA ) using the Hologic QDR-4500 W densitometer . Multiple regression was used to compare BMD in depressed and non-depressed subjects , controlling for confounding variables . In the study sample 8.5 % of men were found to be depressed , and the BMD at the total hip in these subjects was 2.1 % lower than in non-depressed subjects ( 95 % CI −0.13 to −4.1 ) , after adjustment for age , body weight , medical history , alcohol consumption , cigarette smoking , calcium intake , physical activity and antidepressant use . Depression was associated with a 1.4-fold ( 95 % CI 1.00 to 2.08 ) relative risk ( RR ) of being diagnosed with a T-score equal to or less than −1.0 ( low bone mass ) . We conclude that depression is associated with lower BMD ; however , to determine whether depression causes lower BMD or vice versa , we will need to await findings from future prospect i ve studies Osteoporosis is a significant health problem and contributor to disability and premature mortality among older men . Incidence rates for hip fracture have stabilized in women , but continue to increase in men . A major risk factor for hip fracture is bone mineral density level . The determinants of bone mineral density ( BMD ) are well defined in women , but not in men . The primary goal of the current research was to increase our underst and ing of the determinants of BMD of the proximal femur in a large community-based sample of older male volunteers . Eligibility requirements included age of 50 years or older , ambulatory , and not having undergone a bilateral hip replacement . Five hundred twenty-three men , mean mean age 66.6 years , met all eligibility requirements and participated in the Study of Osteoporotic Risk in Men or STORM . Information on demographics , medical history , anthropometry , leisure-time and occupational physical activity , muscular strength , cigarette smoking , alcohol consumption , dietary calcium intake , and medication use ( thiazide diuretics and glucocorticoids ) were obtained by question naire , interview , and examination , BMD of the proximal femur ( femoral neck , greater trochanter , and Ward 's triangle ) was measured by dual-energy X-ray absorptiometry using the Hologic QDR-1000 and QDR-2000 . The cross-sectional determinants of BMD included age , blond hair color , current body weight , thiazide diuretic use , historical physical activity , and quadriceps strength . Several variables commonly thought to be determinants of BMD were not related to BMD in this population of older men , including current cigarette smoking , alcohol consumption , current leisure-time physical activity , dietary calcium intake , vitamin D use , and caffeine intake . However , failure to find associations among BMD and some of the potential determinants may be due to lack of statistical power . Identification of the determinants of BMD could lead to the development of interventions aim ed at maximizing BMD in men and could potentially decrease the risk of hip fractures BACKGROUND Risedronate increases bone mineral density in elderly women , but whether it prevents hip fracture is not known . METHODS We studied 5445 women 70 to 79 years old who had osteoporosis ( indicated by a T score for bone mineral density at the femoral neck that was more than 4 SD below the mean peak value in young adults [ -4 ] or lower than -3 plus a nonskeletal risk factor for hip fracture , such as poor gait or a propensity to fall ) and 3886 women at least 80 years old who had at least one nonskeletal risk factor for hip fracture or low bone mineral density at the femoral neck ( T score , lower than -4 or lower than -3 plus a hip-axis length of 11.1 cm or greater ) . The women were r and omly assigned to receive treatment with oral risedronate ( 2.5 or 5.0 mg daily ) or placebo for three years . The primary end point was the occurrence of hip fracture . RESULTS Overall , the incidence of hip fracture among all the women assigned to risedronate was 2.8 percent , as compared with 3.9 percent among those assigned to placebo ( relative risk , 0.7 ; 95 percent confidence interval , 0.6 to 0.9 ; P=0.02 ) . In the group of women with osteoporosis ( those 70 to 79 years old ) , the incidence of hip fracture among those assigned to risedronate was 1.9 percent , as compared with 3.2 percent among those assigned to placebo ( relative risk , 0.6 ; 95 percent confidence interval , 0.4 to 0.9 ; P=0.009 ) . In the group of women selected primarily on the basis of nonskeletal risk factors ( those at least 80 years of age ) , the incidence of hip fracture was 4.2 percent among those assigned to risedronate and 5.1 percent among those assigned to placebo ( P=0.35 ) . CONCLUSIONS Risedronate significantly reduces the risk of hip fracture among elderly women with confirmed osteoporosis but not among elderly women selected primarily on the basis of risk factors other than low bone mineral density BACKGROUND The objective of this study was to examine the association of Joint National Committee ( JNC-V ) blood pressure and National Cholesterol Education Program ( NCEP ) cholesterol categories with coronary heart disease ( CHD ) risk , to incorporate them into coronary prediction algorithms , and to compare the discrimination properties of this approach with other noncategorical prediction functions . METHODS AND RESULTS This work was design ed as a prospect i ve , single-center study in the setting of a community-based cohort . The patients were 2489 men and 2856 women 30 to 74 years old at baseline with 12 years of follow-up . During the 12 years of follow-up , a total of 383 men and 227 women developed CHD , which was significantly associated with categories of blood pressure , total cholesterol , LDL cholesterol , and HDL cholesterol ( all P<.001 ) . Sex-specific prediction equations were formulated to predict CHD risk according to age , diabetes , smoking , JNC-V blood pressure categories , and NCEP total cholesterol and LDL cholesterol categories . The accuracy of this categorical approach was found to be comparable to CHD prediction when the continuous variables themselves were used . After adjustment for other factors , approximately 28 % of CHD events in men and 29 % in women were attributable to blood pressure levels that exceeded high normal ( > or = 130/85 ) . The corresponding multivariable-adjusted attributable risk percent associated with elevated total cholesterol ( > or = 200 mg/dL ) was 27 % in men and 34 % in women . CONCLUSIONS Recommended guidelines of blood pressure , total cholesterol , and LDL cholesterol effectively predict CHD risk in a middle-aged white population sample . A simple coronary disease prediction algorithm was developed using categorical variables , which allows physicians to predict multivariate CHD risk in patients without overt CHD Several osteoporosis risk instruments have been proposed to select women for bone densitometry , but no vali date d instruments are currently available for men . This study aims to address this deficiency by developing and validating a Male Osteoporosis Screening Tool ( MOST ) for Chinese men . Two thous and ambulatory men , aged 65 and above , were recruited from the general community in Hong Kong , and a cohort of 1,970 men with valid total hip and lumbar spine dual-energy X-ray absorptiometry ( DXA ) measurements was included in the current analysis . A 60 % r and om sample was selected as the training sample for developing the screening tool , and the remaining 40 % constituted the validation sample . Logistic regression and receiver operating characteristic ( ROC ) analysis were used to identify the simplest combination of risk factors to be included in the screening tool for predicting osteoporosis at the femoral neck , total hip , or lumbar spine . Body weight and quantitative ultrasound index ( QUI ) were found to contribute significantly to the area under the ROC curve ( AUC ) , yielding an AUC of 0.823 in the training sample . The result ing MOST had a sensitivity of 94 % and a specificity of 46 % when using a cutoff score of 3 . MOST had an AUC of 0.839 in the validation sample . The risk of osteoporosis was 1 % among those with MOST scores ≤2 , but 72 % among those with MOST scores > 7 . Using a cutoff of 3 , the negative predictive value was 97.5 % which suggests that the 42 % with MOST scores ≤3 may be accurately screened out as being without osteoporosis , thus saving two fifths of our DXA re sources . The positive predictive value was 72 % when using a cutoff of 7 , implying that MOST can not replace DXA for case-finding purpose s. Nevertheless , for re source allocation and patient satisfaction , it is prudent and economical to offer DXA screening first to the 6 % with MOST scores > 7 OBJECTIVE To examine prognostic factors and outcomes after hip fracture in men aged 60 years and older . DESIGN AND SETTING Cohort study of all men presenting to St George Hospital ( a 650-bed tertiary care centre ) with hip fractures in 1995 , recruited retrospectively from medical records and evaluated prospect ively at six and 12 months after fracture . PATIENTS 51 men aged 60 years or more ( and , for comparison , 51 age-matched women ) who presented with hip fracture not caused by high impact injuries or local bone disease . MAIN OUTCOME MEASURES Prognostic factors ( such as pre-existing illness and osteoporotic risk factors ) and outcome data ( such as fracture-related complications , mortality , and level of function as measured by the Barthel index of activities of daily living at six and 12 months postfracture ) . RESULTS Median age of the 51 men was 80 years ( interquartile range , 74 - 86 years ) ; four were aged under 70 years . Outcome assessment was possible for 41 men ( 80 % ) . Similar proportions of men and women came from institutions ( 32 % v. 28 % ) , and similar additional proportions required institutionalisation after discharge ( 18 % v. 14 % ) . Fracture-related complications affected similar proportions of men and women ( 30 % v. 32 % ) , and mean length of hospital stay was similar . Fourteen per cent of men died in hospital compared with only 6 % of women ( P = 0.06 ) . Men had more risk factors for osteoporosis ( P < 0.01 ) . Physical functioning ( measured by the Barthel index ) deteriorated significantly in men from 14.9 at baseline to 13.4 at six months ( P < 0.05 ) and 12.4 at 12 months ( P < 0.05 ) after fracture . CONCLUSION Compared with women , elderly men presenting with hip fracture have higher mortality and have more risk factors for osteoporosis . Like women with hip fracture , men are usually fragile , with pre-existing medical illness and fracture-related complications contributing to their overall poor outcomes Abstract : Quantitative ultrasound ( QUS ) measurement , a different approach to bone fragility assessment , has already been attempted in women with osteoporosis but rarely in men . In order to test its value and ability to identify osteoporotic men , a case – control prospect i ve study was conducted using the Lunar Achilles , a device that measures attenuation and velocity parameters . Broadb and ultrasound attenuation ( BUA ) , speed of sound ( SOS ) and stiffness index ( SI ) , a composite parameter , were assessed through the heel of 66 osteoporotic patients , and compared with the results in 35 controls . Patients had sustained a low-trauma fracture and /or had a lumbar and /or femoral bone mineral density ( BMD ) more than 2.5 SD below the young male reference value . As expected , all QUS parameters were statistically lower in patients , as were the dual-energy X-ray absorptiometry ( DXA ) measurements at the hip and lumbar spine . The two methods were compared for their ability to predict the risk of osteoporotic fractures . The odds ratios ( ORs ) , with their 95 % confidence limits , for fractures per 1 SD decrease were significant , especially for SOS and SI ( OR = 2.3 [ 1.4–3.6 ] and 2.1 [ 1.3 - 3.3 ] respectively ) and to a lesser extent for BUA ( 1.6 [ 1.0–2.4 ] ) . Our study suggests that QUS is associated with a history of low-trauma fracture in men ; sensitivity is , however , less than when results are compared with BMD measurements ( OR = 2.8 [ 1.6–5.0 ] and 3.4 [ 1.6–7.0 ] for lumbar spine and hip , respectively ) . Prospect i ve studies are required before QUS can be recommended for clinical use in male osteoporosis BACKGROUND The determinants of change in bone mineral density ( BMD ) have been well characterized in women but not in men . This prospect i ve study describes the patterns of BMD change at the hip and spine , incidence of osteoporosis , and modifiable predictors of bone loss in 507 ambulatory community-dwelling men aged 45 to 92 years . METHODS Bone mineral density was assessed at the hip and lumbar spine by dual-energy x-ray absorptiometry ( DEXA ) between 1988 and 1992 and again 4 years later . BMD change was examined both as a continuous and a dichotomous ( BMD loss vs no change/gain ) variable . Incidence of osteoporosis was evaluated based on t -scores . Data were analyzed in 2002 . RESULTS Annual BMD loss averaged 0.47 % at the total hip and 0.34 % at the femoral neck with an annual average of 0.22 % gain at the spine . The rate of BMD loss at the hip and incidence of osteoporosis increased significantly with age . The main predictors of BMD loss were age > /=75 years , baseline BMI < 24 kg/m(2 ) , 4-year weight loss of > /=5 % , current smoking , and physical inactivity . Moderate alcohol consumption showed some bone-sparing effect . Diuretic and calcium supplement use were not associated with bone loss . CONCLUSIONS Relatively healthy community-dwelling men lose bone with age , and men aged > /=75 years are particularly vulnerable . Potentially modifiable characteristics such as low body mass , weight loss , smoking , and physical inactivity were important predictors of bone loss and should be considered for the prevention of osteoporosis in men BACKGROUND Previous studies have shown that alendronate can increase bone mineral density ( BMD ) and prevent radiographically defined ( morphometric ) vertebral fractures . The Fracture Intervention Trial aim ed to investigate the effect of alendronate on the risk of morphometric as well as clinical ly evident fractures in postmenopausal women with low bone mass . METHODS Women aged 55 - 81 with low femoral-neck BMD were enrolled in two study groups based on presence or absence of an existing vertebral fracture . Results for women with at least one vertebral fracture at baseline are reported here . 2027 women were r and omly assigned placebo ( 1005 ) or alendronate ( 1022 ) and followed up for 36 months . The dose of alendronate ( initially 5 mg daily ) was increased ( to 10 mg daily ) at 24 months , with maintenance of the double blind . Lateral spine radiography was done at baseline and at 24 and 36 months . New vertebral fractures , the primary endpoint , were defined by morphometry as a decrease of 20 % ( and at least 4 mm ) in at least one vertebral height between the baseline and latest follow-up radiograph . Non-spine clinical fractures were confirmed by radiographic reports . New symptomatic vertebral fractures were based on self-report and confirmed by radiography . FINDINGS Follow-up radiographs were obtained for 1946 women ( 98 % of surviving participants ) . 78 ( 8.0 % ) of women in the alendronate group had one or more new morphometric vertebral fractures compared with 145 ( 15.0 % ) in the placebo group ( relative risk 0.53 [ 95 % Cl 0.41 - 0.68 ] ) . For clinical ly apparent vertebral fractures , the corresponding numbers were 23 ( 2.3 % ) alendronate and 50 ( 5.0 % ) placebo ( relative hazard 0.45 [ 0.27 - 0.72 ] ) . The risk of any clinical fracture , the main secondary endpoint , was lower in the alendronate than in the placebo group ( 139 [ 13.6 % ] vs 183 [ 18.2 % ] ; relative hazard 0.72 [ 0.58 - 0.90 ] ) . The relative hazards for hip fracture and wrist fracture for alendronate versus placebo were 0.49 ( 0.23 - 0.99 ) and 0.52 ( 0.31 - 0.87 ) . There was no significant difference between the groups in numbers of adverse experiences , including upper-gastrointestinal disorders . INTERPRETATION We conclude that among women with low bone mass and existing vertebral fractures , alendronate is well tolerated and substantially reduces the frequency of morphometric and clinical vertebral fractures , as well as other clinical fractures The Multiple Outcomes of Raloxifene Evaluation trial studied 7705 postmenopausal women with osteoporosis r and omized to placebo , or raloxifene 60 or 120 mg/d [ JAMA 282(1999 ) : 637 ] . This report assesses the efficacy of raloxifene on the long-term cumulative incidence new vertebral fractures through 4 yr . New vertebral fractures was assessed from radiographs taken at baseline , yr 2 - 4 . The primary analysis was the cumulative incidence of new vertebral fractures through 4 yr . A posthoc analysis compared the vertebral fracture risk in yr 4 alone with that observed in the first 3 yr . The 4-yr cumulative relative risks ( RR ) for one or more new vertebral fractures were 0.64 [ 95 % confidence interval ( CI ) 0.53 , 0.76 ] with raloxifene 60 mg/d and 0.57 ( 95 % CI 0.48 , 0.69 ) with raloxifene 120 mg/d . In yr 4 alone , raloxifene 60 mg/d reduced the new vertebral fracture risk by 39 % [ RR 0.61 ( 95 % CI 0.43 , 0.88 ) ] , which was not found to be significantly different from the RR observed in the first 3 yr in both raloxifene groups , irrespective of prevalent fracture status . The nonvertebral fracture risk was not significantly reduced [ RR 0.93 ( 95 % CI 0.81 , 1.06 ) ] . The safety profile after 4 yr was similar to that observed after 3 yr . Raloxifene 60 and 120 mg/d through 4 yr decreased the cumulative risk of new vertebral fractures in postmenopausal women with osteoporosis . The decreased vertebral fracture risk in yr 4 alone was not different from that observed in the first 3 yr Background : Osteoporosis in men is an important public health problem . Because of the tendency of the numbers of the elderly population to increase , and age-specific incidence of fractures , it is inevitable that the health burden due to fractures will increase . Chronic alcoholism is associated with other risk factors , such as poor nutrition , leanness , liver disease , malabsorption , vitamin D deficiency , hypogonadism , hemosiderosis , parathyroid dysfunction and tobacco use , and these may contribute to the pathogenesis of bone disease related to alcoholism . Chronic alcohol intake may reduce bone density , but can also increase bone density . It is well established that liver disease also induces bone density changes , thus it is difficult to distinguish the role of liver disease from that of alcohol itself in the bone alterations occurring in patients with chronic alcohol consumption . Chronic male alcoholics , not having liver cirrhosis were studied to assess the effect of chronic alcohol consumption on their bone mineral density . Methods : The study subjects comprised of 18 chronic heavy drinkers of more than 40 g of alcohol per day for at least 3 years and 18 age-matched controls who drank less than 20 g of alcohol per day . The serum and urinary parameters of bone and mineral metabolism were determined . The bone mineral density ( BMD ) was measured by dual-energy X-ray absorptiometry at four axial sites ( lumbar spine , femoral neck , Ward ’s triangle and trochanter ) . Results : The alcoholic and control patients drank an average of 97.6 g and 7.2 g of alcohol per day . Osteocalcin , a marker of bone formation , was slightly decreased in alcoholic patients , and deoxypyridinoline , a marker of bone resorption , was slightly increased , but the difference was not statistically significant ( p>0.05 ) . There were no differences between the two groups in the levels of free testosterone , estradiol , 25(OH ) vitamin D and parathyroid hormone . The Ward ’s triangle and trochanter BMDs of the femur were significantly lower in the alcoholics than the controls , and lumbar spine BMD was decreased in proportion to the total alcohol intake in the alcoholics ( r=−0.625 , p=0.01 ) . Conclusion : We suggest that chronic alcohol consumption induces low bone density in the femur Ward ’s triangle and trochanter . There was also a significant inverse correlation between the lumbar spine BMD and the total amount of alcohol consumed . Large scaled r and omized and prospect i ve studies are needed to clarify the pathogenesis of alcohol-induced osteoporosis Abstract : The aims of this study were to identify risk factors for hip fracture in men aged 50 years or more . We identified 730 men with hip fracture from 14 centers from Portugal , Spain , France , Italy , Greece and Turkey during the course of a prospect i ve study of hip fracture incidence and 1132 age-stratified controls selected from the neighborhood or population registers . The question naire examined aspects of work , physical activity past and present , diseases and drugs , height , weight , indices of co-morbidity and consumption of tobacco , alcohol , calcium , coffee and tea . Significant risk factors identified by univariate analysis included low body mass index ( BMI ) , low sunlight exposure , a low degree of recreational physical activity , low consumption of milk and cheese , and a poor mental score . Co-morbidity including sleep disturbances , loss of weight , impaired mental status and poor appetite were also significant risk factors . Previous stroke with hemiplegia , prior fragility fractures , senile dementia , alcoholism and gastrectomy were associated with significant risk , whereas osteoarthrosis , nephrolithiasis and myocardial infa rct ion were associated with lower risks . Taking medications was not associated with a difference in risk apart from a protective effect with the use of analgesics independent of co-existing osteoarthrosis and an increased risk with the use of anti-epileptic agents . Of the potentially ‘ reversible ’ risk factors , BMI , leisure exercise , exposure to sunlight and consumption of tea and alcohol and tobacco remained independent risk factors after multivariate analysis , accounting for 54 % of hip fractures . Excluding BMI , 46 % of fractures could be explained on the basis of the risk factors sought . Of the remaining factors low exposure to sunlight and decreased physical activity accounted for the highest attributable risks ( 14 % and 9 % respectively ) . The use of risk factors to predict hip fractures had relatively low sensitivity and specificity ( 59.6 % and 61.0 % respectively ) . We conclude that lifestyle factors are associated with significant differences in the risk of hip fracture . Potentially remediable factors including a low degree of physical exercise and a low BMI account for a large component of the total risk Background and aims : Osteoporosis is an important problem for men as well as women , but data and trials for male osteoporosis , prevalence , evaluation and prognosis are limited . There are insufficient r and omized placebo-controlled , multicenter trial data . The aim of this study was to determine the frequency of osteoporosis in patients admitted to the Division of Geriatric Medicine of Hacettepe University , to compare osteoporosis in men and women , and to determine risk factors , relations with social and cultural differences , body weight and functional status . Methods : A retrospective study was conducted from February 2002 through July 2003 . Participants were 783 female and 464 male patients aged 65 years and over . BMD measures were performed using dual-energy X-ray absorptiometry at femoral neck and lumbar spine . Data on calcium intake , history of fractures , smoking , alcohol habits , other possible risk factors , serum 25OH-Vitamin D and iPTH levels were obtained . Creatinine clearance was calculated with the Cockcroft-Gaut formula . Functional status was evaluated by geriatric evaluation scales . Results : 29.5 % of cases of osteoporosis were found in males ; 45.9 % of male patients had osteoporosis , 36.6 % had osteopenia . Risk factors for male osteoporosis were evaluated . Men with low body weight ( < 57 kg ) , BMI < 19 , physically inactive , and poorly educated men were significantly more osteoporotic . No relationships between 25OH-Vitamin D , iPTH levels , creatinine clearance , quality of life scales or osteoporosis were found . Conclusions : Geriatrists and internists should focus on male as well as female osteoporosis . Nutritional support and physical activity should be encouraged . Age over 65 is identified as a ma’pr risk factor . Every man over 65 years of age should undergo BMD testing for osteoporosis screening The bone mineral density ( BMD ) has been analyzed in 200 male patients divided in 4 groups of age as follows : ( A ) 40 - 49 , ( B ) 50 - 59 , ( C ) 60 - 69 , and ( D ) 70 years and above . BMD was measured by using the DEXA technique both in the ultradistal and mediodistal region of radius of the non-dominant side . In addition , the serum levels of testosterone ( Ts ) , dihydrotestosterone ( DHT ) and 17-beta estradiol ( E-2 ) have also been measured . The data obtained have shown that bone mineral density values are decreasing also in the males with advancing age , and the positive correlation ( p < 0.05 ) of BMD with the E-2 levels also tend to decrease . These results suggest the hypothesis that the true sexual hormones regulating the rhythm of osteogenesis may be the estrogens in the males , too Summary Quantitative ultrasound ( QUS ) is associated with fracture risk in women , but there are few data in men . We studied 5,607 older men and found that QUS predicts hip and any non-spine fracture risk nearly as well as BMD . Combined measurements of QUS and BMD are not superior to either measurement alone . Introduction Quantitative ultrasound ( QUS ) predicts fracture risk among older women , but there are few prospect i ve studies among older men . We studied the ability of QUS and BMD measurements to predict hip and other non-spine fractures in a population -based study of older men . Methods Calcaneal QUS and hip BMD were measured in 5,607 men aged ≥65 years recruited from six US centers . At baseline duplicate QUS measurements with repositioning were obtained , and subsequent hip and other non-spine fractures were documented by review of x-rays or x-ray reports . The relationships between QUS and fractures were examined with proportional hazard models adjusted for age and clinic . We used receiver operating characteristic curves and predicted fracture risk models to determine the utility of QUS alone , BMD alone or the combination of QUS+BMD . Results During a mean follow-up of 4.2 years with 99 % complete follow-up , 239 men suffered a non-spine fracture , including 49 hip fractures . Each st and ard deviation reduction in broadb and ultrasonic attenuation ( BUA ) was associated with an increased risk of hip ( relative hazard=2.0 , CI : 1.5 , 2.8 ) and any non-spine fracture ( relative hazard=1.6 , CI : 1.4 , 1.8 ) . The area under the receiver operating characteristic curve and the predicted probability of fracture were similar for BUA alone , BMD alone and the combination of BUA+BMD , indicating that once BUA or BMD is known , the other measurement does not add useful information . Other QUS parameters gave similar results . Conclusions QUS measurements predict the risk of hip and any non-spine fracture in older men , and do so nearly as well as hip BMD measurements . Combined measurements of QUS and BMD are not superior to either measurement alone In order to evaluate the usefulness of calcaneal quantitative ultrasound ( QUS ) in the assessment of male osteoporosis , a cross-sectional , population -based study was performed . A cohort of 4,832 men , r and omly selected , community-dwelling , aged 60–80 years and representative of the general older male Italian population was recruited . QUS measurements were assessed in 83 centers distributed all over Italy and equipped with an Achilles device ( GE-Lunar , Madison , Wisconsin , USA ) . All participants were administered a question naire covering lifestyle variables and medical history . Low-energy fractures that had occurred since age 50 were recorded . Overall , 43 subjects reported a previous hip fracture and 455 subjects reported other non-spinal fractures . Univariate analysis showed that fractured subjects were older , with a lower level of outdoor physical activity and a more frequent history of prolonged bedridden periods in comparison with unfractured subjects . Men reporting non-spinal fractures showed a higher prevalence of smoking , while no difference was found among groups in anthropometric measures and calcium intake . QUS measurements showed that all QUS parameters were significantly lower in both fracture groups ( p < 0.001 ) . Multiple logistic regression analysis demonstrated that each SD reduction in QUS measures was associated with an approximate doubling of the risk for hip fracture , independent of age and other clinical variables ( broadb and ultrasound attenuation [ BUA ] : odds ratio [OR]=2.24 ; 95 % confidence interval [ CI ] 1.61–3.08 ; stiffness index : OR=2.19 ; CI 1.56–3.11 ; speed of sound [ SOS ] : OR=1.71 ; CI 1.18–3.24 ) and with an increase of the risk of other non-spinal fractures ( BUA : 1.38 ; CI 1.22–1.59 ; stiffness index : OR=1.27 ; CI 1.17–1.38 ; SOS : OR=1.14 ; CI 0.96–1.40 ) . It can be concluded that calcaneal QUS measurement is associated with the risk for hip fracture and any non-spinal fractures among a community-dwelling cohort of elderly men . The strength of the association between QUS measurement and fracture is similar to that observed in elderly women To examine the incidence of osteoporosis in patients with advanced prostate cancer ( using forearm densitometry ) before commencing and rogen deprivation therapy ( ADT ) , as osteoporotic fractures are more frequent in patients with prostate cancer who have undergone either medical or surgical castration , because of rapid loss of bone mass Study design : Cross-sectional study comparing a group of active spinal cord injured ( SCI ) males carefully matched for age , height , and weight with active able-bodied male controls . Objectives : To compare bone mass of the total body , upper and lower limbs , hip , and spine regions in active SCI and able-bodied individuals . Setting : Outpatient study undertaken in two centres in New Zeal and . Methods : Dual energy X-ray absorptiometry ( DEXA ) scanning was used to determine bone mass . Question naires were used to ascertain total time spent in weekly physical activity for each individual . The criterion for entry into the study was regular participation in physical activity of more than 60 min per week , over and above that required for rehabilitation . Results : Seventeen SCI and their able-bodied controls met our required activity criterion . Bone mineral density ( BMD ) values of the total body and hip regions were significantly lower in the SCI group than in their controls ( P=0.0001 ) . Leg BMD and bone mineral content ( BMC ) were also significantly lower in the SCI group ( P=0.0001 ) . By contrast , lumbar spine BMD and arm BMD and BMC did not differ between the SCI and control groups . Arm BMD and BMC were greater ( not significant ) than the reference norms ( LUNAR data base ) for both groups . Conclusion : Intensive exercise regimens may contribute to preservation of arm bone mass in SCI males , but does not prevent demineralisation in the lower body . Sponsorship : Funding provided by the DEXA Group Bone Health Dunedin , New Zeal and and The Lamar Trust , Christchurch , New Zeal and UNLABELLED We examined determinants of nonvertebral fracture in elderly men from six U.S. communities followed an average of 4.1 years . Six clinical risk factors predicted fracture risk independent of hip BMD : tricyclic antidepressant use , previous fracture , inability to complete a narrow walk trial , falls in previous year , age > or = 80 years , and depressed mood . INTRODUCTION There are few prospect i ve studies of fracture determinants in men . We examined the associations between a comprehensive set of clinical risk factors and risk of nonspine fracture in older men and whether determinants of fracture risk were independent of total hip BMD . MATERIAL S AND METHODS A total of 5995 men > or = 65 years of age were recruited from six communities in the Unites States and followed prospect ively for an average of 4.1 years . Baseline assessment s of demographic , lifestyle , medical history , functional status , anthropometry , and cognitive , visual , and neuromuscular function were assessed by question naire or examination . Triannual mailed question naires ascertained incident fracture ; reported fractures were adjudicated by physicians using medical records and X-ray reports . Proportional hazards models were used to develop multivariable models , selecting variables and controlling for BMD . RESULTS Of 5876 men , 4.7 % ( N = 275 ) reported an incident nonspine fracture during follow-up ( 11.46/1000 person-years ) . Tricyclic antidepressant use ( hazard ratio [ HR ] , 2.36 ; 95 % CI , 1.25 - 4.46 ) , history of fracture at or after age 50 ( HR , 2.07 ; 95 % CI , 1.62 - 2.65 ) , inability to complete a narrow walk trial ( HR , 1.70 ; 95 % CI , 1.23 - 2.34 ) , falls in previous year ( HR , 1.59 ; 95 % CI , 1.23 - 2.05 ) , age > or = 80 years ( HR , 1.33 ; 95 % CI , 1.01 - 1.76 ) , depressed mood ( HR , 1.72 ; 95 % CI , 1.00 - 2.95 ) , and decreased total hip BMD ( HR , 1.53 ; 95 % CI , 1.34 - 1.74 ) were independently related to increased risk . Compared with having none ( 48.0 % of men ) , having three or more of the clinical risk factors ( 4.9 % of men ) increased fracture risk 5-fold , independent of BMD . Having three or more risk factors and being in the lowest tertile of BMD was associated with a 15-fold greater risk than having no risk factors and being in the highest BMD tertile . CONCLUSIONS Several clinical risk factors were independently associated with nonspine fractures in elderly men . The combination of multiple risk factors and low BMD was a very powerful indicator of fracture risk Osteoporotic studies conducted exclusively in men have been limited by the discrepancies in defining densitometric osteoporosis and , also , because osteoporosis has traditionally been associated only with women . The aims of this study were to describe the prevalence of low bone mineral density ( BMD ) and osteoporotic fractures as well as the rate of bone loss . The analysis of some risk factors for accelerated bone loss was also evaluated . Men aged 50 years and over , r and omly selected from the Oviedo municipal register ( n=308 ) , completed a question naire regarding risk factors related to osteoporosis ; they underwent two lateral radiographs of the dorsal and lumbar spine and a dual X-ray absorptiometry ( DXA ) study at the lumbar spine and hip . In the 4th year of the follow-up period , participants were invited to undergo repeats of the same tests that had been carried out in the initial study . The prevalence of densitometric osteoporosis in men older than 50 years , st and ardized by age , was 8.1 % with regard to at least one of the four studied bone areas , with a slight increase with age . The prevalence of osteoporotic fracture , st and ardized by age , was 24.4 % , with a marked increase with age . Osteoporotic prevalent fracture was independently associated only with the rate of change in lumbar spine BMD . From all the osteoporotic risk factors analyzed , only low milk consumption and regular smoking were independently associated with loss of bone mass . In summary , prevalent osteoporotic fracture was independently associated with the rate of change in the lumbar spine BMD but not in the other segments studied . Avoiding smoking and ensuring an adequate milk intake might prevent the loss of bone mass in men Caucasians and Asians are among those with the highest risk for involutional osteoporosis . To obtain accurate data about the prevalence of osteoporosis or osteopenia in different age groups , a large epidemiological study is necessary . Quantitative ultrasound ( QUS ) of bone is a promising technique in assessing bone microarchitecture in addition to bone mass . This study had two aims . The first was to establish bone mineral density ( BMD ) using QUS in subjects with no obvious disease undergoing routine health examination . The second was to determine risk factors for osteoporosis in Taiwan in order that better prevention and treatment measures may be provided for these patients . A prospect i ve study of the risk factors for fracture was conducted in the health examination division of Chang Gung Medical Center in Linkou , Taiwan , from January 1996 to December 1997 . Broadb and ultrasound attenuation of the right heel was measured with an achilles bone densitometer ( Lunar , Nauheim , Germany ) . A total of 16,862 subjects were examined , including 9,314 women ( mean age 51.5+/-11.7 years ) and 7,548 men ( mean age 51.1+/-12.1 years ) . The incidence of osteoporosis in all subjects increased from 1.13 % in the 21 - -30-year-old age group to 54.55 % in those over 80 years of age . 12.02 % of the subjects had osteoporosis and 34.45 % had osteopenia . From multivariate analysis , bone density evaluated by QUS showed a relationship with age , gender , body mass index , waist/hip ratio , smoking and frequency of exercise . In conclusion , BMD evaluated by QUS is not found to be higher in Taiwan than elsewhere . The role of QUS in predicting fractures in Taiwan requires further investigation Tobacco exposure has been implicated as a risk factor for decreased bone density , which might result in osteoporosis . Cotinine , a metabolite of nicotine , is commonly used as a marker for tobacco exposure ( active or passive ) . The objective of the present study was to compare tobacco exposure with other predictive factors for low bone mineral content ( BMC ) , as determined by dual photon bone absorptiometry ( DXA ) in a national U.S. sample . Publicly available interview and clinical examination data from the Third National Health and Nutrition Examination Survey , 1988 - 1994 ( NHANES-III ) were used . Our data included 14,060 subjects from 19,528 r and omly selected representative U.S. households . Clinical laboratory data included serum values for calcium and cotinine . BMC was assessed radiologically by DXA at five proximal femur sites . BMC values were adjusted for age , as well as height , weight , and bone area to correct for bone and body size . We used t tests to compare continuous variables and chi-square tests to explore associations between categorical variables . Multivariate regression models were developed for each gender with appropriate covariates . Intertrochanter BMC explained the most variation ( highest R2 ) and was selected as the basis of the comparison . Serum cotinine had a significant inverse relationship to BMC in both males ( p = .0069 ) and females ( p = .0063 ) . Serum cotinine , as a marker for tobacco exposure , is a statistically significant risk factor for decreased BMC in both genders and should be included in multivariate regression models to predict low BMC There are few data exploring clustering of osteoporotic fractures within families . The aim of this study was to determine the influence of maternal and paternal history of hip fracture on the risk of vertebral deformity . 12,816 men and women aged 50 to 75 years were recruited from population based sampling frames across Europe . Subjects were invited to attend by letter of invitation for an interviewer administered question naire and lateral spinal radiographs . Vertebral deformity was defined morphometrically using the McCloskey-Kanis method . 6.4 % of men and 7.1 % of women reported that their mother had suffered a hip fracture , while 1.7 % of both men and women reported that their father had suffered a hip fracture . A maternal history of hip fracture was associated with a modest increased risk of vertebral deformity in men [ odds ratio ( OR ) 1.3 , 95 % confidence interval ( CI ) 1.0 - 1.8 ] , the risk being greater among those aged 65 years and over ( OR = 1.5 ; 95 % CI 1.0 - 2.4 ) and in those from low prevalence areas . There was no increased risk in women . Paternal history of hip fracture was not associated with vertebral deformity in either sex . In conclusion , maternal history of hip fracture appears to be a risk factor for vertebral deformity , particularly in men Quantitative ultrasound ( QUS ) can be used as a screening tool for low bone mineral density ( BMD ) , but clinical guidelines have not been set . The aim of this population -based , cross-sectional study was to compare age-related changes in bone mass measured by QUS ( Lunar , Achilles Plus ) and dual-energy X-ray absorptiometry ( DXA ) in a r and om sample of 1630 individuals ( 1041 females , 589 males ) 30 - 85 yr of age . Individuals with DXA T-scores < or = -2.5 at the femoral neck or total hip were identified and receiver operating curves ( ROCs ) were used to calculate cutoff points for QUS . Sensitivity , specificity , and kappa statistics were calculated . Age-related bone loss was significantly larger with QUS than DXA at all sites in women . For men , the curves were similar for QUS and DXA in the hip . Similar correlations were found between QUS and DXA in different age groups of both sexes ( 0.36 - 0.60 ) . For women aged 50 - 65 yr , a QUS T-score > -1.0 was found to be the most applicable for identifying normal BMD . In the 70 - 85 yr age group , a T-score < -2.5 for women and a T-score < -0.5 for men seemed reasonable cutoffs for identifying normal BMD ( sensitivity : 86 - 93 % ; specificity : 28 - 44 % ; discordance : 33 - 73 % ) . Calcaneal QUS can not be used for the diagnosis of osteoporosis according to WHO criteria , but it can be of use to exclude osteoporosis in 30 - 40 % of our cases Vertebral fractures are associated with osteoporosis . This study examined men and women with vertebral deformation/fractures , as defined by vertebral morphometry . These were compared with a population derived group measured contemporaneously who were defined as having no vertebral deformation/fracture by the radiographs . All patients underwent a dual energy X-ray absorptiometry ( DXA ) scan of the spine and hip , and a broadb and ultrasound attenuation ( BUA ) scan of their os calcis . The abilities of these two techniques were compared for their discriminatory powers in this type of fracture . The results showed that DXA hip and spine had a better discriminatory power in the female vertebral group compared with BUA . In males none of the bone measurements could discriminate between the fracture and non-fracture groups The influence of alcohol consumption on the risk of osteoporosis is not well established . The aim of this study was to determine the relationship between frequency of alcohol consumption and the risk of vertebral deformity across different European population s. A population survey method was used . Men and women aged 50 years and over were recruited from population -based sampling frames in 36 centres from 19 European countries . Subjects were invited to attend by letter of invitation for an interviewer-administered question naire and lateral spinal radiographs . Vertebral deformity was defined morphometrically using the McCloskey-Kanis method . Data from 14 237 individuals were available for this analysis . Alcohol consumption was compared between the 809 men and 884 women with vertebral deformity and the 5905 men and 6639 women without vertebral deformity . The frequency of alcohol intake was greater in men than women . Overall , there was no detectable association between frequency of alcohol intake and vertebral deformity in either men or women . Stratification by age showed that women 65 years and over who took alcohol on more than 5 days per week had a reduced risk of vertebral deformity compared with those taking alcohol less than once per week . This protection was most obvious after adjusting for age , centre , body mass index , smoking , current level of physical activity and previous fractures ( odds ratio [OR]=0.65 ; 95 % confidence intervals [CI]=0.43 , 0.99 ) . There was a smaller and non-significant protective effect amongst men aged 65 years and over and this was most apparent amongst moderately frequent drinkers ( 1–4 days per week ) ( OR=0.81 ; 95 % CI=0.62 , 1.08 ) . There was no association between the occurrence of vertebral deformity and frequency of alcohol consumption in younger men and women . Overall , the effects of the frequency of alcohol consumption on vertebral deformity were modest . In older women , regular consumption on more than 5 days per week is associated with a reduced risk . Further , prospect i ve data are required to confirm these findings . It is also necessary to investigate , in terms of amount of alcohol consumed , at what level the benefits of regular intake are obviated by the increased risks from alcohol excess The risk of MTHF in hypogonadal elderly men was investigated with a case-control model . Cases and controls were selected from males age 65 years and older residing in the 120-bed McGuire Veterans Affairs Medical Center Nursing Home Care Unit over a 5-day interval . Historical data and serum free testosterone ( fTe ) were available on 17 subjects with MTHF and 61 controls . When groups were compared for differences in age , race , alcohol abuse , cigarette abuse , and diseases or drugs that may be associated with MTHF , only race was significantly different . Although 25.6 % of residents were black , 100 % of MTHF subjects were white ( P = 0.004 ) . Hypogonadism was defined as a r and om fTe less than 9 pg/mL ( normal 9 to 46 pg/mL ) and was found in 21 subjects ( 26.9 % ) . Of cases with a MTHF , 58.8 % were hypogonadal compared with only 18.0 % of controls . Utilizing logistic regression , a highly significant association was found between hypogonadism and MTHF ( P = 0.008 ) , and using the odds ratio , subjects with hypogonadism were 6.5 times more likely to have a MTHF ( 95 % CI 2.0 to 20.6 ) . To adjust for race , the odds ratio was repeated excluding black subjects , and the results remained highly significant ( 4.6 , 95 % CI 1.3 to 16.2 ) . We conclude that hypogonadal elderly white men may be at increased risk for MTHF The authors prospect ively studied the association between quantity and type of alcohol intake and risk of hip fracture among 17,868 men and 13,917 women . Analyses were based on pooled data from three population studies conducted in 1964 - 1992 in Copenhagen , Denmark . During follow-up , 500 first hip fractures were identified in women and 307 in men . A low to moderate weekly alcohol intake ( 1 - 27 drinks for men and 1 - 13 drinks for women ) was not associated with hip fracture . Among men , the relative risk of hip fracture gradually increased for those who drank 28 drinks or more per week ( relative risk ( RR ) = 1.75 , 95 % confidence interval ( CI ) 1.06 - 2.89 for 28 - 41 drinks ; RR = 5.28 , 95 % CI 2.60 - 10.70 for 70 or more drinks ) as compared with abstainers . Women who drank 14 - 27 drinks per week had an age-adjusted relative risk of hip fracture of 1.44 ( 95 % CI 1.03 - 2.03 ) , but the association weakened after adjustment for confounders ( RR = 1.32 , 95 % CI 0.92 - 1.87 ) . The risk of hip fracture differed according to the type of alcohol preferred : preferrers of beer had a higher risk of hip fracture ( RR = 1.46 , 95 % CI 1.11 - 1.91 ) than preferrers of other types of alcoholic beverages . The corresponding relative risks for preferrers of wine and spirits were 0.77 ( 95 % CI 0.58 - 1.03 ) and 0.82 ( 95 % CI 0.58 - 1.14 ) , respectively . In conclusion , an alcohol intake within the current European drinking limits does not influence the risk of hip fracture , whereas an alcohol intake of more than 27 drinks per week is a major risk factor for men BACKGROUND Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia , but their effects on fractures are unknown . METHODS We r and omly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone ( 1 - 34 ) or placebo , administered subcutaneously by the women daily . We obtained vertebral radiographs at base line and at the end of the study ( median duration of observation , 21 months ) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry . RESULTS New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent , respectively , of the women in the 20-microg and 40-microg parathyroid hormone groups ; the respective relative risks of fracture in the 20-microg and 40-microg groups , as compared with the placebo group , were 0.35 and 0.31 ( 95 percent confidence intervals , 0.22 to 0.55 and 0.19 to 0.50 ) . New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group ( relative risk , 0.47 and 0.46 , respectively [ 95 percent confidence intervals , 0.25 to 0.88 and 0.25 to 0.861 ) . As compared with placebo , the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck ; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points . Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo . Parathyroid hormone had only minor side effects ( occasional nausea and headache ) . CONCLUSIONS Treatment of postmenopausal osteoporosis with parathyroid hormone ( 1 - 34 ) decreases the risk of vertebral and nonvertebral fractures ; increases vertebral , femoral , and total-body bone mineral density ; and is well tolerated . The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects The incidence of all non-vertebral fractures , as well as the relation to bone mineral density ( BMD ) , was quantified in 7806 men and women from the Rotterdam Study , a prospect i ve , population -based cohort study of men and women aged 55 years and older . In addition , the sensitivity of using a T-score at or below -2.5 for identifying subjects at risk for fractures was assessed . At baseline , between 1990 and 1993 , femoral neck BMD was measured by dual energy X-ray absorptiometry ( DXA ) . Subsequently , gender-specific T-scores were calculated using the NHANES reference population . During a mean follow-up of 6.8 years , information on incident non-vertebral fractures was gathered . In general , hip , wrist and upper humerus fractures are the most frequent fractures in both men and women . Femoral neck BMD appears to be an equally important risk factor in both genders , and is especially related to hip fractures . For all non-vertebral fractures , the age-adjusted hazard ratio ( 95 % confidence interval ) per st and ard deviation decrease in femoral neck BMD was 1.5 ( 1.4 - 1.6 ) for women and 1.4 ( 1.2 - 1.6 ) for men . For hip fractures , the hazard ratios were 2.1 ( 1.7 - 2.5 ) for women and 2.3 ( 1.6 - 3.3 ) for men . Only 44 % of all non-vertebral fractures occurred in women with a T-score below -2.5 ; in men , this percentage was even lower ( 21 % ) . Thus , there is a clear need for the development of more sensitive risk assessment tools , using not only BMD , but also other clinical predictors of fractures PURPOSE We wanted to develop and vali date a clinical prediction rule to identify men at risk for osteoporosis and subsequent hip fracture who might benefit from dual-energy x-ray absorptiometry ( DXA ) . METHODS We used risk factor data from the National Health and Nutrition Examination Survey III to develop a best fitting multivariable logistic regression model in men aged 50 years and older r and omized to either the development ( n = 1,497 ) or validation ( n = 1,498 ) cohorts . The best fitting model was transformed into a simplified scoring algorithm , the Male Osteoporosis Risk Estimation Score ( MORES ) . We vali date d the MORES , comparing sensitivity , specificity , and area under the receiver operating characteristics ( ROC ) curve in the 2 cohorts and assessed clinical utility with an analysis of the number needed-to-screen ( NNS ) to prevent 1 additional hip fracture . RESULTS The MORES included 3 variables — age , weight , and history of chronic obstructive pulmonary disease— and showed excellent predictive validity in the validation cohort . A score of 6 or greater yielded an overall sensitivity of 0.93 ( 95 % CI , 0.85–0.97 ) , a specificity of 0.59 ( 95 % CI , 0.56–0.62 ) , and an area under the ROC curve of 0.832 ( 95 % CI , 0.807–0.858 ) . The overall NNS to prevent 1 additional hip fracture was 279 in a cohort of men representative of the US population . CONCLUSIONS Osteoporosis is a major predictor of hip fractures . Experts believe bisphosphonate treatment in men should yield results similar to that in women and reduce hip fracture rates associated with osteoporosis . In men aged 60 years and older , the MORES is a simple approach to identify men at risk for osteoporosis and refer them for confirmatory DXA scans UNLABELLED Vertebral fractures are common but usually remain unrecognized in primary care . Data from 2908 women and 2653 men in the EPOS study were used to derive algorithms to indicate the need for a spine X-ray to identify a fracture using easily elicited determinants . At a sensitivity of 50 % for identifying cases , the specificity was increased from 50 % to 78 % in women and from 50 % to 72 % in men compared with a r and om allocation of X-rays . Use of X-rays can be optimized by selecting patients at high risk using a short screening procedure . INTRODUCTION Previous osteoporotic fracture is an independent risk factor for further fractures and an indication for treatment . Vertebral fractures are the most common osteoporotic fractures before age 75 , accounting for 48 % of all fractures in men and 39 % in women over 50 . They usually remain unrecognized , so many patients requiring treatment are denied it , doubling their risk of a further fracture . Our objective was to develop an efficient algorithm indicating the need for an X-ray . MATERIAL S AND METHODS Data from 2908 women and 2653 men > or=50 years of age in the European Prospect i ve Osteoporosis Study ( EPOS ) were analyzed . Lateral thoracic and lumbar spine radiographs were taken at baseline and at an average of 3.8 years later . Prevalent fractures were qualitatively diagnosed by an experienced radiologist . Fracture risk was modeled as a function of age , statural height loss since age 25 , gender , and fracture history including limb fractures in the last 3 years using negative binomial regression . Receiver operating characteristic ( ROC ) curves were used to summarize a model 's predictive ability , and a prediction algorithm was devised to identify those most likely to have a fracture . RESULTS In a multivariate model for women , the risk of prevalent vertebral fracture significantly increased with age ( RR , 1.67 [ 95 % CI , 1.46 , 1.93 ] per decade ) , statural height loss ( 1.06 , [ 1.03 , 1.10 ] per centimeter decrease ) , self-reported history of spine fracture ( 7.52 [ 5.52 , 10.23 ] ) , and history of other major fracture ( 1.83 [ 1.46 , 2.28 ] ) . Higher body weight reduced risk ( 0.86 [ 0.79 , 0.95 ] per 10-kg increase ) . In men , the respective RR estimates were as follows : age ( 1.32 [ 1.18 , 1.49 ] ) ; height loss ( 1.06 [ 1.04 , 1.09 ] ) ; self-reported spine fracture ( 5.05 [ 3.69 , 6.90 ] ) ; other major fracture ( 1.42 [ 1.12 , 1.81 ] ) ; and weight ( 0.86 [ 0.79 , 0.94 ] ) . Using algorithms based on these easily elicited determinants , specificity was increased from 50 % to 78 % in women and from 50 % to 72 % in men at a sensitivity of 50 % compared with a r and om allocation of X-rays . At a sensitivity of 75 % , the specificity was 50 % in women and 40 % in men . Inclusion of hip BMD ( femoral neck or trochanter ) , measured in 1360 women and 1046 men , significantly improved the area under the ROC curves by 4 % in women ( p < 0.002 ) but not in men ( p > 0.350 ) . Spine BMD , measured in 982 women and 847 men , produced a significant 5 % AUC improvement in women ( p = 0.007 ) but not in men ( p = 0.554 ) . CONCLUSION A woman 65 years of age with one vertebral fracture has a one in four chance of another fracture over 5 years , which can be reduced to one in eight by treatment . Positive treatment decisions are often contingent on identifying a vertebral fracture . Selective use of lateral vertebral X-rays can be optimized using a 2-minute screening procedure administered by a nurse |
13,606 | 11,405,965 | REVIEW ER 'S CONCLUSIONS Antibiotic treatment is effective in reducing the risk of pyelonephritis in pregnancy . | BACKGROUND Up to 30 % of mothers develop acute pyelonephritis if asymptomatic bacteriuria is untreated .
Asymptomatic bacteriuria may have a role in preterm birth or it may be a marker for low socioeconomic status which is associated with low birth weight .
OBJECTIVES The objective of this review was to assess the effect of antibiotic treatment for asymptomatic bacteriuria on persistent bacteriuria during pregnancy , the risk of preterm delivery , and the development of pyelonephritis . | The presence of group-B streptococci in the urine of pregnant women seems to be associated with preterm labour . Urine sample s from 4122 women at 27 - 31 weeks ' gestation were examined for bacteria . Group-B streptococci were found in the urine of 69 women . In a double-blind , controlled study these patients were given either penicillin ( 10(6 ) IU three times daily for 6 days ; 37 patients ) or placebo ( 32 patients ) . The rates of primary rupture of the membranes ( 11 % v 53 % ; p less than 0.001 ) and preterm labour ( 5.4 % v 38 % ; p less than 0.002 ) were significantly lower in the penicillin group than in the placebo group . These results suggest that treatment and follow-up to prevent recolonisation in pregnant women with group-B streptococci in the urine may reduce the frequency of preterm labour in these patients A total of 1,661 pregnant women aged between 13 and 45 years were screened for bacteriuria by urine culture . Of the 1,661 culture results , 615 ( 37 % ) yielded no growth ; 728 ( 43.8 % ) yielded no significant growth ( presence of < 10(5 ) organisms/ml urine of one or more types of bacteria ) ; 286 ( 17.2 % ) yielded mixed growth ( presence of > 10(5 ) organisms/ml urine of more than one type of bacteria ) and only 32 ( 1.9 % ) showed significant growth ( presence of > 10(5 ) organisms/ml urine of a single bacterium ) . Urine microscopy was also conducted . Two hundred and twenty-four ( 13.5 % ) specimens had > 10 white blood cells/ml urine , of which 66 had > 100 white blood cells ; 13 were from the significant growth group . Three hundred and seventy-four ( 22.5 % ) specimens showed the presence of bacteria , 42 ( 2.5 % ) had red blood cells , 370 ( 22.3 % ) had epithelial cells , 58 ( 3.5 % ) had crystals , and 14 ( 0.8 % ) had yeasts . The most common bacterium isolated was Escherichia coli ( 12 ; 40 % ) ; the others included group B Streptococcus ( 5 ; 15 % ) , Klebsiella spp ( 5 ; 15 % ) , Diphtheroids ( 2 ) , and C and ida albicans ( 2 ) . Fifty-two percent of tested strains were sensitive to ampicillin ; 24 of 28 strains ( 85.7 % ) were sensitive to ciprofloxacin ; all 7 strains tested were sensitive to nitrofurantoin and all 20 strains tested were sensitive to cotrimoxazole ; 14/20 ( 70 % ) and 16/17 ( 94.1 % ) were sensitive to cephalexin and cefuroxime respectively . This study shows that asymptomatic bacteriuria does occur in pregnant women , albeit at a very low rate in an urban setting like Cheras . Urine microscopy is not specific and only serves as a guide to bacteriuria . The commonest causative organisms are those from the gastrointestinal tract and vagina . The antibiogram showed that cefuroxime and cephalexin are likely to be effective in treating bacteriuria : ampicillin must be reserved for Gram-negative organisms . For Gram-positive organisms , of which Group B Streptococcus is important , ampicillin is still effective in vitro . Nitrofurantion and cotrimoxazole have excellent activity in vitro and should be considered for therapy . 17.2 % of the urine culture yielded mixed growth : likely to indicate that contamination of urine specimens still happens despite the strict instructions given to patients about the collection of a midstream urine specimen . Proper collection , appropriate transport , and the early processing of urine specimens remain essential Abstract Objective : To evaluate the performance of reagent test strips in screening pregnant women for asymptomatic bacteriuria at their first visit to an antenatal clinic . Design : Prospect i ve case series . Setting : Antenatal clinic of a large inner city maternity hospital . Subjects : All women attending for their first antenatal clinic . Patients taking antibiotics for any reason and those with urinary tract symptoms were excluded . Intervention : A midstream urine specimen was divided ; half was sent for microscopy and formal bacteriological culture and the other half was tested with a commercial reagent strip test for the presence of blood , protein , nitrite , and leucocyte esterase . Main outcome measures : Sensitivity , specificity , and positive and negative predictive values of the reagent strips in diagnosing asymptomatic bacteriuria ( defined as 105 colony forming units/ml urine ) . Results : Sensitivity was low , with a maximum of 33 % when all four tests were used in combination . Specificity was high , with typical values of 99 % or more . Positive predictive value reached a maximum of 69 % and negative predictive value was typically 95 % or more . Conclusion : Urine reagent strips are not sufficiently sensitive to be of use in the screening for asymptomatic bacteriuria and therefore many patients would be missed . In view of the potentially serious sequelae of this condition in pregnant women we recommend that formal bacteriological investigation remain the investigation of choice in this group of patients . Key messages Asymptomatic bacteriuria is a potentially serious clinical condition Early antenatal urine screening should identify all cases to ensure adequate treatment Commercially available reagent strips for testing urine do perform to a sufficient st and ard The cost savings associated with reagent strips can not be justified in this group of women All patients should have at least one urine specimen formally cultured in early pregnancy to exclude Pivmecillinam was given to 44 women with bacteriuria in pregnancy . Treatment was successful in 33 ( 87 % ) out of the 38 patients assessed . Thirty women subsequently received at r and om either a low-dose of pivmecillinam for up to three months or acted as a control group . Further bacteriuric episodes during pregnancy were recorded only in three patients in the control group . Thirty-nine out of the 41 women followed to term delivered healthy babies . One infant was stillborn and another child had a cleft palate . Neither was considered to be related to treatment with pivmecillinam The incidence of impaired renal concentrating ability in pregnant women with asymptomatic significant bacteriuria is significantly less than previously reported when osmolality readings are performed on every urine specimen obtained during the 24 hours ' deprivation of fluids . The concentrating defect is more considerable as pregnancy progresses . The lower the maximum urinary osmolality the more difficult is the treatment of the patient , and the higher the incidence of acute pyelonephritis Although it has been shown that bacteriuria of pregnancy can be eradicated by keeping patients on antibacterial agents throughout pregnancy [ 1 ] , this regimen of treatment would be unacceptable to most individuals , particularly when asymptomatic ; and there are many who would question the ethical justification for such prolonged antibacterial therapy in pregnancy . This paper presents the results of a study design ed to determine whether antibacterial therapy of limited duration would eradicate |
13,607 | 27,996,088 | Authors ' conclusions In areas where the prevalence of zinc deficiency or the prevalence of malnutrition is high , zinc may be of benefit in children aged six months or more .
The current evidence does not support the use of zinc supplementation in children less six months of age , in well‐nourished children , and in setting s where children are at low risk of zinc deficiency . | Abstract Background In developing countries , diarrhoea causes around 500,000 child deaths annually .
Zinc supplementation during acute diarrhoea is currently recommended by the World Health Organization ( WHO ) and the United Nations Children 's Fund ( UNICEF ) .
Objectives To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea . | Abstract Objective : To evaluate the effect of simultaneous zinc and vitamin A supplementation on diarrhoea and acute lower respiratory infections in children . Study design : R and omised double blind placebo controlled trial . Setting : Urban slums of Dhaka , Bangladesh . Participants and methods : 800 children aged 12 - 35 months were r and omly assigned to one of four intervention groups : 20 mg zinc once daily for 14 days ; 200 000 IU vitamin A , single dose on day 14 ; both zinc and vitamin A ; placebo . The children were followed up once a week for six months , and morbidity information was collected . Results : The incidence and prevalence of diarrhoea were lower in the zinc and vitamin A groups than in the placebo group . Zinc and vitamin A interaction had a rate ratio ( 95 % confidence interval ) of 0.79 ( 0.66 to 0.94 ) for the prevalence of persistent diarrhoea and 0.80 ( 0.67 to 0.95 ) for dysentery . Incidence ( 1.62 ; 1.16 to 2.25 ) and prevalence ( 2.07 ; 1.76 to 2.44 ) of acute lower respiratory infection were significantly higher in the zinc group than in the placebo group . The interaction term had rate ratios of 0.75 ( 0.46 to 1.20 ) for incidence and 0.58 ( 0.46 to 0.73 ) for prevalence of acute lower respiratory infection . Conclusions : Combined zinc and vitamin A synergistically reduced the prevalence of persistent diarrhoea and dysentery . Zinc was associated with a significant increase in acute lower respiratory infection , but this adverse effect was reduced by the interaction between zinc and vitamin A. What is already known on this topic Trials of vitamin A supplementation have failed to show a beneficial effect on morbidity in children Experimental studies have shown that , in the presence of zinc deficiency , vitamin A supplementation fails to reverse vitamin A deficiency Coexistence of deficiencies of zinc and vitamin A could be a reason for the failure of vitamin A supplementation , but data in humans are limited What this paper adds Combined zinc and vitamin A supplementation is more effective in reducing persistent diarrhoea and dysentery than either vitamin A or zinc alone Zinc alone increased respiratory illnesses , but interaction between zinc and vitamin A reduced this adverse OBJECTIVE . The purpose of this work was to evaluate whether education about zinc supplements and provision of zinc supplements to caregivers is effective in the treatment of acute diarrhea and whether this strategy adversely affects the use of oral rehydration salts . PATIENTS AND METHODS . Six clusters of 30 000 people each in Haryana , India , were r and omly assigned to intervention and control sites . Government and private providers and village health workers were trained to prescribe zinc and oral rehydration salts for use in diarrheal episodes in 1-month-old to 5-year-old children in intervention communities ; in the control sites , oral rehydration salts alone was promoted . In 2 cross-sectional surveys commencing 3 months ( survey 2 ) and 6 months ( survey 3 ) after the start of the intervention , care-seeking behavior , drug therapy , and oral rehydration salts use during diarrhea , diarrheal and respiratory morbidity , and hospitalization rates were measured . RESULTS . In the 2 surveys , zinc was used in 36.5 % ( n = 1571 ) and 59.8 % ( n = 1649 ) and oral rehydration salts in 34.8 % ( n = 1571 ) and 59.2 % ( n = 1649 ) of diarrheal episodes occurring in the 4 weeks preceding interviews in the intervention areas . In control areas , oral rehydration salts were used in 7.8 % ( n = 2209 ) and 9.8 % ( n = 2609 ) of episodes . In the intervention communities , care seeking for diarrhea reduced by 34 % ( survey 3 ) , as did the prescription of drugs of unknown identity ( survey 3 ) and antibiotics ( survey 3 ) for diarrhea . The 24-hour prevalences of diarrhea and acute lower respiratory infections were lower in the intervention communities ( survey 3 ) . All-cause , diarrhea , and pneumonia hospitalizations in the preceding 3 months were reduced in the intervention compared with control areas ( survey 3 ) . CONCLUSIONS . Diarrhea is more effectively treated when caregivers receive education on zinc supplementation and have ready access to supplies of oral rehydration salts and zinc , and this approach does not adversely affect the use of oral rehydration salts ; in fact , it greatly increases use of the same Objective Oral rehydration solution remains the mainstay of acute gastroenteritis therapy . The aim of this study was to investigate the acceptability of a new zinc-containing hypotonic super-oral rehydration solution ( ORS ) in a gel formulation and its efficacy in reducing the duration and severity of diarrhea in children . Methods This was a r and omized-controlled trial of children ( 5–36 months of age ) observed for diarrhea lasting less than 24 h. Children were r and omized to receive st and ard hypotonic ORS ( group 1 ) or a gel hypotonic super-ORS containing zinc ( group 2 ) . The main study outcome was ORS intake in the first 24 h. ORS intake at 4 h , rate of diarrhea resolution at 72 h of treatment , total duration and severity of diarrhea , hospitalization , and adverse effects were also evaluated . Results Eighty-three children were enrolled ( group 1 : 40 ; group 2 : 43 ) . The amount of ORS consumed at 24 h was significantly higher in group 2 than in group 1 . A similar result was observed at 4 h. The number of children who refused ORS ( < 10 ml/kg/day ) was lower in group 2 versus group 1 ( P=0.001 ) . The number of children presenting diarrhea after 72 h of treatment was lower in group 2 versus group 1 ( P=0.028 ) . Also , the mean duration of diarrhea was shorter in group 2 than in group 1 ( P=0.001 ) . The hypotonic super-ORS containing zinc in a gel formulation had a positive effect on the severity of diarrhea . No patient required hospitalization . No adverse events were observed in either of the two study groups . Conclusion The new zinc-containing hypotonic super-ORS in a gel formulation is effective in the management of childhood acute gastroenteritis Zinc supplementation is recommended in all acute diarrheas in children from developing countries . We aim ed to assess whether zinc supplementation would be equally effective against all the common organisms associated with acute diarrheas . We used data on 801 children with acute diarrhea recruited in a r and omized , double blind controlled trial ( IS RCT N85071383 ) of zinc and copper supplementation . Using prespecified subgroup analyses , multidimensionality reduction analyses , tests of heterogeneity , and stepwise logistic regression for tests of interactions , we found that the influence of zinc on the risk of diarrhea for more than 3 days depended on the isolated organism — beneficial in Klebsiella , neutral in Esherichia coli and parasitic infections , and detrimental in rotavirus coinfections . Although we found similar results for the outcome of high stool volume , the results did not reach statistical significance . Our findings suggest that the current strategy of zinc supplementation in all cases of acute diarrheas in children may need appropriate fine tuning to optimize the therapeutic benefit based on the causative organism , but further studies need to confirm and extend our findings Small-quantity lipid-based nutrient supplements ( SQ-LNS ) are promising home fortification products , but the optimal zinc level needed to improve growth and reduce morbidity is uncertain . We aim ed to assess the impact of providing SQ-LNS with varied amounts of zinc , along with illness treatment , on zinc-related outcomes compared with st and ard care . In a placebo-controlled , cluster-r and omized trial , 34 communities were stratified to intervention ( IC ) or non-intervention cohorts ( NIC ) . 2435 eligible IC children were r and omly assigned to one of four groups:1 ) SQ-LNS without zinc , placebo tablet ; 2 ) SQ-LNS containing 5 mg zinc , placebo tablet ; 3 ) SQ-LNS containing 10 mg zinc , placebo tablet ; or 4 ) SQ-LNS without zinc and 5 mg zinc tablet from 9–18 months of age . During weekly morbidity surveillance , oral rehydration salts were provided for reported diarrhea and antimalarial therapy for confirmed malaria . Children in NIC ( n = 785 ) did not receive SQ-LNS , tablets , illness surveillance or treatment . At 9 and 18 months , length , weight and hemoglobin were measured in all children . Reported adherence was 97±6 % for SQ-LNS and tablets . Mean baseline hemoglobin was 89±15g/L. At 18 months , change in hemoglobin was greater in IC than NIC ( + 8 vs -1g/L , p<0.0001 ) , but 79.1 % of IC were still anemic ( vs. 91.1 % in NIC ) . Final plasma zinc concentration did not differ by group . During the 9-month observation period , the incidence of diarrhea was 1.10±1.03 and of malaria 0.54±0.50 episodes per 100 child-days , and did not differ by group . Length at 18 months was significantly greater in IC compared to NIC ( 77.7±3.0 vs. 76.9±3.4 cm ; p<0.001 ) and stunting prevalence was significantly lower in IC ( 29.3 % ) than NIC ( 39.3 % ; p<0.0001 ) , but did not differ by intervention group within IC . Wasting prevalence was also significantly lower in IC ( 8.7 % ) than in NIC ( 13.5 % ; p = 0.0003 ) . Providing SQ-LNS daily with or without zinc , along with malaria and diarrhea treatment , significantly increased growth and reduced stunting , wasting and anemia prevalence in young children . Trial Registration Clinical Trials.gov In a double‐blind r and omized controlled clinical trial , moderately malnourished Bangladeshi children ( 61–75 % of the median weight/age ) were studied for the effect of zinc and /or vitamin A supplementation on the clinical outcome of persistent diarrhea . Children 6 mo to 2 y of age with diarrhea for more than 14 d were r and omly allocated into 4 groups of 24 receiving a multivitamin syrup and ( i ) zinc ( 20 mg elemental ) , ( ii ) vitamin A , ( iii ) both zinc and vitamin A , or ( iv ) neither , in 2 doses daily for 7 d. Clinical data on recovery and on stool output , consistency and frequency were recorded for 7 d , and weight change from day 1 to day 7 was assessed . The baseline characteristics of the four study groups were comparable . The mean daily stool outputs from days 2 to 7 of therapy were significantly less in the zinc and zinc plus vitamin A groups , but not in the vitamin A group , in comparison with the control group . In children receiving zinc , the cumulative stool weight in the 7 d was 39 % less than in the control group ( p < 0.001 ) and 32 % less than in the vitamin A group ( p= 0.006 ) . The cumulative stool weight in the zinc plus vitamin A group was 24 % less than in the control group ( p < 0.001 ) , but the 14 % lower output than in the vitamin A group was not statistically different The change in body weight over the 7d study period was significantly different between the group receiving zinc and the control group ( + 111 g vs –90 g , p = 0.045 ) . The rate of clinical recovery of children within 7 d was significantly greater in the zinc group ( 88 % ) compared with the control group ( 46 % , p= 0.002 ) or vitamin A group ( 50 % , p= 0 005 ) , but not statistically different from the zinc plus vitamin A group ( 67 % , p= 0.086 ) OBJECTIVE To evaluate the role of zinc and vitamin A supplementation in the recovery of Indigenous children hospitalised for acute diarrhoea . DESIGN A r and omised controlled 2 by 2 factorial trial of supplementation with zinc and vitamin A. SETTING AND PARTICIPANTS Aboriginal children ( aged < 11 years ) hospitalised for acute diarrhoea at Alice Springs Hospital , Northern Territory , April 2001-July 2002 . MAIN OUTCOME MEASURES Duration of diarrhoeal illness ; re-admission for diarrhoeal illness within 120 days . RESULTS Our study involved 392 Aboriginal children with 436 episodes of diarrhoea . Supplementation with zinc , vitamin A , or combined zinc and vitamin A had no significant effect on duration of diarrhoea or rate of re-admission compared with placebo . Median diarrhoea duration after starting supplementation was 3.0 days for the vitamin A and zinc supplemented and placebo groups ( P values 0.25 and 0.69 , respectively ) . The number of re-admissions did not differ significantly between those receiving vitamin A or zinc and the relevant placebo groups ( relative risk [ 95 % CI ] , 1.2 [ 0.7 - 2.1 ] and 1.3 [ 0.8 - 2.1 ] , respectively ) . CONCLUSION Vitamin A and zinc supplementation may not be indicated for in-hospital management of acute diarrhoeal disease in Aboriginal children living in remote areas . This finding may not apply to children with malnutrition , for whom other studies suggest a benefit . Larger trials incorporating more comprehensive data on the vitamin A and zinc status as well as nutritional status of study population s might help to explain the different results in different population Poor complementary feeding practice s are associated with stunting and growth faltering throughout the developing world . The objective was to compare the effect of using peanut-/soy-based fortified spread ( FS ) and corn porridge fortified with fish powder ( FP ) as complementary foods on growth in rural Malawian children . A total of 240 children were enrolled at the age of 6 mo and r and omized to receive FS or FP . Both complementary foods provided 836 kJ/d from 6 to 9 mo of age and 1254 kJ/d from 9 to 18 mo of age . Children were followed monthly for anthropometry and fortnightly for the symptoms of fever , cough , or diarrhea until they were 18 mo old . Zn and Se status were assessed at 6 and 12 mo . The primary outcomes were the rates of weight and length gain from 6 - 12 mo and from 12 - 18 mo . Children who received FS gained 110 g more ( 95 % CI 220 to 10 ) from 6 - 12 mo of age than children receiving FP . Weight gain did not differ between children receiving FS and FP between 12 and 18 mo of age , nor did statural growth from 6 to 12 mo or 12 to 18 mo . A total of 23 % of all children were Zn deficient at 6 mo of age and this increased to 37 % at 12 mo of age . Neither FS nor FP was associated with significantly improved Zn status . FS was associated with better weight gain from 6 - 12 mo of age and may be useful in conjunction with additional interventions to improve infant growth in the developing world BACKGROUND Reductions in iodine and zinc deficiencies and improvements in hemoglobin were achieved from a micronutrient-fortified seasoning powder consumed in school lunches by children in northeast Thail and . OBJECTIVE The objective was to determine whether fortification with 4 micronutrients in a school lunch results in changes in children 's growth , morbidity , and cognitive function compared with no fortification . DESIGN In a r and omized controlled trial of 569 children aged 5.5 - 13.4 y from 10 schools , we compared the efficacy of a seasoning powder fortified with or without 5 mg Fe , 5 mg Zn , 50 mug I , and 270 mug vitamin A per serving consumed with a school lunch 5 d/wk . Here we report on results of the secondary functional outcomes . RESULTS The groups were comparable concerning compliance and loss to follow-up . The intervention had no statistically significant effect on anthropometric measures over 31 wk , but reduced the incidence of respiratory-related illnesses [ rate ratio ( RR ) : 0.83 ; 95 % CI : 0.73 , 0.94 ] , symptoms of runny nose ( RR : 0.80 ; 95 % CI : 0.70 , 0.92 ) , cough ( RR : 0.80 ; 95 % CI : 0.66 , 0.96 ) , and diarrhea ( RR : 0.38 ; 95 % CI : 0.16 , 0.90 ) . For the visual recall test , those in the fortified group recalled 0.5 more items ( 95 % CI : 0.1 , 0.9 ) than did the controls . There were no statistically significant differences between groups in the results of the digits forward and backward tests or in school grade s at the conclusion of the 2 semesters . CONCLUSION The beneficial effects on morbidity and visual recall over a short period , in addition to some biochemical improvements , highlight the potential of this micronutrient-fortified seasoning powder supplied in a school lunch . This trial was registered at clinical trials.gov as ACTRN12605000341628 Persistent diarrhea ( PD ) and dysentery ( DD ) account for most diarrhea-associated deaths among children in developing countries . Zinc deficiency can cause stunting and impaired immune function , both of which are risk factors for these diarrheal illnesses . We investigated the effect of zinc supplementation on the incidence of PD and DD in a community-based , double-blind r and omized trial in children 6 - 35 mo of age . Increase over baseline in plasma zinc concentrations in the supplemented group compared with a control group ( 3.61 vs. 0.009 mumol . L-1 ) , indicated successful supplementation . The overall reductions in the zinc supplemented group of 21 % in the incidence of PD ( 95 % CI -6 to 42 % ) and 14 % in the incidence of dysentery ( 95 % CI -15 to 36 % ) were not significant . There was a significant interaction of treatment effect with baseline plasma zinc concentration and age for PD and with gender for DD . In the zinc-supplemented group compared with the control group , the incidence of PD was reduced by 73 % ( P < 0.05 ; 95 % CI 34 to 91 % ) in children with a baseline zinc < 7.65 mumol . L-1 and by 49 % ( P < 0.05 ; 95%CI 24 to 66 % ) in children > 11 mo of age . Zinc supplementation result ed in a 38 % ( P < 0.05 95%CI 8 to 59 % ) reduction in the incidence of DD in boys . There was no effect on PD among children 6 - 11 mo old or on DD in girls . In conclusion , zinc supplementation had a significant impact on the incidence of persistent diarrhea in children > 1 y old and in children with low plasma zinc , as well as on dysentery in boys . These findings may have important implication s for reducing diarrhea-related morbidity and mortality BACKGROUND Zinc is lost during diarrheal diseases , and zinc deficiency induces intestinal morphology-altering inflammatory responses that zinc supplementation can correct . OBJECTIVE We assessed the in vivo effect of zinc supplementation on systemic and mucosal responses in mildly to moderately malnourished ( defined as < -1 but > -2 and < -2 but > -3 weight-for-height z scores , respectively , based on the National Center for Health Statistics growth reference ) children with shigellosis . DESIGN A double-blind placebo-controlled trial was conducted in Shigella flexneri-infected children aged 12 - 59 mo . Daily for 14 d , elemental zinc ( 20 mg ) and multivitamins ( vitamins A and D , thiamine , riboflavin , and nicotinamide ) plus calcium were given at twice the US recommended dietary allowance to the zinc group ( n=28 ) , and multivitamins plus calcium were given to the control group ( n=28 ) . All subjects received st and ard antibiotic therapy . RESULTS There was no significant interaction between zinc supplementation and time , but zinc supplementation showed a significant effect on serum zinc concentrations . With a > or=4-fold increase in serum shigellacidal antibody titers from baseline used as the cutoff , the proportion of children with shigellacidal antibody response was greater in the zinc group than in the control group ( P<0.03 ) . There was a significant ( P=0.02 ) treatment x time interaction for the proportions of circulating CD20 + and CD20+CD38 + cells , which were higher on day 7 in the zinc group than in the control group ( P<0.007 ) . No effect was seen on histopathologic features or the expression of innate and inflammatory mediators in the rectum . CONCLUSION Adjunct therapy with zinc during acute shigellosis significantly improved seroconversion to shigellacidal antibody response and increased the proportions of circulating B lymphocytes and plasma cells BACKGROUND Undernourished children have poor levels of development that benefit from stimulation . Zinc deficiency is prevalent in undernourished children and may contribute to their poor development . OBJECTIVE We assessed the effects of zinc supplementation and psychosocial stimulation given together or separately on the psychomotor development of undernourished children . DESIGN This was a r and omized controlled trial with 4 groups : stimulation alone , zinc supplementation alone , both interventions , and control ( routine care only ) . Subjects were 114 children aged 9 - 30 mo and below -1.5 z scores of the National Center for Health Statistics weight-for-age references who were recruited from 18 health clinics . Clinics were r and omly assigned to receive stimulation or not ; individual children were r and omly assigned to receive zinc or placebo . The stimulation program comprised weekly home visits during which play was demonstrated and maternal-child interactions were encouraged . The supplementation was 10 mg Zn as sulfate daily or placebo . Development ( assessed by use of the Griffiths Mental Development Scales ) , length , and weight were measured at baseline and 6 mo later . Weekly morbidity histories were taken . RESULTS Significant interactions were found between zinc supplementation and stimulation . Zinc benefited the developmental quotient only in children who received stimulation , and benefits from zinc to h and and eye coordination were greater in stimulated children . Zinc supplementation alone improved h and and eye coordination , and stimulation alone benefited the developmental quotient , hearing and speech , and performance . Zinc supplementation also reduced diarrheal morbidity but did not significantly improve growth . CONCLUSION Zinc supplementation benefits development in undernourished children , and the benefits are enhanced if stimulation is also provided A r and omized , double-blind trial was undertaken to measure the effects of zinc supplementation on catch-up growth in severe protein-energy malnutrition , with particular reference to linear growth . One hundred forty-one children between the ages of 6 mo and 3 y were enrolled after admission to a nutritional rehabilitation unit in Dhaka , Bangladesh , and r and omly assigned to receive elemental zinc by mouth , 1.5 mg/kg for 15 d , 6.0 mg/kg for 15 d , or 6.0 mg/kg for 30 d , and thereafter they were followed for a total of 90 d. Anthropometric outcome measures included change in knee-heel length , midupper arm circumference , subscapular and triceps skinfold thicknesses , and change in height-for-age , weight-for-age , and weight-for-height z scores . Higher zinc doses were not associated with significant change in any anthropometric measurement , but mortality was significantly greater in children who received high-dose zinc ( 6.0 mg/kg ) initially as opposed to those who received low-dose zinc supplementation ( 1.5 mg/kg ) ( Yates-corrected chi-square P value of 0.033 and a risk ratio of 4.53 ; 95 % CI : 1.09 < risk ratio < 18.8 ) . We conclude that there is no benefit to using high-dose zinc supplementation regimens and that they could contribute to increased mortality in severely malnourished children Multiple micronutrient deficiencies are highly prevalent in Indonesia , but the interventions are still focused on single micronutrients . This study aim ed to investigate the efficacy of multiple micronutrient supplements for improving micronutrient status , anemia , growth , and morbidity of Indonesian infants . In this double-blind , placebo-controlled trial , 284 infants aged 6 - 12 mo were r and omly allocated to 4 treatment groups for 23 wk ; 260 ( 92 % ) infants completed the study . Group 1 ( DMM ) received one adequate intake of multiple micronutrient supplements daily ( n = 66 ) ; group 2 ( WMM ) received 2 adequate intakes of multiple micronutrient on 1d plus 6 d of placebo ( n = 60 ) ; group 3 ( DI ) received 10 mg of iron supplement daily ( n = 69 ) ; group 4 received a placebo supplement daily ( n = 65 ) . Blood sample s were collected at baseline and at posttreatment to assess anemia and micronutrient status . Anthropometric measurements were taken monthly , and morbidity was recorded daily . At baseline , 58.1 % of infants were anemic , 34.2 % were iron deficient , 21.3 % were vitamin A deficient , and 11 % were zinc deficient . The DMM and DI supplements both corrected iron deficiency , but DMM supplements were more efficacious in improving hemoglobin levels of anemic infants than the other supplements . However , anemia still persisted in one-third of DMM infants posttreatment . The DMM supplement was more efficacious than WMM or DI supplementation in improving infant status of other micronutrients , including zinc , tocopherol , and riboflavin , whereas DI exacerbated zinc deficiency . There were no significant differences in growth and morbidity among treatment groups , and growth faltering was not prevented Adolescent girls have high nutrient needs and are susceptible to micronutrient deficiencies . The objective of this study was to test the effect of a multiple-micronutrient-fortified beverage on hemoglobin ( Hb ) concentrations , micronutrient status , and growth among adolescent girls in rural Bangladesh . A total of 1125 girls ( Hb > or = 70 g/L ) enrolled in a r and omized , double-blind , placebo-controlled trial and were allocated to either a fortified or nonfortified beverage of similar taste and appearance . The beverage was provided at schools 6 d/wk for 12 mo . Concentrations of Hb and serum ferritin ( sFt ) , retinol , zinc , and C-reactive protein were measured in venous blood sample s at baseline , 6 mo , and 12 mo . In addition , weight , height , and mid-upper arm circumference ( MUAC ) measurements were taken . The fortified beverage increased the Hb and sFt and retinol concentrations at 6 mo ( P < 0.01 ) . Adolescent girls in the nonfortified beverage group were more likely to suffer from anemia ( Hb < 120 g/L ) , iron deficiency ( sFt < 12 microg/L ) , and low serum retinol concentrations ( serum retinol < 0.70 micromol/L ) ( OR = 2.04 , 5.38 , and 5.47 , respectively ; P < 0.01 ) . The fortified beverage group had greater increases in weight , MUAC , and BMI over 6 mo ( P < 0.01 ) . Consuming the beverage for an additional 6 mo did not further improve the Hb concentration , but the sFt level continued to increase ( P = 0.01 ) . The use of multiple-micronutrient-fortified beverage can contribute to the reduction of anemia and improvement of micronutrient status and growth in adolescent girls in rural Bangladesh BACKGROUND Multiple studies have shown the benefits of zinc supplementation among young children in high-risk population s. However , the optimal dose and safe upper level of zinc have not been determined . OBJECTIVES The objectives of this study were to measure the effects of different doses of supplemental zinc on the plasma zinc concentration , morbidity , and growth of young children ; to detect any adverse effects of 10 mg supplemental Zn on markers of copper or iron status ; and to determine whether any adverse effects are alleviated by providing copper with zinc . DESIGN This r and omized , double-masked , community-based intervention trial was conducted in 631 Ecuadorian children who were 12 - 30 mo old at baseline and who had initial length-for-age z scores < -1.3 . Children received 1 of 5 daily supplements for 6 mo : 3 , 7 , or 10 mg Zn as zinc sulfate , 10 mg Zn + 0.5 mg Cu as copper sulfate , or placebo . RESULTS The change in plasma zinc concentration from baseline was positively related to the zinc dose ( P < 0.001 ) . Zinc supplementation , including doses as low as 3 mg/d , reduced the incidence of diarrhea by 21 - 42 % ( P < 0.01 ) . There were no other significant group-wise differences . CONCLUSIONS Zinc supplementation with a dose as low as 3 mg/d increased plasma zinc concentrations and reduced diarrhea incidence in the study population . There were no observed adverse effects of 10 mg Zn/d on indicators of copper or iron status . The current tolerable upper level of zinc recommended by the Institute of Medicine should be reassessed for young children BACKGROUND Zinc supplementation decreases morbidity from infections and increases growth of stunted children , but there is little information on functional responses to zinc delivered in fortified foods . OBJECTIVE The aim was to examine the effects of zinc fortification on the growth , morbidity from infections , and plasma zinc concentrations of young children . DESIGN We compared the physical growth , morbidity , and micronutrient status of 6 - 8-mo-old Peruvian children with initial length-for-age z score ( LAZ ) < -0.50 who were r and omly assigned to receive one of the following treatments daily for 6 mo : 1 ) 30 g dry weight of an iron-fortified cereal porridge and a separate dose of an aqueous multivitamin ( MV ) supplement between meals ( control group ) , 2 ) the same porridge and MV with 3 mg Zn added to the supplement dose ( ZnSuppl group ) , or 3 ) the porridge with added zinc ( 150 mg/kg dry weight ) and MV without zinc ( ZnFort group ) . RESULTS The children consumed a mean of 22 - 26 g dry porridge/d and 96 % of the possible MV doses . After adjustment for small baseline differences in socioeconomic status and morbidity , no significant differences in weight or length increments were observed between the groups , even among the subset with an initial LAZ < -1.5 , and no significant differences in the rates of common illnesses were observed . Mean plasma zinc concentrations decreased in the control group ( -3.9 microg/dL ) , increased in the ZnSuppl group ( 4.3 microg/dL ) , and did not change significantly in the ZnFort group ( -1.5 microg/dL ; P < 0.001 for group-wise comparison ) . CONCLUSIONS Provision of additional zinc , either in an aqueous supplement or a fortified porridge , did not significantly affect the children 's physical growth or morbidity from infections , possibly because they were not sufficiently growth-restricted or zinc-deficient initially or because the level of zinc intake or absorption was inadequate . Additional studies of the functional effect of zinc-fortified foods are needed in population s that are known to respond to zinc supplements Studies have found a substantial reduction in diarrhea and respiratory morbidity in young children receiving zinc supplementation . The impact of daily zinc supplementation administered with iron plus folic acid ( IFA ) in young children on all-cause hospitalizations and mortality in comparison with IFA alone was evaluated . In a double blind cluster-r and omized controlled trial , 94,359 subjects aged 1 - 23 mo were administered a daily dose of zinc plus IFA or IFA alone for a duration of 12 mo after enrollment . The intervention group tablet contained 10 mg of elemental zinc , 12.5 mg of iron , and 50 microg of folic acid . The control group tablets were similar except that they contained a placebo for zinc . Infants aged < 6 mo were administered half a tablet , and those older received 1 tablet dissolved in breast milk or water . Hospitalizations were captured by trained study physicians through the surveillance of 8 hospitals . Deaths and hospitalizations were ascertained through visits to households by study supervisors once every 2 mo . The overall death rates did not differ significantly between the 2 groups when adjusted for cluster r and omization ( hazard ratio = 1.02 , 95 % CI 0.87 , 1.19 ) . Zinc and IFA supplementation compared with IFA alone did not affect adjusted hospitalization rates ( overall rate ratio = 1.08 , 95 % CI 0.98 , 1.19 ; diarrhea-specific rate ratio = 1.15 , 95 % CI 0.99 , 1.34 ; or pneumonia-specific rate ratio = 1.09 , 95 % CI 0.94 , 1.25 ) . The lack of impact of zinc on mortality and hospitalization rates in this study may have been due to the use of lower daily zinc dosing than used in some of the morbidity prevention trials or from an interaction between zinc and iron , where the addition of iron may have adversely affected potential effects of zinc on immune function and morbidity . Future research should address iron and zinc interaction effects on important functional outcomes INTRODUCTION Anemia is the most prevalent nutritional deficiency in the world . Attempts to improve iron indexes are affected by deficiency of and interaction between other micronutrients . OBJECTIVE Our goal was to assess whether zinc added to iron treatment alone or with vitamin A improves iron indexes and affects diarrheal episodes . DESIGN This was a r and omized , placebo-controlled , double-blind trial conducted in Peru . Anemic children aged 6 - 35 mo were assigned to 3 treatment groups : ferrous sulfate ( FS ; n = 104 ) , ferrous sulfate and zinc sulfate ( FSZn ; n = 109 ) , and ferrous sulfate , zinc sulfate , and vitamin A ( FSZnA ; n = 110 ) . Vitamin A or its placebo was supplied only once ; iron and zinc were provided under supervision > /=1 h apart 6 d/wk for 18 wk . RESULTS The prevalence of anemia was 42.97 % . The increase in hemoglobin in the FS group ( 19.5 g/L ) was significantly less than that in the other 2 groups ( 24.0 and 23.8 g/L in the FSZn and FSZnA groups , respectively ) . The increase in serum ferritin in the FS group ( 24.5 mug/L ) was significantly less than that in the other 2 groups ( 33.0 and 30.8 mug/L in the FSZn and FSZnA groups , respectively ) . The median duration of diarrhea and the mean number of stools per day was significantly higher in the FS group than in other 2 groups ( P < 0.005 ) . CONCLUSION Adding zinc to iron treatment increases hemoglobin response , improves iron indexes , and has positive effects on diarrhea . No additional effect of vitamin A was found BACKGROUND Evidence for an effect of zinc supplementation on growth and morbidity in very young infants in developing countries is scarce and inconsistent . OBJECTIVE We assessed the effect of zinc supplementation on growth and morbidity in poor Bangladeshi infants aged 4 - 24 wk . DESIGN Infants from Dhaka slums were enrolled at 4 wk of age and r and omly assigned to receive 5 mg elemental Zn/d ( n = 152 ) or placebo ( n = 149 ) until 24 wk of age . They were followed weekly for information on compliance and morbidity ; anthropometric measurements were performed monthly . Serum zinc was assessed at baseline and at 24 wk of age . RESULTS At 24 wk of age , serum zinc concentrations were higher in the zinc than in the placebo group ( 13.3 + /- 3.8 and 10.7 + /- 2.9 micro mol/L , respectively ; P < 0.001 ) . Significantly greater weight gains were observed in the zinc than in the placebo group for 43 infants who were zinc deficient ( < 9.18 micro mol/L ) at baseline ( 3.15 + /- 0.77 and 2.66 + /- 0.80 kg , respectively ; P < 0.04 ) . In the other infants , no significant differences were observed in mean weight and length gains during the study period . Zinc-deficient infants showed a reduced risk of incidence of acute lower respiratory infection after zinc supplementation ( relative risk : 0.30 ; 95 % CI : 0.10 , 0.92 ) ; among the non-zinc-deficient infants there were no significant differences between treatment groups . CONCLUSIONS Zinc-deficient Bangladeshi infants showed improvements in growth rate and a reduced incidence of acute lower respiratory infection after zinc supplementation . In infants with serum zinc concentrations > 9.18 micro mol/L , supplementation improved only biochemical zinc status BACKGROUND It has been documented that growth patterns differ between breastfed and formula-fed infants . Some investigators have suggested that these differences may be related to differences in zinc nutriture . OBJECTIVE The objective of this study was to examine the effect of zinc supplementation on growth , morbidity , and motor development in healthy , term , breastfed infants . DESIGN We conducted a r and omized double-blind intervention comparing zinc supplementation ( 5 mg/d as zinc sulfate ) with placebo in breastfed infants aged 4 - 10 mo . Growth and indexes of body composition and gross motor development were measured monthly from 3 to 10 mo . Morbidity data were collected weekly . RESULTS Eighty-five infants were enrolled , and 70 completed the study . The baseline characteristics , attained weight or length at 10 mo , growth velocity , gross motor development , and morbidity did not differ significantly between groups , even after control for potentially confounding variables . CONCLUSIONS The dietary zinc intake of these breastfed infants appeared to be adequate , given that zinc supplementation did not affect growth , development , or risk of infection ( although sample size for detection of differences in development or infection was limited ) . Previously described differences in growth between breastfed and formula-fed infants in such population s do not appear to be due to differences in zinc nutriture A community-based , double-blind , r and omized trial was conducted in a population of low socioeconomic status in urban India to determine whether daily zinc supplementation reduces the incidence and prevalence of acute diarrhea , especially in those with zinc deficiency . Children 6 - 35 mo of age were r and omly assigned to zinc ( n = 286 ) and control ( n = 293 ) groups and received a supplement daily for 6 mo . Zinc gluconate ( 10 mg elemental Zn ) was given , with both zinc and control groups also receiving multivitamins . The primary outcome measures determined by home visits every fifth day and physician examinations were the number of acute diarrheal episodes ( incidence ) and total diarrheal days ( prevalence ) . Zinc supplementation had no effect in children 6 - 11 mo old . In children aged > 11 mo there was significantly less diarrhea in the zinc group . In boys > 11 mo old , supplementation result ed in a 26 % ( 95 % CI : 13 % , 38 % ) lower diarrheal incidence and a 35 % ( 95 % CI : 20 % , 50 % ) lower prevalence . In zinc-supplemented girls > 11 mo of age , the incidence was 17 % ( 95 % CI : 2 % , 30 % ) lower and the prevalence was 19 % ( 95 % CI : 4 % , 47 % ) lower . Overall , zinc supplementation result ed in a 17 % ( 95 % CI : 1 % , 30 % ) lower diarrheal incidence in children with plasma zinc concentrations < 9.18 mumol/L at enrollment and a 33 % ( 95 % CI : 6 % , 52 % ) lower incidence in children with concentrations < 50 mumol/L. In conclusion , zinc supplementation had a significant effect on acute diarrheal morbidity in children > 11 mo old and in children with low plasma zinc concentrations Anemia , micronutrient deficiencies , and growth faltering are still common in Peru . The study objective was to determine the efficacy of different micronutrient supplements in preventing growth failure , anemia , and micronutrient deficiencies in Peruvian infants . Three hundred and thirteen infants aged 6 to 12 mo participated in a double-blind , masked , controlled trial in which they were r and omly assigned to receive either a daily dose of iron ( DI ) , a daily dose of multiple micronutrients ( DMM ) , a weekly dose of multiple micronutrients , or a placebo ( P ) for 6 mo . None of the supplements tested prevented growth faltering or the morbidities common during infancy . Anemia and plasma homocysteine concentrations fell significantly in all groups during the study , but the mean change of plasma homocysteine during the trial period was significantly smaller in the DI group than in other groups , and the increase in hemoglobin concentrations was smaller in the P group than the micronutrient treatment groups . Plasma ferritin concentrations decreased least in the groups taking daily micronutrient supplements containing iron ( DI and DMM ) . There were no significant differences among groups in mean final values or changes in plasma zinc , retinol , tocopherol , or riboflavin . Although the DMM intervention was the most efficacious for preventing anemia , iron , and zinc deficiencies , 15 % , 20 % , and 50 % of this group still remained anemic , zinc deficient , and iron deficient , respectively , at the end of the study . Further research thus should investigate whether higher doses of iron and zinc , together with infection control measures , are more efficacious BACKGROUND Several studies showed benefits of long-term zinc supplementation on the incidence , severity , and duration of diarrhea and on the incidence of respiratory infections . Prolonged zinc supplementation also improves cell-mediated immunity in severely malnourished children . OBJECTIVE We studied the effect of short-term zinc supplementation on intrinsic and specific immune and inflammatory responses in moderately malnourished children with acute shigellosis . DESIGN A r and omized , double-blind , placebo-controlled trial was conducted in Shigella-infected children aged 12 - 59 mo . Elemental zinc ( 20 mg ) and a multivitamin containing vitamins A and D , thiamine , riboflavin , nicotinamide , and calcium at twice the recommended dietary allowance were given daily for 2 wk to the zinc group ( n = 28 ) , whereas the multivitamin alone was given to the control group ( n = 28 ) . St and ard antibiotic therapy was given to all patients . RESULTS Serum zinc concentrations increased in both groups during convalescence ; however , zinc supplementation showed a significant effect . The lymphocyte proliferation response in the zinc group increased relative to that in the control group ( P = 0.002 ) , but no significant effects were seen on concentrations of cytokines ( interleukin 2 and interferon gamma ) released from mitogen-stimulated mononuclear cells or on concentrations of cytokines ( interleukin 2 , interferon gamma , and interleukin 1beta ) in feces . Among the antigen [ lipopolysaccharide and invasion plasmid-encoded antigen (Ipa)]-specific antibodies , plasma Ipa-specific immunoglobulin G responses at day 30 were significantly higher in the zinc group than in the control group . However , the 2 groups did not differ significantly in the other antigen-specific responses in plasma and stool . CONCLUSION A 14-d course of zinc supplementation during acute shigellosis increases the lymphocyte proliferation response and the Ipa-specific immunoglobulin G response In this study the effects of supplementation of iron and zinc , alone or combined , on iron status , zinc status and growth in Indonesian infants is investigated . Micronutrient deficiencies are prevalent in infants in developing countries , and deficiencies often coexist ; thus , combined supplementation is an attractive strategy . However , little is known about interactions between micronutrients . In a r and omized , double-blind , placebo-controlled supplementation trial , 478 infants , 4 mo of age , were supplemented for 6 mo with iron ( 10 mg/d ) , zinc ( 10 mg/d ) , iron + zinc ( 10 mg of each/d ) or placebo . Anthropometry was assessed monthly , and micronutrient status was assessed at the end of supplementation . Supplementation significantly reduced the prevalence of anemia , iron deficiency anemia and zinc deficiency . Iron supplementation did not negatively affect plasma zinc concentrations , and zinc supplementation did not increase the prevalence of anemia or iron deficiency anemia . However , iron supplementation combined with zinc was less effective than iron supplementation alone in reducing the prevalence of anemia ( 20 % vs. 38 % reduction ) and in increasing hemoglobin and plasma ferritin concentrations . There were no differences among the groups in growth . The growth of all groups was insufficient to maintain the same Z-scores for height for age and weight for height . There is a high prevalence of deficiencies of iron and zinc in these infants , which can be overcome safely and effectively by supplementation of iron and zinc combined . However , overcoming these deficiencies is not sufficient to improve growth performance in these infants BACKGROUND Recent studies reported that zinc significantly reduced the duration and volume of acute watery diarrhea in children aged > or = 4 mo , but there were no data specifically on infants aged < 6 mo . OBJECTIVE This study investigated the effect of zinc on the duration of illness and the stool quantity in acute watery diarrhea of infants aged 1 - 6 mo by comparing a 20 mg Zn/d dose with a 5 mg Zn/d dose . DESIGN Infants hospitalized with at least some dehydration ( by World Health Organization classification ) were enrolled in a double-blind , r and omized , placebo-controlled trial . Infants were r and omly assigned to receive 20 mg Zn (acetate)/d , 5 mg Zn/d , or placebo for the duration of illness . RESULTS Two hundred seventy-five infants were enrolled between 20 September 1998 and 18 December 2000 . Neither diarrhea duration nor mean stool volume differed between groups . There were no significant differences in fluid intake , the need for unscheduled intravenous fluid , weight gain , or vomiting rates between the groups . CONCLUSIONS Zinc supplementation did not affect diarrhea duration or stool volume in young infants . Young infants tolerated both zinc doses . A beneficial effect on subsequent illness can not be ruled out BACKGROUND Micronutrient deficiencies are common during infancy , and optimal approaches for their prevention need to be identified . OBJECTIVE The objective was to compare the efficacy and acceptability of Sprinkles ( SP ) , crushable Nutritabs ( NT ) , and fat-based Nutributter ( NB ; 108 kcal/d ) , which provide 6 , 16 , and 19 vitamins and minerals , respectively , when used for home fortification of complementary foods . DESIGN Ghanaian infants were r and omly assigned to receive SP ( n = 105 ) , NT ( n = 105 ) , or NB ( n = 103 ) daily from 6 to 12 mo of age . We assessed dietary intake , morbidity , and compliance weekly . Hemoglobin and plasma ferritin , TfR , C-reactive protein , and zinc were measured at 6 and 12 mo . We used an exit interview to assess acceptability . A r and omly selected control group of infants who received no intervention ( NI ; n = 96 ) were assessed at 12 mo . RESULTS All supplements were well accepted , and the mean percentage of days that supplements were consumed ( 87 % ) did not differ between groups . At 12 mo , all 3 intervention groups had significantly higher ferritin and lower TfR concentrations than did the NI control group . Mean ( + /- SD ) hemoglobin was significantly higher in NT ( 112 + /- 14 g/L ) and NB ( 114 + /- 14 g/L ) but not in SP ( 110 + /- 14 g/L ) infants than in NI infants ( 106 + /- 14 g/L ) . The prevalence of iron deficiency anemia was 31 % in the NI control group compared with 10 % in the intervention groups combined ( P < 0.0001 ) . CONCLUSION All 3 options for home fortification of complementary foods are effective for reducing the prevalence of iron deficiency in such population BACKGROUND Zinc supplements reduce childhood morbidity in population s in whom zinc deficiency is common . In such population s , deficiencies in other micronutrients may also occur . OBJECTIVE The objective was to determine whether the administration of other micronutrients with zinc modifies the effect of zinc supplementation on children 's morbidity and physical growth . DESIGN Two hundred forty-six children aged 6 - 35 mo with persistent diarrhea were r and omly assigned to 1 of 3 groups to receive a daily supplement of 10 mg Zn alone ( Zn ; n = 81 ) , zinc plus vitamins and other minerals at 1 - 2 times recommended daily intakes ( Zn+VM ; n = 82 ) , or placebo ( n = 83 ) for approximately 6 mo after the diarrhea episode ended . Morbidity information was collected on weekdays . Weight , length , and other anthropometric indicators were measured monthly , and plasma zinc and other indicators of micronutrient status were measured at baseline and 6 mo . RESULTS Supplement consumption was high ( approximately 90 % ) in all groups , although slightly more vomiting was reported in the Zn+VM group ( P < 0.0001 , analysis of variance ) . The change in plasma zinc from baseline to 6 mo was greater in the 2 zinc groups ( 6.1 , 27.3 , and 16.2 micro g/dL in the placebo , Zn , and Zn+VM groups , respectively ; P < 0.0001 , analysis of variance ) . The Zn group had fewer episodes of diarrhea , dysentery , and respiratory illness and a lower prevalence of fever and cough than did the Zn+VM group and a lower prevalence of cough than did the placebo group ( P = 0.05 ) . No significant effects of supplementation on growth were observed . CONCLUSION Morbidity was greater after supplementation with zinc plus multivitamins and minerals than it was after supplementation with zinc alone Although iron deficiency is the most common single-nutrient deficiency in infants and children , other deficiencies may develop concurrently , including zinc deficiency . In previous studies , we used home-fortification with " Sprinkles , " single-serve sachets containing microencapsulated ferrous fumarate added to weaning foods , to successfully treat anemia . This mode of micronutrient delivery is amenable to the delivery of other micronutrients . However , the relative efficacy of multiple micronutrient supplements for the treatment of anemia requires evaluation due to possible nutrient interactions . Thus , we evaluated the relative efficacy of Sprinkles formulated with iron and zinc in anemic infants , compared with Sprinkles formulated with iron alone . We studied 304 anemic infants ( mean age 10.3 + /- 2.5 mo ; hemoglobin 87.4 + /- 8.4 g/L ) in rural Ghana . A combined supplementation group ( FeZn ) received daily Sprinkles containing 80 mg iron and 10 mg zinc ; a comparison group ( Fe ) received Sprinkles ( 80 mg iron ) without zinc for 2 mo . The rate of recovery from anemia was higher in the Fe group compared with the FeZn group ( 74.8 vs. 62.9 % ; P = 0.048 ) . The plasma zinc concentration decreased significantly in both groups ( P < 0.05 ) . A significant decline in the height for age Z-score was observed in the FeZn group ( P = 0.0011 ) , but there was no change in the Fe group . These results suggest that in a controlled setting , home-fortification using micronutrient Sprinkles with iron , or iron and zinc , was very successful in treating anemia ; however , this intervention alone was insufficient to improve zinc status or promote catch-up growth in this stunted and wasted population BACKGROUND The efficacy of micronutrient supplementation in improving childhood health and survival in developing countries may be specific to the micronutrient used and health outcome measured . OBJECTIVE We evaluated the effect of vitamin A and zinc supplementation on overall rates of childhood diarrheal disease and respiratory tract infections and rates stratified by household and personal characteristics . DESIGN A double-blind , r and omized , placebo-controlled trial was carried out in which 736 children aged 6 - 15 mo living in a periurban area of Mexico City were assigned to receive vitamin A every 2 mo , zinc daily , vitamin A and zinc together , or placebo . Children were followed for 12 mo to determine overall counts of diarrheal episodes and respiratory tract infections . RESULTS Vitamin A supplementation was associated with a 27 % increase in diarrheal disease [ risk ratio ( RR ) : 1.27 ; 95 % CI : 1.10 , 1.45 ; P < 0.001 ] and a 23 % increase in cough with fever ( RR : 1.23 ; 95 % CI : 1.02 , 1.47 ; P = 0.02 ) , whereas zinc had no effect on these outcomes . Vitamin A supplementation decreased diarrhea in children from households with dirt floors but increased diarrhea in children from households with nondirt floors , piped water , and indoor bathrooms . Zinc supplementation decreased diarrhea in children from households with dirt floors and whose mothers were more educated . Vitamin A supplementation increased cough with fever in children from less-crowded households that lacked indoor bathrooms and in children of less-educated mothers . CONCLUSIONS Vitamin A increases diarrheal disease and respiratory tract infections in young children in periurban areas of Mexico City . Vitamin A and zinc have more heterogeneous effects in different subgroups of children BACKGROUND Deficiencies of iron and zinc are associated with delayed development , growth faltering , and increased infectious-disease morbidity during infancy and childhood . Combined iron and zinc supplementation may therefore be a logical preventive strategy . OBJECTIVE The objective of the study was to compare the effects of combined iron and zinc supplementation in infancy with the effects of iron and zinc as single micronutrients on growth , psychomotor development , and incidence of infectious disease . DESIGN Indonesian infants ( n = 680 ) were r and omly assigned to daily supplementation with 10 mg Fe ( Fe group ) , 10 mg Zn ( Zn group ) , 10 mg Fe and 10 mg Zn ( Fe+Zn group ) , or placebo from 6 to 12 mo of age . Anthropometric indexes , developmental indexes ( Bayley Scales of Infant Development ; BSID ) , and morbidity were recorded . RESULTS At 12 mo , two-factor analysis of variance showed a significant interaction between iron and zinc for weight-for-age z score , knee-heel length , and BSID psychomotor development . Weight-for-age z score was higher in the Zn group than in the placebo and Fe+Zn groups , knee-heel length was higher in the Zn and Fe groups than in the placebo group , and the BSID psychomotor development index was higher in the Fe group than in the placebo group . No significant effect on morbidity was found . CONCLUSIONS Single supplementation with zinc significantly improved growth , and single supplementation with iron significantly improved growth and psychomotor development , but combined supplementation with iron and zinc had no significant effect on growth or development . Combined , simultaneous supplementation with iron and zinc to infants can not be routinely recommended at the iron-to-zinc ratio used in this study BACKGROUND Preventing illness and improving growth in the first 6 mo of life is critical to reducing infant mortality . Zinc given for 14 d at the start of diarrhea has been shown to decrease the incidence and prevalence of diarrhea and pneumonia and improve growth in the 2 - 3 mo after , but no trial has been done in infants < 6 mo of age . OBJECTIVE This study sought to assess the effect of 14 d of zinc supplementation on subsequent morbidity and growth among infants 1 - 5 mo of age living in Pakistan , India , and Ethiopia . DESIGN Infants with acute diarrhea were r and omly assigned to receive zinc ( 10 mg/d ; n = 538 ) or placebo ( n = 536 ) for 2 wk . Weekly follow-up visits were conducted for 8 wk after the diarrhea episode . Incidence and prevalence of diarrhea and prevalence of respiratory infections including pneumonia were compared between the groups . Changes in weight , length , and corresponding z scores during the 8 wk of follow-up were also compared . RESULTS One thous and seventy-four infants were enrolled at the start of follow-up . The groups did not differ significantly in the proportion of infants with at least one episode of diarrhea or respiratory infections . Infants who received zinc had more days of diarrhea ( rate ratio = 1.20 ) than did the infants who received placebo . The groups had similar prevalences of pneumonia and overall respiratory infections . No significant differences in the mean changes in weight-for-age , length-for-age , and weight-for-length z scores were observed between the groups overall or in stratified analyses . CONCLUSION Young infants do not appear to benefit from 2 wk of zinc , unlike what has been observed among older children Given the high prevalence of micronutrient deficiencies and infectious diseases in infants in developing countries , an evaluation of the efficacy of different micronutrient formulations on infant morbidity is a priority . The efficacy of weekly supplementation of four different micronutrient formulations on diarrhea and acute lower respiratory infection ( ALRI ) morbidity was evaluated in Bangladeshi infants . In a double-blind , r and omized , controlled community trial , 799 infants aged 6 mo were r and omly assigned to one of the following 5 groups : 1 ) 20 mg elemental iron with 1 mg riboflavin , 2 ) 20 mg elemental zinc with 1 mg riboflavin , 3 ) 20 mg iron and 20 mg zinc with 1 mg riboflavin , 4 ) a micronutrient mix ( MM ) containing 20 mg iron , 20 mg zinc , 1 mg riboflavin along with other minerals and vitamins and 5 ) a control treatment , 1 mg riboflavin only . Health workers visited each infant weekly until age 12 mo to feed the supplement and to collect data on diarrhea and ALRI morbidity . Hemoglobin , serum ferritin and serum zinc levels of a sample of infants were measured at 6 and 12 mo . Compared with the control group , at 12 mo , serum ferritin levels were higher in the iron + zinc group , and serum zinc levels were higher in the zinc and iron + zinc groups . Simultaneous supplementation with iron + zinc was associated with lower risk of severe diarrhea , 19 % lower in all infants and 30 % lower in less well-nourished infants with weight-for-age Z-score below -1 . Iron + zinc supplementation was also associated with 40 % lower risk of severe ALRI in less well-nourished infants . MM supplementation was associated with a 15 % higher risk of diarrhea in all infants and 22 % higher risk in less well-nourished infants . Intermittent simultaneous supplementation with iron + zinc seems promising ; it will be useful to determine whether higher doses would provide greater benefits OBJECTIVE To evaluate the efficacy of a hypotonic oral rehydration solution ( ORS ) containing zinc and prebiotics for treatment of acute diarrhea in children . STUDY DESIGN We conducted a single-blind , prospect i ve , controlled trial including children ( age range , 3 - 36 months ) with acute diarrhea r and omly assigned to st and ard hypotonic ORS ( group 1 ) or to new hypotonic ORS containing zinc and prebiotics ( group 2 ) . The main outcome was the rate of resolution of diarrhea at 72 hours . RESULTS A total of 60 children in group 1 ( 34 male ; mean age , 18.58 months ; 95 % CI , 15.5 - 21.6 ) and 59 in group 2 ( 36 male ; mean age , 19.26 months ; 95 % CI , 15.9 - 22.6 ) completed the study protocol . The rate of diarrhea resolution at 72 hours was higher in group 2 ( 50 % versus 72.9 % , P = .010 ) . Total ORS intake in the first 24 hours was higher in group 2 ( 50 mL/kg ; 95 % CI , 41 - 59 versus 22 mL/kg ; 95 % CI , 17 - 29 ; P < .001 ) . The mean number of missed working days by the parents of children in group 2 was lower ( 0.39 ; 95 % CI , 0.08 - 0.70 versus 1.45 ; 95 % CI 1.02 - 1.88 ; P < .001 ) . Fewer patients in group 2 needed adjunctive drugs for the treatment of diarrhea 6/59 versus 19/60 , P = .004 . No adverse events were observed in either of the two groups . CONCLUSION The addition of zinc and prebiotics to ORS limits diarrhea duration in children A r and omized double-blind placebo-controlled study was conducted in children admitted to hospital with gastroenteritis ( ≥3 loose stools per day ) . All were treated for 5 days following admission with either zinc ( Zn , 3 mg ) or without Zn-fortified rice-based oral rehydration solution ( ORS ) . 13C-sucrose breath test ( SBT ) and intestinal permeability ( lactulose/rhamnose or L/R ratio ) were performed concurrently prior to commencement of ORS with or without Zn and at day 5 post-admission . There was a significant improvement in the SBT results in both the Zn-fortified group , median ( 5th-95th percentile ) 2.1 % ( 0.4 % to 8.3 % ) versus 4.4 % ( 0.4 % to 10.4 % ) , P < .05 , and control group , 1.4 % ( 0.1 % to 5.4 % ) versus 4.3 % ( 0.4 % to 11.4 % ) , P < .05 , between the day of admission and day 5 post-admission . In the Zn-fortified group , there was also a significant improvement in L/R ratio between the day of admission and day 5 post-admission , 53.0 ( 19.5 - 90.6 ) versus 17.7 ( 13.4 - 83.2 ) , P < .05 . Low levels of Zn improved intestinal permeability but did not enhance short-term recovery following diarrheal illness OBJECTIVE To evaluate the impact of 4 months of daily zinc supplementation on the incidence of severe and recurrent diarrhea in children 6 to 30 months of age . METHODS A double-blind , r and omized , placebo-controlled trial was conducted on children who were identified by a door-to-door survey to be aged 6 to 30 months and residing in the urban slum of Dakshinpuri , New Delhi . They were r and omized to receive daily zinc gluconate ( elemental zinc 10 mg to infants and 20 mg to older children ) or placebo . A field attendant administered the syrup daily at home for 4 months except on Sundays , when the mother did so . One bottle that contained 250 mL was kept in the child 's home and replaced monthly . Field workers visited households every seventh day during the 4-month follow-up period . At each visit , information was obtained for the previous 7 days on history of fever , number and consistency of stools , and presence of cough . When the child was ill , illness characteristics and treatment seeking outside the home were determined . If the child had diarrhea or vomiting , then dehydration was assessed . At household visits , 2 packets of oral rehydration salts were given when a child had diarrhea . Children who visited the study clinic spontaneously for illness or were referred by the field workers were treated according to the st and ard national program guidelines . Antibiotics were advised only for diarrhea with bloody stools or for associated illnesses . For using generalized estimating equations for longitudinal analysis of a recurring event such as diarrhea , the follow-up data for each child was divided into 17 child-periods of 7 days each and presence or absence of an incident episode of diarrhea or severe diarrhea within each 7-day period was coded . This method of analysis does not assume independence of events and therefore prevents underestimation of variance that results because of correlation of morbidity within the same child . A logistic generalized estimating equations model with exchangeable correlation covariance-variance matrix was then used to estimate the effect size . RESULTS Zinc or placebo doses were administered on 88.8 % and 91.2 % , respectively , of study days during the 4 months of follow-up . There was a small but significant increase in the average number of days with vomiting in the zinc group ( 4.3 [ st and ard deviation ( SD ) : 5.8 ] vs 2.6 [ SD 3.9 ] days ; difference in means : 1.7 [ 95 % confidence interval ( CI ) : 1.3 - 2.1 ] days ) . At the baseline , mean plasma zinc was 62.0 microg/dL ( SD : 14.3 microg/dL ) in the zinc and 62.0 microg/dL ( SD : 11.2 microg/dL ) in the placebo group ; 45.8 % and 42 % , respectively , had low plasma zinc levels below 60 microg/dL. At the end of the study , plasma zinc levels were substantially higher in the zinc group ( ratio of geometric means : 1.94 [ 95 % CI : 1.86 - 2.03 ] ) and the proportion with low plasma zinc was lower ( difference in proportions : -46.7 % [ 95 % CI : -41.8 % to -51.4 % ] ) . The incidence of diarrhea during follow-up was lower in the zinc-supplemented as compared with the placebo group ( odds ratio [ OR ] : 0.88 ; 95 % CI : 0.82 - 0.95 ) . The beneficial impact of zinc was greater on the incidence of diarrhea with progressively increasing duration : episodes of diarrhea that lasted 1 to 6 days ( OR : 0.92 ; 95 % CI : 0.85 - 1.00 ) , 7 to 13 days ( OR : 0.79 ; 95 % CI : 0.65 - 0.95 ) , and > or = 14 days ( OR : 0.69 ; 95 % CI : 0.48 - 0.98 ) . The impact was also greater on the incidence of episodes with progressively higher stool frequency : 3 to 5 stools per day ( OR : 0.90 ; 95 % CI : 0.83 - 0.98 ) , 6 to 9 stools per day ( OR : 0.87 ; 95 % CI : 0.77 - 0.98 ) , and > or = 10 per day ( OR : 0.77 ; 95 % CI : 0.63 - 0.94 ) . In the zinc group , significantly more children experienced no diarrheal episode during the study period ( risk ratio [ RR ] : 1.22 ; 95 % CI : 1.02 - 1.44 ) . Furthermore , substantially fewer children ( RR : 0.51 ; 95 % CI : 0.36 - 0.73 ) experienced recurrent diarrhea , defined as > 6 diarrheal episodes in the follow-up period as compared with children in the placebo group . The number of children who were hospitalized for any cause tended to be lower in the zinc group , but the difference was not statistically significant ( 1.79 % vs 2.43 % ; RR : 0.74 ; 95 % CI : 0.43 - 1.27 ) . The baseline mean plasma copper ( microg/dL ) was similar in the 2 groups ( difference in means : 1.6 ; 95 % CI : -2.9 to 6.1 ) . The end study plasma copper levels were significantly lower in the zinc group ( difference in means : -15.5 ; 95 % CI : -19.9 to - 11.1 ) . CONCLUSIONS Zinc supplementation substantially reduced the incidence of severe and prolonged diarrhea , the 2 important determinants of diarrhea-related mortality and malnutrition . This intervention also substantially reduced the proportion of children who experienced recurrent diarrhea . Prompt measures to improve zinc status of deficient population s are warranted . The potential approaches to achieve this goal include food fortification , dietary diversification , cultivation of plants that are zinc dense or have a decreased concentration of zinc absorption inhibitors , and supplementation of selected groups of children . Future studies should assess the impact of increased zinc intakes on childhood mortality in developing countries . For facilitating intervention , there is a need to obtain reliable estimates of zinc deficiency , particularly in developing countries . The functional consequences of the effect of various doses of zinc on plasma copper levels merits additional study Objective To investigate the impact of zinc supplementation in children with cholera . Design Double blind , r and omised , placebo controlled trial . Setting Dhaka Hospital , Bangladesh . Participants 179 children aged 3 - 14 years with watery diarrhoea and stool dark field examination positive for Vibrio cholerae and confirmed by stool culture . Intervention Children were r and omised to receive 30 mg elemental zinc per day ( n=90 ) or placebo ( n=89 ) until recovery . All children received erythromycin suspension orally in a dose of 12.5 mg/kg every six hours for three days . Main outcome measures Duration of diarrhoea and stool output . Results 82 children in each group completed the study . More patients in the zinc group than in the control group recovered by two days ( 49 % v 32 % , P=0.032 ) and by three days ( 81 % v 68 % , P=0.03 ) . Zinc supplemented patients had 12 % shorter duration of diarrhoea than control patients ( 64.1 v 72.8 h , P=0.028 ) and 11 % less stool output ( 1.6 v 1.8 kg/day , P=0.039 ) . Conclusion Zinc supplementation significantly reduced the duration of diarrhoea and stool output in children with cholera . Children with cholera should be supplemented with zinc to reduce its duration and severity . Trial registration Clinical trials NCT00226616 OBJECTIVE To evaluate the efficacy and safety of zinc in the treatment of acute gastroenteritis ( AGE ) in children in Pol and . STUDY DESIGN Children aged 3 to 48 months with AGE were enrolled in a r and omized , double-blind , placebo-controlled trial in which they received zinc sulfate ( 10 or 20 mg/day depending on age ) or placebo for 10 days . A total of 141 of 160 children recruited were available for intention-to-treat analysis . The primary outcome was the duration of diarrhea . RESULTS In the experimental group ( n = 69 ) compared with the control group ( n = 72 ) , there was no significant difference in the duration of diarrhea ( P > .05 ) . Similarly , there was no significant difference in the groups in secondary outcome measures such as stool frequency on days 1 , 2 , and 3 , vomiting frequency , intravenous fluid intake , and the number of children with diarrhea lasting > 7 days . CONCLUSION Children living in a country where zinc deficiency is rare do not appear to benefit from the use of zinc in the treatment of AGE UNLABELLED Intervention trials have shown that zinc is efficacious in treating acute diarrhea in children of developing countries . In a r and omized , placebo-controlled trial , we assessed the effectiveness and efficacy of giving 3 Recommended Daily Allowances of elemental zinc to 6- to 35-month-old children with acute diarrhea . METHODS Seventeen hundred ninety-two cases of acute diarrhea in Nepalese children were r and omized to 4 study groups . Three groups were blinded and the children supplemented daily by field workers with placebo syrup , zinc syrup , or zinc syrup and a massive dose of vitamin A at enrollment . The fourth group was open and the caretaker gave the children zinc syrup daily . Day-wise information on morbidity was obtained by household visits every fifth day . RESULTS The relative hazards for termination of diarrhea were 26 % ( 95 % confidence interval [ CI ] : 8 % , 46 % ) , 21 % ( 95 % CI : 4 % , 38 % ) , and 19 % ( 95 % CI : 2 % , 40 % ) higher in the zinc , zinc-vitamin A , and zinc-caretaker groups , respectively , than in the placebo group . The relative risks of prolonged diarrhea ( duration > 7 days ) in these groups were 0.57 ( 95 % CI : 0.38 , 0.86 ) , 0.53 ( 95 % CI : 0.35 , 0.81 ) , and 0.55 ( 0.37 , 0.84 ) ; zinc accordingly reduced the risk of prolonged diarrhea with 43 % to 47 % . Five percent and 5.1 % of all syrup administrations were followed by regurgitation in the zinc and zinc-vitamin A group , respectively , whereas this occurred after only 1.3 % of placebo administrations . Vomiting during diarrhea was also more common in children receiving zinc . CONCLUSIONS Three Recommended Daily Allowances of zinc given daily by caretakers or by field workers substantially reduced the duration of diarrhea . The effect of zinc was not dependent on or enhanced by concomitant vitamin A administration Background : To assess the therapeutic effects of oral zinc supplementation on acute watery diarrhea of children with moderate dehydration . Methods : All 9-month to 5-year-old children who were admitted with acute watery diarrhea and moderate dehydration to the Children Ward of Motahari Hospital , Urmia , Iran in 2008 were recruited . After the application of the inclusion and exclusion criteria , the patients were r and omly allocated to two groups : one group to receive zinc plus oral rehydration solution ( ORS ) and the other one to receive ORS plus placebo . All the patients were rehydrated using ORS and then receiving ORS for ongoing loss ( 10 ml/kg after every defecation ) . Additionally , the patients in the intervention group received zinc syrup ( 1 mg/kg/day ) divided into two doses . A detailed question naire was filled daily for each patient by trained pediatrics residents ; it contained required demographic characteristics , nutrition and hydration status , and disease progression . The primary outcome ( frequency and consistency of diarrhea ) and the secondary outcomes ( duration of hospitalization and change in patients ’ weight ) were compared between the two groups . Results : The mean diarrhea frequency ( 4.5±2.3 vs. 5.3±2.1 ; P=0.004 ) was lower in the group receiving zinc + ORS ; however , the average weight was relatively similar between the two groups ( 10.5±3.1 vs. 10.1±2.3 ; P=0.14 ) . The qualitative assessment of stool consistency also confirmed earlier improvement in the treatment group in the first three days of hospitalization ( P < 0.05 ) . The mean duration of hospitalization was significantly lower in the patients receiving zinc supplements ( 2.5±0.7 vs. 3.3±0.8 days ; P=0.001 ) . Conclusion : Our results imply the beneficial effects of therapeutic zinc supplementation on disease duration and severity in patients with acute diarrhea and moderate dehydration in Iran . Trial Registration Number : I RCT OBJECTIVE To compare the clinical efficacy of supplementation of zinc , zinc plus vitamin A , and zinc plus combination of micronutrients and vitamins ( iron , copper , selenium , vitamin B(12 ) , folate , and vitamin A ) on acute diarrhea in children . STUDY DESIGN This was a double-blind , r and omized , placebo-controlled trial . Children aged 6 to 24 months with diarrhea and moderate dehydration were r and omized to receive zinc plus placebo vitamin A ( group 1 ) , zinc plus other micronutrients plus vitamin A ( group 2 ) , zinc plus vitamin A ( group 3 ) , or placebo ( group 4 ) as an adjunct to oral rehydration solution . Duration , volume of diarrhea , and consumption of oral rehydration solution were compared as outcome variables within the supplemented groups and with the placebo group . RESULTS The 167 study subjects included 41 in group 1 , 39 in group 2 , 44 in group 3 , and 43 in group 4 . All 3 supplemented groups demonstrated a significant reduction in outcome variables ( P < .0001 ) compared with the placebo group . Group 3 had the lowest reduction of outcome variables and group 2 had a speedy recovery , but differences among the supplemented groups were not statistically significant . CONCLUSIONS Supplementation with a combination of micronutrients and vitamins was not superior to zinc alone , confirming the clinical benefit of zinc in children with diarrhea Background Prophylactic zinc supplementation has been shown to reduce diarrhea and respiratory illness in children in many developing countries , but its efficacy in children in Africa is uncertain . Objective To determine if zinc , or zinc plus multiple micronutrients , reduces diarrhea and respiratory disease prevalence . Design R and omized , double-blind , controlled trial . Setting Rural community in South Africa . Participants Three cohorts : 32 HIV-infected children ; 154 HIV-uninfected children born to HIV-infected mothers ; and 187 HIV-uninfected children born to HIV-uninfected mothers . Interventions Children received either 1250 IU of vitamin A ; vitamin A and 10 mg of zinc ; or vitamin A , zinc , vitamins B1 , B2 , B6 , B12 , C , D , E , and K and copper , iodine , iron , and niacin starting at 6 months and continuing to 24 months of age . Homes were visited weekly . Outcome Measures Primary outcome was percentage of days of diarrhea per child by study arm within each of the three cohorts . Secondary outcomes were prevalence of upper respiratory symptoms and percentage of children who ever had pneumonia by maternal report , or confirmed by the field worker . Results Among HIV-uninfected children born to HIV-infected mothers , median percentage of days with diarrhea was 2.3 % for 49 children allocated to vitamin A ; 2.5 % in 47 children allocated to receive vitamin A and zinc ; and 2.2 % for 46 children allocated to multiple micronutrients ( P = 0.852 ) . Among HIV-uninfected children born to HIV-uninfected mothers , median percentage of days of diarrhea was 2.4 % in 56 children in the vitamin A group ; 1.8 % in 57 children in the vitamin A and zinc group ; and 2.7 % in 52 children in the multiple micronutrient group ( P = 0.857 ) . Only 32 HIV-infected children were enrolled , and there were no differences between treatment arms in the prevalence of diarrhea . The prevalence of upper respiratory symptoms or incidence of pneumonia did not differ by treatment arms in any of the cohorts . Conclusion When compared with vitamin A alone , supplementation with zinc , or with zinc and multiple micronutrients , did not reduce diarrhea and respiratory morbidity in rural South African children . Trial Registration Clinical Trials.gov After age 6 mo , the combination of breast-feeding and unfortified plant-based complementary feeding provides inadequate zinc ( Zn ) . Additionally , high phytate intakes compromise the bioavailability of zinc . Our principal objective in this r and omized controlled , doubly masked trial was to determine the effect of substituting low-phytate maize , a daily 5-mg zinc supplement , or both , in infants between ages 6 - 12 mo on impaired linear growth velocity , a common feature of zinc deficiency . In the Western Highl and s of Guatemala , 412 infants were r and omized to receive low-phytate or control maize . Within each maize group , infants were further r and omized to receive a zinc supplement or placebo . Length , weight , and head circumference were measured at 6 , 9 , and 12 mo of age . There were no significant differences between the 2 maize groups or between the Zn supplement and placebo groups and no treatment interaction was observed for length-for-age ( LAZ ) , weight-for-length ( WLZ ) or head circumference Z-scores . Overall mean ( + /- SD ) Z-scores at 6 mo for combined treatment groups were : LAZ , -2.1 + /- 1.1 ; WLZ , 0.7 + /- 1.0 ; and head circumference Z-score , -0.7.0 + /- 1.0 . At 12 mo , these had declined further to : LAZ , -2.5 + /- 1.1 ; WLZ , -0.0 + /- 0.9 ; and head circumference Z-score , -0.9 + /- 1.1 ; 83.3 % were stunted and 2 % were wasted . Low linear growth in older Guatemalan infants was not improved with either low-phytate maize or a daily 5-mg zinc supplement . Low contribution of maize to the complementary food of the infants negated any potential advantage of feeding low-phytate maize BACKGROUND Stunting is highly prevalent in Ethiopia and many other developing countries but the reason for it is poorly understood . Zinc is essential for growth but diets in such countries often do not contain zinc in sufficient quantity or of sufficient bioavailability . Thus zinc deficiency may play a major role in stunting . The aim of the study was to investigate whether the low rate of linear growth of apparently healthy breastfed infants in a rural village in Ethiopia could be improved by zinc supplementation . METHODS A r and omised , double-blind , placebo-controlled trial was done on apparently healthy breastfed infants aged 6 - 12 months . 100 non-stunted ( length-for-age , Z score < -2 ) were matched for age and sex with 100 r and omly selected stunted ( > -2 ) infants . Infants , both stunted and non stunted , were matched by sex , age ( within 2 months ) and recumbent length ( within 3 cm ) for r and om assignment , to receive a zinc supplement ( 10 mg zinc per day , as zinc sulphate ) or placebo , 6 days a week for 6 months . Anthropometric measurements were taken monthly , data on illness and appetite were collected daily , and sample s of serum and hair were taken at the end of the intervention for the analysis of zinc . FINDINGS The length of stunted infants increased significantly more ( p<0.001 ) when supplemented with zinc ( 7.0 cm [ SE 1.1 ] ) than with placebo ( 2.8 cm [ 0.9 ] ) ; and the effect was greater ( p<0.01 ) than in non-stunted infants ( 6.6 [ 0.9 ] vs 5.0 [ 0.8 ] cm for the zinc and placebo groups respectively , p<0.01 ) . Zinc supplementation also increased the weight of stunted children ( 1.73 [ 0.39 ] vs 0.95 [ 0.39 ] kg for the corresponding placebo group , p<0.001 ) and of non-stunted children ( 1.19 [ 0.39 ] vs 1.02 [ 0.32 ] kg for the corresponding placebo group , p<0.05 ) . Zinc supplementation result ed in a markedly lower incidence of anorexia and morbidity from cough , diarrhoea , fever , and vomiting in the stunted children . The total number of these conditions per child was 1.56 and 1.11 in the stunted and non-stunted zinc supplemented children versus 3.38 and 1.64 in the stunted and non-stunted placebo-treated children , respectively . At the end of the intervention period , the concentrations of zinc in serum and hair of stunted infants , who had not been supplemented with zinc , were lower than the respective concentrations of zinc in serum and hair of their non-stunted counterparts . INTERPRETATION Combating zinc deficiency can increase the growth rate of stunted children to that of non-stunted infants in rural Ethiopia . This would appear to be due , at least in part , to reduction in morbidity from infection and increased appetite Background Diarrhea causes an estimated 2.5 million child deaths in developing countries each year , 35 % of which are due to acute diarrhea . Zinc and copper stores in the body are known to be depleted during acute diarrhea . Our objectives were to evaluate the efficacy of zinc and copper supplementation when given with st and ard treatment to children with acute watery or bloody diarrhea . Methods We conducted a double-blind r and omized controlled clinical trial in the Department of Pediatrics at Indira G and hi Government Medical College Nagpur , India . Eight hundred and eight children aged 6 months to 59 months with acute diarrhea were individually r and omized to placebo ( Pl ) , zinc ( Zn ) only , and zinc and copper ( Zn+Cu ) together with st and ard treatment for acute diarrhea . Results The mean duration of diarrhea from enrolment and the mean stool weight during hospital stay were 63.7 hours and 940 grams , respectively , and there were no significant differences in the adjusted means across treatment groups . Similarly , the adjusted means of the amount of oral rehydration solution or intravenous fluids used , the proportion of participants with diarrhea more than 7 days from onset , and the severity of diarrhea indicated by more than three episodes of some dehydration or any episode of severe dehydration after enrolment , did not differ across the three groups . Conclusion The expected beneficial effects of zinc supplementation for acute diarrhea were not observed . Therapeutic Zn or Zn and Cu supplementation may not have a universal beneficial impact on the duration of acute diarrhea in children . Trial registration The study was registered as an International St and ard R and omized Controlled Trial ( IS RCT N85071383 ) Background / Objectives : Micronutrient deficiencies are prevalent worldwide , and a major cause of infant death . Supplementation with multiple micronutrients during pregnancy might improve micronutrient status of the newborn , thereby reducing morbidity and death . Moreover , maternal supplementation might affect the newborn 's immune development . Therefore , this study investigated the effects of maternal zinc and β-carotene supplementation on the infant 's morbidity and immune function during the first 6 months of life . Subjects/ Methods : Mothers were supplemented during pregnancy with β-carotene and /or zinc , in addition to iron and folic acid , in a r and omized , double-blind controlled trial . Newborn infants ( n=136 ) were followed up for 6 months . Results : Infants born from mothers receiving zinc during pregnancy had significantly fewer episodes of diarrhoea than infants born from mothers not receiving zinc ( 0.2 and 0.4 , respectively ) , but more episodes of cough ( 1.3 and 0.9 respectively ) during the first 6 months . Maternal β-carotene supplementation had no effect on infants ’ morbidity . Cytokine production in the newborns was affected by maternal zinc and β-carotene supplementation , with zinc supplementation giving higher interleukin-6 production ( 16 % higher ) , and β-carotene supplementation leading to lower interferon-γ production ( 36 % lower ) . Conclusions : This study shows that maternal supplementation with zinc and β-carotene affected the newborn 's immune development in specific ways , but only maternal zinc supplementation significantly affected morbidity in the infants . Addition of zinc to routine iron and folic acid supplements for pregnant women could be an effective way to reduce diarrhoeal disease during the first 6 months of life , albeit at the expense of more episodes of cough BACKGROUND Studies from Asia have suggested that zinc supplementation can reduce morbidity and mortality in children , but evidence from malarious population s in Africa has been inconsistent . Our aim was to assess the effects of zinc supplementation on overall mortality in children in Pemba , Zanzibar . METHODS We enrolled 42,546 children aged 1 - 36 months , contributing a total of 56,507 child-years in a r and omised , double-blind , placebo-controlled trial in Pemba , Zanzibar . R and omisation was by household . 21 274 children received daily supplementation with zinc 10 mg ( 5 mg in children younger than 12 months ) for mean 484.7 days ( SD 306.6 ) . 21,272 received placebo . The primary endpoint was overall mortality , and analysis was by intention to treat . This study is registered as an International St and ard R and omised Clinical Trial , number IS RCT N59549825 . FINDINGS Overall , there was a non-significant 7 % ( 95 % CI -6 % to 19 % ; p=0.29 ) reduction in the relative risk of all-cause mortality associated with zinc supplementation . INTERPRETATION We believe that a meta- analysis of all studies of mortality and morbidity , will help to make evidence -based recommendations for the role of zinc supplementation in public health policy to improve mortality , morbidity , growth , and development in young children OBJECTIVE To evaluate the impact of zinc supplementation on the clinical course , stool weight , duration of diarrhoea , changes in serum zinc , and body weight gain of children with acute diarrhoea . DESIGN R and omised double blind controlled trial . Children were assigned to receive zinc ( 20 mg elemental zinc per day ) containing multivitamins or control group ( zinc-free multivitamins ) daily in three divided doses for two weeks . SETTING A diarrhoeal disease hospital in Dhaka , Bangladesh . PATIENTS 111 children , 3 to 24 months old , below 76 % median weight for age of the National Center for Health Statistics st and ard with acute diarrhoea . Children with severe infection and /or oedema were excluded . MAIN OUTCOME MEASURES Total diarrhoeal stool output , duration of diarrhoea , rate of weight gain , and changes in serum zinc levels after supplementation . RESULTS Stool output was 28 % less and duration 14 % shorter in the zinc supplemented group than placebo ( p = 0.06 ) . There were reductions in median total diarrhoeal stool output among zinc supplemented subjects who were shorter ( less than 95 % height for age ) , 239 v 326 g/kg ( p < 0.04 ) , and who had a lower initial serum zinc ( < 14 mmol/l ) , 279 v 329 g/kg ( p < 0.05 ) ; a shortening of mean time to recovery occurred ( 4.7v 6.2 days , p < 0.04 ) in those with lower serum zinc . There was an increase in mean serum zinc in the zinc supplemented group ( + 2.4 v −0.3 μmol/l , p < 0.001 ) during two weeks of supplementation , and better mean weight gain ( 120 v 30 g , p < 0.03 ) at the time of discharge from hospital . CONCLUSIONS Zinc supplementation is a simple , acceptable , and affordable strategy which should be considered in the management of acute diarrhoea and in prevention of growth faltering in children specially those who are malnourished . Key messages 20 mg of daily zinc supplementation reduced diarrhoeal stool in shorter children Zinc reduced diarrhoeal stool in those with low serum zinc Zinc reduced duration of diarrhoea in children with low serum zinc Zinc increased body weight of children during acute diarrhoeal episode Malnourished children are likely to benefit more from zinc This study was conducted to explore whether supplementation of zinc to children during persistent diarrhoea has any subsequent effect on morbidity and growth . A prospect i ve follow-up study was conducted among children , aged 3–24 months , with persistent diarrhoea , who participated earlier in a double-blind r and omized placebo-controlled trial . During persistent diarrhoea , children were r and omly allocated to receive either zinc in multivitamin syrup or only multivitamin syrup for two weeks . After recovering from diarrhoea , 76 children in the multi-vitamin syrup and 78 children in the zinc plus multivitamin syrup group were followed up for subsequent morbidity and growth . Weekly morbidity and two-weekly anthropometric data were collected for the subsequent 12 weeks . Data showed that episodes and duration of diarrhoea were reduced by 38 % and 44 % respectively with supplementation of zinc . There was no significant difference in the incidence or duration of respiratory tract infection between the zinc-supplemented and the non-supplemented group . Improved linear growth was observed in underweight children ( weight-for-age < 70 % of the National Center for Health Statistics st and ard ) who received zinc compared to those who did not receive To investigate whether micronutrient supplementation could improve the vibriocidal antibody response of children to a killed oral cholera vaccine , 2 - 5-year-old children were r and omly assigned to receive vitamin A and zinc ( AZ group ) , vitamin A and a placebo ( A group ) , zinc and a placebo ( Z group ) , or both placebos ( P group ) . All children received 2 doses of the vaccine . The number of children who had a > or = 4-fold increase in vibriocidal antibody was significantly greater in the AZ group than in the P group ( P = .025-.028 ) . Factorial analysis suggested that the proportion of children with a > or = 4-fold increase in vibriocidal antibody titer was significantly greater in the zinc-supplemented groups than in the groups that did not receive zinc ( P = .013-.048 ) and that vitamin A supplementation did not have a significant effect . Thus , supplementation with zinc improves seroconversion to vibriocidal antibody and , hence , has the potential to improve the efficacy of oral cholera vaccine in children The duration of pneumonia and of diarrhea is reported to be longer in HIV-infected than in uninfected children . We assessed the effect of a multi-micronutrient supplement on the duration of hospitalization in HIV-infected children . In a double-blind , r and omized trial , HIV-infected children ( 4 - 24 mo ) who were hospitalized with diarrhea or pneumonia were enrolled ( n = 118 ) and given a daily dose of a multi-micronutrient supplement ( containing vitamins A , B complex , C , D , E , and folic acid , as well as copper , iron , and zinc at levels based on recommended daily allowances ) or a placebo until discharge from the hospital . Children 's weights and heights were measured after enrollment and micronutrient concentrations were measured before discharge . On recovery from diarrhea or pneumonia , the children were discharged and the duration of hospitalization was noted . Anthropometric indices and micronutrient concentrations did not differ between children who received supplements and those who received placebos . Overall , the duration of hospitalization was shorter ( P < 0.05 ) among children who were receiving supplements ( 7.3 + /- 3.9 d ) ( mean + /- SD ) than in children who were receiving placebos ( 9.0 + /- 4.9 ) ; this was independent of admission diagnosis . In children admitted with diarrhea , the duration of hospitalization was 1.6 d ( 19 % ) shorter among children receiving supplements than in those receiving placebos , and hospitalization for pneumonia was 1.9 d ( 20 % ) shorter among children receiving supplements . Short-term multi-micronutrient supplementation significantly reduced the duration of pneumonia or diarrhea in HIV-infected children who were not yet receiving antiretroviral therapy and who remained alive during hospitalization Background and Aim : The World Health Organization recommends oral zinc ( tablets or syrups ) as adjunct therapy with oral rehydration solution ( ORS ) for acute childhood diarrhea . Mixing zinc with ORS can be an attractive approach for simultaneous provision of these 2 effective interventions . This double-masked r and omized controlled trial evaluated the efficacy of ORS containing 40 mg/L elemental zinc per liter ( zinc-ORS ) in reducing stool weight and duration of diarrhea . Patients and Methods : Five hundred northern Indian children ages 1 to 35 months with diarrhea < 7 days ’ duration were r and omized to zinc-ORS or ORS . The primary outcomes were total stool output and time to recovery . Results : The median total stool output was 2.12 g · kg−1 · h−1 ( interquartile range [ IQR ] 0.9–3.76 ) in the zinc-ORS group compared with 1.78 g · kg−1 · h−1 ( IQR 0.83–3.45 ) in the ORS group . The time to recovery was also similar in the 2 groups ( hazard ratio 1.06 [ 95 % confidence interval 0.88–1.27 ] ) . In subjects who received zinc-ORS , the median ( IQR ) zinc intakes were 27 ( 16–46 ) mg on day 1 , 15 ( 6–27 ) mg on day 2 , and negligible thereafter . Conclusions : The World Health Organization – recommended daily dose of zinc for diarrhea was not achieved in most children beyond the first day of treatment . This is the likely explanation for the lack of improvement in outcomes from zinc-ORS when compared with ORS alone . Our findings do not support a change from using zinc syrup or dispersible tablets for treatment of acute diarrhea in children Abstract Although oral rehydration therapy greatly reduces mortality from diarrhoeal diseases , it has little effect on stool frequency . However , there is mounting evidence that zinc is an effective adjunct to the treatment of diarrhoea , although few studies have examined its efficacy in Latin America . This study assessed the efficacy of zinc supplementation in children with acute diarrhoea in Brazil . The study was a double-blind , placebo-controlled , r and omised , clinical trial in children < 5 years of age attending emergency services in Sergipe , Brazil . Subjects received zinc or vitamin C as placebo . There was a marked reduction in the duration of the diarrhoea ( 1.1 vs 2.6 days ) and of watery stools in the zinc-supplemented group . The efficacy of zinc was independent of the presence of viral enteropathogens in the stools . It is concluded that , similar to studies in India and Bangladesh , zinc could be an important adjunct for treating acute diarrhoea in Brazilian children A controlled r and omized trial was conducted in 40 infants ( 6 - 18 months old ) with persistent diarrhoea ( greater than 2 weeks ' duration ) to evaluate the effect of oral zinc supplementation . After completion of rehydration , 20 infants in group A received oral zinc sulphate ( 20 mg elemental zinc twice daily ) and an equal number in group B were given a placebo ( glucose ) . Each child was given oral nalidixic acid and a similar milk-free feeding schedule . Both the groups were comparable with respect to various initial characteristics including nutrition , diarrhoeal disease , serum alkaline phosphatase and serum and rectal mucosal zinc content . During therapy , all the assessed parameters of zinc status ( serum alkaline phosphatase and serum and rectal zinc ) recorded significant elevation and reduction in groups A and B , respectively . At recovery , the zinc status of group A was significantly higher than that of group B. The diarrhoeal duration and frequency in the zinc-supplemented group were lower but the differences were not statistically significant ( p = 0.078 and p = 0.076 , respectively ) . Weight gain in both groups was comparable . It is concluded that in persistent diarrhoea there is depletion of zinc with the progression of disease and oral zinc administration can improve the zinc status . The possible anti-diarrhoeal effect of zinc , however , merits further study BACKGROUND Adequate zinc is critical for immune function ; however , zinc deficiency occurs in > 50 % of human immunodeficiency virus (HIV)-infected adults . We examined the safety and efficacy of long-term zinc supplementation in relation to HIV disease progression . METHODS A prospect i ve , r and omized , controlled clinical trial was conducted involving 231 HIV-infected adults with low plasma zinc levels ( < 0.75 mg/L ) , who were r and omly assigned to receive zinc ( 12 mg of elemental zinc for women and 15 mg for men ) or placebo for 18 months . The primary end point was immunological failure . HIV viral load and CD4(+ ) cell count were determined every 6 months . Question naires , pill counts , and plasma zinc and C-reactive protein levels were used to monitor adherence to study supplements and antiretroviral therapy . Intent-to-treat analysis used multiple-event analysis , treating CD4(+ ) cell count < 200 cells/mm(3 ) as a recurrent immunological failure event . Cox proportional hazard models and the general-linear model were used to analyze morbidity and mortality data . RESULTS Zinc supplementation for 18 months reduced 4-fold the likelihood of immunological failure , controlling for age , sex , food insecurity , baseline CD4(+ ) cell count , viral load , and antiretroviral therapy ( relative rate , 0.24 ; 95 % confidence interval , 0.10 - 0.56 ; P<.002 ) . Viral load indicated poor control with antiretroviral therapy but was not affected by zinc supplementation . Zinc supplementation also reduced the rate of diarrhea by more than half ( odds ratio , 0.4 ; 95 % confidence interval , 0.183 - 0.981 ; P=.019 ) , compared with placebo . There was no significant difference in mortality between the 2 groups . CONCLUSIONS This study demonstrated that long-term ( 18-month ) zinc supplementation at nutritional levels delayed immunological failure and decreased diarrhea over time . This evidence supports the use of zinc supplementation as an adjunct therapy for HIV-infected adult cohorts with poor viral control . Trial registration . Clinical Trials.gov identifier : NCT00149552 In a community-based double-blind r and omized trial in children aged 6–35 months , both intervention and control groups received a multi-vitamin syrup containing vitamin A , while the intervention group had zinc gluconate ( equivalent to 10 mg of elemental zinc ) additional in the syrup . There was a significant decrease in diarrhoea and pneumonia in the intervention group . This study was undertaken to investigate if addition of zinc to vitamin A had improved plasma retinol levels , which , in turn , was responsible for the effects observed in the intervention group . In a r and omly-selected sub sample of 200 children—100 each from the intervention and the control group , plasma retinol levels after 120 days of supplementation were measured . There was no difference in the mean plasma retinol levels [ the difference in the mean 0.46 μg/dL ( 95 % confidence interval -1.42–2.36 ) ] between the two groups following supplementation . No difference in plasma retinol levels was observed in the subgroups based on baseline nutritional status and plasma zinc levels . Addition of zinc to low-dose vitamin A in this study did not improve the vitamin A status of children and can not explain morbidity effects of the intervention Community-based data relating to factors influencing zinc deficiency among preschool children in India are inadequate . Data of a large , double-blinded , r and omized , controlled zinc-supplementation trial were used for assessing the descriptive epidemiology of zinc deficiency among children aged 6–35 months ( n=940 ) . In total , 609 children were followed up for 120 days for information on morbidity . Of these children , 116 from the control group belonging to the upper and the lower 25th quartile of plasma zinc status at baseline were selected for assessing the association of zinc deficiency with prospect i ve morbidity . At baseline , demographic , socioeconomic and dietary information was collected , and anthropometric measurements and levels of plasma zinc were assessed . At baseline , 73.3 % of the children were zinc-deficient ( plasma zinc < 70 µg/dL ) , of which 33.8 % had levels of plasma zinc below 60 µg/dL. A significantly higher risk of morbidity was prevalent among the subjects with lower plasma zinc compared to those with higher levels of plasma zinc Background Diarrhea remains one of the leading public health issues in developing countries and is a major contributor in morbidity and mortality in children under five years of age . Interventions such as ORS , Zinc , water purification and improved hygiene and sanitation can significantly reduce the diarrhea burden but their coverage remains low and has not been tested as packaged intervention before . This study attempts to evaluate the package of evidence based interventions in a “ Diarrhea Pack ” through first level health care providers at domiciliary level in community based setting s. This study sought to evaluate the acceptability , feasibility and impact of diarrhea Pack on diarrhea burden . Methods A cluster r and omized design was used to evaluate the objectives of the project a union council was considered as a cluster for analysis , a total of eight clusters , four in intervention and four in control were included in the study . We conducted a baseline survey in all clusters followed by the delivery of diarrhea Pack in intervention clusters through community health workers at domiciliary level and through sales promoters to health care providers and pharmacies . Four quarterly surveillance rounds were conducted to evaluate the impact of diarrhea pack in all clusters by an independent team of Field workers . Results Both the intervention and control clusters were similar at the baseline but as the study progress we found a significant increase in uptake of ORS and Zinc along with the reduction in antibiotic use , diarrhea burden and hospitalization in intervention clusters when compared with the control clusters . We found that the Diarrhea Pack was well accepted with all of its components in the community . Conclusion The intervention was well accepted and had a productive impact on the uptake of ORS and zinc and reduction in the use of antibiotics . It is feasible to deliver interventions such as diarrhea pack through community health workers in community setting s. The intervention has the potential to be scaled up at national level In Brazil , the highest incidence of low birth weight ( LBW ) occurs in the northeast , and diarrhea and respiratory infections are the main causes of infant mortality and morbidity . We hypothesized that LBW infants may be zinc deficient , and that this might be adversely affecting their immune function , morbidity , and postnatal growth . We therefore examined the effect of zinc supplementation on these outcomes during the first 6 mo of life . LBW full-term infants ( mean birth weight 2337 g ) were given daily for 8 wk either 5 mg Zn ( n = 71 ) , 1 mg Zn ( n = 68 ) , or a placebo ( n = 66 ) . Morbidity was determined prospect ively through daily home visits ( except on Sunday ) during weeks 0 - 8 , then twice weekly in weeks 9 - 26 . Anthropometric measurements were made at 0 , 4 , 8 , 17 , and 26 wk . Immune function was assessed at 8 wk by the phytohemagglutinin skin test . Supplementation ( 5 mg Zn ) was associated with a 28 % reduction in diarrhea prevalence over the 6-mo period [ after adjustment for confounders ( P = 0.043 ) ] , and a 33 % reduction in the prevalence of cough ( NS , adjusted prevalence P = 0.073 ) . All infants had a positive immune response at 8 wk . Although supplementation had no significant effect on weight and length gains from 0 to 26 wk , infants given 5 mg Zn gained more weight than infants given placebo during weeks 17 - 26 ( P = 0.024 , analysis of variance ) . There was no effect on any outcome with 1 mg Zn . We conclude that 5 mg Zn/d is of benefit to LBW , full-term infants who only have a modest weight deficit Abstract Objective : To evaluate the effect on morbidity and mortality of providing daily zinc for 14 days to children with diarrhoea . Design : Cluster r and omised comparison . Setting : Matlab field site of International Center for Diarrhoeal Disease Research , Bangladesh . Participants : 8070 children aged 3 - 59 months contributed 11 881 child years of observation during a two year period . Intervention : Children with diarrhoea in the intervention clusters were treated with zinc ( 20 mg per day for 14 days ) ; all children with diarrhoea were treated with oral rehydration therapy . Main outcome measures : Duration of episode of diarrhoea , incidence of diarrhoea and acute lower respiratory infections , admission to hospital for diarrhoea or acute lower respiratory infections , and child mortality . Results : About 40 % ( 399/1007 ) of diarrhoeal episodes were treated with zinc in the first four months of the trial ; the rate rose to 67 % ( 350/526 ) in month 5 and to > 80 % ( 364/434 ) in month 7 and was sustained at that level . Children from the intervention cluster received zinc for about seven days on average during each episode of diarrhoea . They had a shorter duration ( hazard ratio 0.76 , 95 % confidence interval 0.65 to 0.90 ) and lower incidence of diarrhoea ( rate ratio 0.85 , 0.76 to 0.96 ) than children in the comparison group . Incidence of acute lower respiratory infection was reduced in the intervention group but not in the comparison group . Admission to hospital of children with diarrhoea was lower in the intervention group than in the comparison group ( 0.76 , 0.59 to 0.98 ) . Admission for acute lower respiratory infection was lower in the intervention group , but this was not statistically significant ( 0.81 , 0.53 to 1.23 ) . The rate of non-injury deaths in the intervention clusters was considerably lower ( 0.49 , 0.25 to 0.94 ) . Conclusions : The lower rates of child morbidity and mortality with zinc treatment represent substantial benefits from a simple and inexpensive intervention that can be incorporated in existing efforts to control diarrhoeal disease . What is already known on this topic Zinc deficiency is highly prevalent in children in developing countries Zinc supplements given during diarrhoea reduce the duration and severity of treated episodes If given for 14 days during and after diarrhoea , zinc reduces the incidence of diarrhoea and pneumonia in the subsequent two to three months What this study adds Zinc used as a treatment for diarrhoea reduces mortality in children Zinc reduces admissions to hospital for diarrhoea The impact of zinc on mortality and morbidity can be achieved in a realistic large scale public health Background The period of complementary feeding , starting around 6 months of age , is a time of high risk for growth faltering and morbidity . Low micronutrient density of locally available foods is a common problem in low income countries . Children of HIV-infected women are especially vulnerable . Although antiretroviral prophylaxis can reduce breast milk HIV transmission in early infancy , there are no clear feeding guidelines for after 6 months . There is a need for acceptable , feasible , affordable , sustainable and safe ( AFASS by WHO terminology ) foods for both HIV-exposed and unexposed children after 6 months of age . Methods and Findings We conducted in Lusaka , Zambia , a r and omised double-blind trial of two locally made infant foods : porridges made of flour composed of maize , beans , bambaranuts and groundnuts . One flour contained a basal and the other a rich level of micronutrient fortification . Infants ( n = 743 ) aged 6 months were r and omised to receive either regime for 12 months . The primary outcome was stunting ( length-for-age Z<−2 ) at age 18 months . No significant differences were seen between trial arms overall in proportion stunted at 18 months ( adjusted odds ratio 0.87 ; 95 % CI 0.50 , 1.53 ; P = 0.63 ) , mean length-for-age Z score , or rate of hospital referral or death . Among children of HIV-infected mothers who breastfed < 6 months ( 53 % of HIV-infected mothers ) , the richly-fortified porridge increased length-for-age and reduced stunting ( adjusted odds ratio 0.17 ; 95 % CI 0.04 , 0.84 ; P = 0.03 ) . Rich fortification improved iron status at 18 months as measured by hemoglobin , ferritin and serum transferrin receptors . Conclusions In the whole study population , the rich micronutrient fortification did not reduce stunting or hospital referral but did improve iron status and reduce anemia . Importantly , in the infants of HIV-infected mothers who stopped breastfeeding before 6 months , the rich fortification improved linear growth . Provision of such fortified foods may benefit health of these high risk infants . Trial registration Controlled-Trials.com IS RCT Zinc for the treatment of childhood diarrhoea was introduced in a pilot area in southern Mali to prepare for a cluster-r and omized effectiveness study and to inform policies on how to best introduce and promote zinc at the community level . Dispersible zinc tablets in 14-tablet blister packs were provided through community health centres and drug kits managed by community health workers ( CHWs ) in two health zones in Bougouni district , Mali . Village meetings and individual counselling provided by CHWs and head nurses at health centres were the principal channels of communication . A combination of methods were employed to ( a ) detect problems in communication about the benefits of zinc and its mode of administration ; ( b ) identify and resolve obstacles to implementation of zinc through existing health services ; and ( c ) describe household-level constraints to the adoption of appropriate home-management practice s for diarrhoea , including administration of both zinc and oral rehydration solution ( ORS ) . Population -based household surveys with caretakers of children sick in the previous two weeks were carried out before and four months after the introduction of zinc supplementation . Household follow-up visits with children receiving zinc from the health centres and CHWs were conducted on day 3 and 14 after treatment for a sub sample of children . A qualitative process evaluation also was conducted to investigate operational issues . Preliminary evidence from this study suggests that the introduction of zinc does not reduce the use of ORS and may reduce inappropriate antibiotic use for childhood diarrhoea . Financial access to treatments , management of concurrent diarrhoea and fever , and high use of unauthorized drug vendors were identified as factors affecting the effectiveness of the intervention in this setting . The introduction of zinc , if not appropriately integrated with other disease-control strategies , has the potential to decrease the appropriate presumptive treatment of childhood malaria in children with diarrhoea and fever in malaria-endemic areas Abstract Objective : To study the effects of zinc supplementation on malaria and other causes of morbidity in young children living in an area holoendemic for malaria in west Africa . Design : R and omised , double blind , placebo controlled efficacy trial . Setting : 18 villages in rural northwestern Burkina Faso . Participants : 709 children were enrolled ; 685 completed the trial . Intervention : Supplementation with zinc ( 12.5 mg zinc sulphate ) or placebo daily for six days a week for six months . Main outcome measures : The primary outcome was the incidence of symptomatic falciparum malaria . Secondary outcomes were the severity of malaria episodes , prevalence of malaria parasite , mean parasite densities , mean packed cell volume , prevalence of other morbidity , and all cause mortality . Results : The mean number of malaria episodes per child ( defined as a temperature ≥37.5 ° C with ≥5000 parasites/μl ) was 1.7 , 99.7 % due to infection with Plasmodium falciparum . No difference was found between the zinc and placebo groups in the incidence of falciparum malaria ( relative risk 0.98 , 95 % confidence interval 0.86 to 1.11 ) , mean temperature , and mean parasite densities during malaria episodes , nor in malaria parasite rates , mean parasite densities , and mean packed cell volume during cross sectional surveys . Zinc supplementation was significantly associated with a reduced prevalence of diarrhoea ( 0.87 , 0.79 to 0.95 ) . All cause mortality was non-significantly lower in children given zinc compared with those given placebo ( 5 v 12 , P=0.1 ) . Conclusions : Zinc supplementation has no effect on morbidity from falciparum malaria in children in rural west Africa , but it does reduce morbidity associated with diarrhoea . What is already known on this topic Zinc deficiency is common in infants in developing countries Zinc supplementation has been shown to reduce morbidity from infectious disease in such population s , particularly through reductions in morbidity from diarrhoea and respiratory infections Limited evidence exists for zinc supplementation being effective in reducing morbidity from malaria What this study adds Zinc supplementation has no effect on falciparum malaria in children in rural west Africa It is effective in reducing morbidity from diarrhoea and may help to reduce mortality from all Background Although micronutrient supplementation can reduce morbidity and mortality due to diarrhoea , nutritional influences on intestinal host defence are poorly understood . We tested the hypothesis that micronutrient supplementation can enhance barrier function of the gut . Methods We carried out two sub- studies nested within a r and omised , double-blind placebo-controlled trial of daily micronutrient supplementation in an urban community in Lusaka , Zambia . In the first sub- study , gastric pH was measured in 203 participants . In the second sub- study , mucosal permeability , lipopolysaccharide ( LPS ) and anti-LPS antibodies , and serum soluble tumour necrosis factor receptor p55 ( sTNFR55 ) concentrations were measured in 87 participants . Up to three stool sample s were also analysed microbiologically for detection of asymptomatic intestinal infection . Gastric histology was subsequently analysed in a third subset ( n = 37 ) to assist in interpretation of the pH data . Informed consent was obtained from all participants after a three-stage information and consent process . Results Hypochlorhydria ( fasting gastric pH > 4.0 ) was present in 75 ( 37 % ) of participants . In multivariate analysis , HIV infection ( OR 4.1 ; 95%CI 2.2 - 7.8 ; P < 0.001 ) was associated with hypochlorhydria , but taking anti-retroviral treatment ( OR 0.16 ; 0.04 - 0.67 ; P = 0.01 ) and allocation to micronutrient supplementation ( OR 0.53 ; 0.28 - 0.99 ; P < 0.05 ) were protective . Hypochlorhydria was associated with increased risk of salmonellosis . Mild ( grade 1 ) gastric atrophy was found in 5 participants , irrespective of Helicobacter pylori or HIV status . Intestinal permeability , LPS concentrations in serum , anti-LPS IgG , and sTNFR55 concentrations did not differ significantly between micronutrient and placebo groups . Anti-LPS IgM was reduced in the micronutrient recipients ( P < 0.05 ) . Conclusions We found evidence of a specific effect of HIV on gastric pH which was readily reversed by anti-retroviral therapy and not mediated by gastric atrophy . Micronutrients had a modest impact on gastric pH and one marker of bacterial translocation . Trial Registration Current Controlled Trials IS RCT The benefit of zinc for the treatment of diarrhoea in a cluster-r and omized trial of children , aged 3–59 months , living in rural Bangladesh was previously reported . Here , the benefits of zinc stratified by age—3–5 months , 6–11 months , and 12–59 months — are reported . Although the sample sizes in the stratified groups were too small to detect statistical significance in the 3–5-month and 6–11-month age-groups , the trends suggest that there may be a benefit of zinc for the treatment of diarrhoea on the duration of diarrhoea and on subsequent morbidity and mortality . Additional research is needed to better underst and the effect of zinc for the treatment of diarrhoea among infants aged less than six months OBJECTIVE To test the hypothesis that daily supplementation of zinc and copper mixed with the oral rehydration solution ( ORS ) reduces the duration and the severity of acute diarrhea in children . METHODS In a r and omized , double blind , placebo controlled trial children aged 6 months to 59 months in an urban hospital with acute diarrhea , were assigned to receive the intervention of once daily 40 mg of zinc sulfate and 5 mg of copper sulfate dissolved in a liter of st and ard ORS ( n = 102 ) or placebo ( 50 mg of st and ard ORS powder ) dissolved in a liter of ORS ( n = 98 ) . RESULT The baseline characteristics in the two groups were similar . The mean survival time ( days ) ( SE ) with diarrhea was not significantly different in the treatment ( 4.34 ( 0.2 ) ) as compared to the placebo group ( 4.48 ( 0.2 ) ) , nor was there any difference in the median time to cure . Cure was less likely with longer duration of diarrhea prior to enrollment ( P < 0.001 ) , if the time taken for rehydration was more ( P = 0.001 ) and if intravenous fluids were used ( P = 0.03 ) regardless of the micronutrient supplementation . The proportion of children with diarrhea > 4 days was 46 % in the placebo group with an adjusted odds ratio ( OR ) ( 95 % CI ) of 1.19 ( 1.58 , 0.9 ; P = 0.2 ) as compared to 39 % in the supplemented group . The most important risk factor for diarrhea > 4 days was diarrheal duration prior to enrollment with OR = 6.25 ( 3.7 , 11.1 ) . The supplemented group however had less severity of diarrhea with a lower proportion of children requiring unscheduled intravenous fluids ( OR = 0.4 ; 95 % CI 0.05 , 2.2 ) , with weight loss ( OR = 0.7 ; 95 % CI ; 0.4 , 1.3 ) , with complications ( OR = 0.15 ; 0.01 , 1.3 ) and had no deaths as compared to two in the placebo group . CONCLUSIONS This study showed that the most important predictor for duration of diarrhea in children was the severity of the disease at enrollment , and , not the supplementation . There were clinical beneficial effects of supplementation on rate of any complications and mortality . A larger trial is warranted before supplementation of micronutrients mixed with ORS are recommended for management of acute diarrhea Objective To evaluate the efficacy of milk fortified with specific multiple micronutrients on morbidity in children compared with the same milk without fortification . Design Community based , double masked , individually r and omised trial . Setting Peri-urban settlement in north India . Participants Children ( n=633 ) aged 1 - 3 r and omly allocated to receive fortified milk ( n=316 ) or control milk ( n=317 ) . Intervention One year of fortified milk providing additional 7.8 mg zinc , 9.6 mg iron , 4.2 � g selenium , 0.27 mg copper , 156 � g vitamin A , 40.2 mg vitamin C , 7.5 mg vitamin E per day ( three feeds ) . Main outcome measures Days with severe illnesses , incidence and prevalence of diarrhoea , and acute lower respiratory illness . Results Study groups were comparable at baseline ; compliance in the groups was similar . Mean number of episodes of diarrhoea per child was 4.46 ( SD 3.8 ) in the intervention ( fortified milk ) group and 5.36 ( SD 4.1 ) in the control group . Mean number of episodes of acute lower respiratory illness was 0.62 ( SD 1.1 ) and 0.83 ( SD 1.4 ) , respectively . The fortified milk reduced the odds for days with severe illnesses by 15 % ( 95 % confidence interval 5 % to 24 % ) , the incidence of diarrhoea by 18 % ( 7 % to 27 % ) , and the incidence of acute lower respiratory illness by 26 % ( 3 % to 43 % ) . Consistently greater beneficial effects were observed in children aged ≤24 months than in older children . Conclusion Milk is well accepted as a means of delivery of micronutrients . Consumption of milk fortified with specific micronutrients can significantly reduce the burden of common morbidities among preschool children , especially in the first two years of life . Trial registration NCT00255385 Objective . To evaluate the potential benefit of dietary supplementation of a rice-lentil ( Khitchri ) and yogurt diet with 3 mg/kg/d of elemental zinc ( as zinc sulfate ) in hospitalized malnourished children ( age 6–36 months ) with persistent diarrhea for 14 days . Methodology . R and omized , double-blind placebo-controlled trial . Setting . Nutrition Research Ward at the National Institute of Child Health , Karachi , Pakistan , where children were admitted for 14 days of inpatient supervised rehabilitation . Main Outcome Measures . Primary outcome : overall weight gain by day 14 . Secondary outcomes : overall energy intake , stool output , time to diarrheal recovery and weight gain ( ≥3 days ) , plasma zinc , copper , prealbumin , and insulin-like growth factor-1 . Results . Of 87 children r and omized for supplementation with either zinc or placebo , the two groups were comparable at admission in terms of severity and duration of diarrhea , as well as nutritional and anthropometric parameters . The overall weight gain , stool volume , stool frequency , as well as the time taken for diarrheal recovery or steady weight gain , were comparable for both supplemented children and controls . Supplemented children had a significant improvement in plasma zinc levels and serum alkaline phosphatase by day 14 of therapy in comparison with controls . Plasma copper levels were low in both groups at admission and although an increase was seen in control children , levels decreased further after zinc supplementation . There was no significant difference between the two groups for hemoglobin , serum albumin , prealbumin , and plasma insulin-like growth factor-1 increments during the course of therapy . Evaluation of primary and secondary outcome criteria among the subset of children with plasma zinc levels < 60 μg/d at admission did not reveal any significant differences . Conclusions . Although there was satisfactory recovery in malnourished children with persistent diarrhea receiving the Khitchri-yogurt diet , there was no evidence of improved weight gain or acceleration of recovery from diarrhea with zinc supplementation . In contrast , the reduction in plasma copper levels in zinc-supplemented malnourished children suggests that caution should be exercised in supplementing severely malnourished children with zinc alone Background / Objective : The efficacy of zinc combined with vitamin A or multiple micronutrients in preventing diarrhoea is unclear in African countries with high prevalence of human immunodeficiency virus (HIV)-exposed children . Potential modifying factors , such as stunting , need to be addressed . The objective of this study was to determine whether adding zinc or zinc plus multiple micronutrients to vitamin A reduces diarrhoea incidence , and whether this differs between the strata of stunted or HIV-infected children . Methods : We analyzed data from a r and omized , controlled , double-blinded trial ( Clinical Trials.gov NCT00156832 ) of prophylactic micronutrient supplementation to children aged 6–24 months . Three cohorts of children : 32 HIV-infected children , 154 HIV-uninfected children born to HIV-infected mothers and 187 uninfected children born to HIV-uninfected mothers , received vitamin A , vitamin A plus zinc or multiple micronutrients , which included vitamin A and zinc . The main outcome was incidence of diarrhoea . Poisson regression was used in intent-to-treat analyses . Stratified analyses followed testing for statistical interaction between intervention and stunting . Results : We observed no significant differences in overall diarrhoea incidence among treatment arms . Stunting modified this effect with stunted HIV-uninfected children having significantly lower diarrhoea incidence when supplemented with zinc or multiple micronutrients compared with vitamin A alone ( 2.04 and 2.23 vs 3.92 episodes/year , respectively , P=0.024 ) . No meaningful subgroup analyses could be done in the cohort of HIV-infected children . Conclusions : Compared with vitamin A alone , supplementation with zinc and with zinc and multiple micronutrients , reduced diarrhoea morbidity in stunted rural South African children . Efficacy of zinc supplementation in HIV-infected children needs confirmation in studies that represent the spectrum of disease severity and age groups Background Asymptomatic carriage of Giardia intestinalis is highly prevalent among children in developing countries , and evidence regarding its role as a diarrhea-causing agent in these setting s is controversial . Impaired linear growth and cognition have been associated with giardiasis , presumably mediated by malabsorption of nutrients . In a prospect i ve cohort study , we aim to compare diarrhea rates in pre-school children with and without Giardia infection . Because the study was conducted in the context of an intervention trial assessing the effects of multi-nutrients on morbidity , we also assessed how supplementation influenced the relationship between Giardia and diarrhoea rates , and to what extent Giardia modifies the intervention effect on nutritional status . Methods and Findings Data were collected in the context of a r and omized placebo-controlled efficacy trial with 2 × 2 factorial design assessing the effects of zinc and /or multi-micronutrients on morbidity ( n = 612 ; height-for-age z-score < −1.5 SD ) . Outcomes measures were episodes of diarrhea ( any reported , or with ≥3 stools in the last 24 h ) and fever without localizing signs , as detected with health-facility based surveillance . Giardia was detected in stool by enzyme-linked immunosorbent assay . Among children who did not receive multi-nutrients , asymptomatic Giardia infection at baseline was associated with a substantial reduction in the rate of diarrhea ( HR 0.32 ; 0.15–0.66 ) and fever without localizing signs ( HR 0.56 ; 0.36–0.87 ) , whereas no such effect was observed among children who received multi-nutrients ( p-values for interaction 0.03 for both outcomes ) . This interaction was independent of age , HAZ-scores and distance to the research dispensary . There was no evidence that Giardia modified the intervention effect on nutritional status . Conclusion Although causality of the Giardia-associated reduction in morbidity can not be established , multi-nutrient supplementation results in a loss of this protection and thus seems to influence the proliferation or virulence of Giardia or associated intestinal pathogens Background The world health organization guidelines for treatment of diarrhea in children emphasize on continued feeding together with prescription of oral rehydration solution ( ORS ) and supplementary zinc therapy . However , conflicting viewpoints exist regarding the optimal diet and dietary ingredients for children with diarrhea . Moreover , few studies have investigated the effect of rice soup along with ORS in the treatment of this disease . Objectives This study aim ed to explore effects of simultaneous taking of glucose oral rehydration solution ( G-ORS ) and rice soup in the treatment of acute diarrhea in 8 to 24-month-old children . Patients and Methods This single-blind controlled clinical trial was conducted in the pediatric ward of 22nd of Bahman hospital , Gonabad , Iran between June 2013 and February 2014 . Forty children aged 8 - 24 months with acute diarrhea were r and omly assigned into an intervention group ( G-ORS plus rice soup group ) comprising 20 babies and a control group ( G-ORS ) of 20 children based on balanced blocking r and omization . The variables under investigation were diarrhea duration , patient hospitalization , need for intravenous ( IV ) fluids and stool output frequency . Data was analyzed using independent sample s t and chi-square test . Results At the end of study , the time for treating acute watery diarrhea in the intervention and control groups were 21.10 ± 8.81 and 34.55 ± 5.82 hours ( P < 0.001 ) and hospital stay were 34.05 ± 6.62 and 40.20 ± 6.32 hours ( P = 0.005 ) . Moreover , stool output frequency were 4.20 ± 0.95 and 8.00 ± 1.37 ( P < 0.001 ) in the first 24 hours , and 2.18 ± 0.60 and 2.80 ± 0.76 ( P = 0.03 ) in the second 24 hours of treatment in intervention and control groups , respectively . Conclusions Rice soup regimen was highly effective and inexpensive in the treatment of acute diarrhea in children . Thus , in addition to the common treatment by G-ORS , rice soup can be consumed simultaneously with G-ORS The long-term benefits of antenatal iron supplementation in child survival are not known . In 1999 - 2001 , 4,926 pregnant women in rural Nepal participated in a cluster-r and omized , double-masked , controlled trial involving 4 alternative combinations of micronutrient supplements , each containing vitamin A. The authors examined the impact on birth weight and early infant mortality in comparison with controls , who received vitamin A only . They followed the surviving offspring of these women at approximately age 7 years to study effects of in utero supplementation on survival . Of 4,130 livebirths , 209 infants died in the first 3 months and 8 were lost to follow-up . Of those remaining , 3,761 were followed , 150 died between ages 3 months and 7 years , and 152 were lost to follow-up . Mortality rates per 1,000 child-years from birth to age 7 years differed by maternal supplementation group , as follows : folic acid , 13.4 ; folic acid-iron , 10.3 ; folic acid-iron-zinc , 12.0 ; multiple micronutrients ; 14.0 ; and controls , 15.2 . Hazard ratios were 0.90 ( 95 % confidence interval ( CI ) : 0.65 , 1.22 ) , 0.69 ( 95 % CI : 0.49 , 0.99 ) , 0.80 ( 95 % CI : 0.58 , 1.11 ) , and 0.93 ( 95 % CI : 0.66 , 1.31 ) , respectively , in the 4 supplementation groups . Maternal iron-folic acid supplementation reduced mortality among these children by 31 % between birth and age 7 years . These results provide additional motivation for strengthening antenatal iron-folic acid programs Background The benefits of zinc or multiple micronutrient supplementations in African children are uncertain . African children may differ from other population s of children in developing countries because of differences in the prevalence of zinc deficiency , low birth weight and preterm delivery , recurrent or chronic infections such as HIV , or the quality of complementary diets and genetic polymorphisms affecting iron metabolism . The aim of this study was to ascertain whether adding zinc or multiple micronutrients to vitamin A supplementation improves longitudinal growth or reduces prevalence of anemia in children aged 6 - 24 months . Methods R and omized , controlled double-blinded trial of prophylactic micronutrient supplementation to children aged 6 - 24 months . Children in three cohorts - 32 HIV-infected children , 154 HIV-uninfected children born to HIV-infected mothers , and 187 uninfected children born to HIV-uninfected mothers - were separately r and omly assigned to receive daily vitamin A ( VA ) [ n = 124 ] , vitamin A plus zinc ( VAZ ) [ n = 123 ] , or multiple micronutrients that included vitamin A and zinc ( MM ) [ n = 126 ] . Results Among all children there were no significant differences between intervention arms in length-for-age Z scores ( LAZ ) changes over 18 months . Among stunted children ( LAZ below -2 ) [ n = 62 ] , those receiving MM had a 0.7 Z-score improvement in LAZ versus declines of 0.3 in VAZ and 0.2 in VA ( P = 0.029 when comparing effects of treatment over time ) . In the 154 HIV-uninfected children , MM ameliorated the effect of repeated diarrhea on growth . Among those experiencing more than six episodes , those receiving MM had no decline in LAZ compared to 0.5 and 0.6 Z-score declines in children receiving VAZ and VA respectively ( P = 0.06 for treatment by time interaction ) . After 12 months , there was 24 % reduction in proportion of children with anemia ( hemoglobin below 11 g/dL ) in MM arm ( P = 0.001 ) , 11 % in VAZ ( P = 0.131 ) and 18 % in VA ( P = 0.019 ) . Although the within arm changes were significant ; the between-group differences were not significant . Conclusions Daily multiple micronutrient supplementation combined with vitamin A was beneficial in improving growth among children with stunting , compared to vitamin A alone or to vitamin A plus zinc . Effects on anemia require further study .Trial registration This study is registered with Clinical Trials.gov , number .NCT00156832 Background Presumably bundling/co-packaging of zinc with ORS encourages the combined use of the products for diarrhea treatment ; however , empirical evidence s are scarce . The purpose of this work is to evaluate whether co-packing using a plastic pouch can enhance the joint adherence to the treatment or not . The study also compares the cost effectiveness ( CE ) of two co-packaging options : ‘ central ’ and ‘ health center ( HC ) ’ level bundling . Methods This cluster-r and omised controlled trial was conducted in 2015 in eight districts of Ethiopia . Thirty two HCs were r and omly assigned to one of the following four intervention arms : ( i ) ‘ Central bundling ’ ( zinc and ORS bundled using a pouch that had instructional message , distributed to HCs ) ; ( ii ) ‘ HC level bundling ’ ( zinc , ORS and a similar pouch distributed to the HCs and bundled by health workers ) ; ( iii ) ‘ Bundling without message ’ ( zinc , ORS and plain pouch distributed and bundled by the health workers ) ; and , ( iv ) ‘ Status quo ’ ( zinc and ORS co-administered without bundling ) . In each of the four arms , 176 children 6–59 months of age , presented with acute diarrhea were enrolled . Twelve days after enrollment , level of adherence was assessed . A composite scale of adherence was developed and modeled using mixed effects linear regression analysis . The unit costs associated with the arms were estimated using secondary data sources . Incremental CE analysis was made by taking the cost and level of adherence in fourth arm as a base value . Results The follow-up rate was 95.6 % . As compared with the ‘ status quo ’ arm , the joint adherences in the ‘ central ’ and ‘ HC level ’ bundling arms raised substantially by 14.8 and 15.7 percentage points ( PP ) , respectively ( P < 0.05 ) . No significant difference was observed between ‘ bundling without message ’ and the ‘ status quo ’ arms . The unit cost incurred by the ‘ central bundling ’ is relatively higher ( USD 0.658/episode ) as compared with the ‘ HC level bundling ’ approach ( USD 0.608/episode ) . The incremental CE ratio in the ‘ central bundling ’ modality was two times higher than in the ‘ HC based bundling ’ approach . Conclusion Bundling zinc with ORS using a pouch with instructional messages increases adherence to the treatment . ‘ HC level bundling ’ is more CE than the ‘ central bundling ’ approach Objective : To determine the effect of zinc supplementation on diarrheal incidence and to discover any operational constraints of zinc supplementation at the community level . Methods : We included 1712 children aged between 6 and 48 months in a r and omized double blind study in rural area comprising of 11 villages . Children were r and omly divided into 2 groups . Zinc/placebo syrup supplementation was continued for 6 months in a weekly schedule from May 2003 . Children were followed up weekly for detection of diarrhea from May 2003 until April 2004 . Around 30 % of the study children were evaluated every 2 months during supplementation period . Results : During the period , 80,534 weekly visits were made giving 1548.73-child years of observation . We detected 1438 diarrheal episodes among 846 children . The incidence of diarrhea was significantly less during the supplemented period ( P < 0.001 ; RR 0.74 ( 0.64–0.87 ) ) in the zinc group . A significant difference was also noted during the follow up period ( P < 0.05 ) . In the zinc group , children < 2 years of age had significantly less diarrhea during supplementation and the follow up period . Multiple episodes of diarrhea ( ≥2 ) were significantly less in the zinc group . Approximately 85 % of the surveillance workers made weekly visits to the houses and 96 % of mothers administered syrup weekly to their children . Around 80 % of mother 's were aware of the possible benefits of zinc supplementation . Conclusion : Weekly zinc supplementation was effective in reducing diarrheal morbidity at the community level and it was operationally feasible OBJECTIVE In a zinc supplementation trial ( with a significant impact on diarrheal morbidity ) , to evaluate effect of zinc supplementation on cellular immune status before and after 120 days of supplementation . DESIGN A double blind , r and omized controlled trial with immune assessment at baseline and after 120 days on supplement . SETTING Community based study in an urban slum population . SUBJECTS R and omly selected children ( zinc 38 , control 48 ) , had a Multitest CMI skin test at both times . In 66 children ( zinc 22 , control 34 ) , proportions of CD3 , CD4 , CD8 , CD16 , CD20 cells and the CD/CD8 ratio were also estimated using a whole blood lysis method and flowcytometry . INTERVENTION Zinc gluconate to provide elemental zinc 10 mg daily and 20 mg during diarrhea . MAIN OUTCOME RESULTS Regarding CMI , the percentage of anergic or hypoergic children ( using in duration score ) decreased from 67 % to 47 % in the zinc group , while in the control group it remained unchanged ( 73 % vs 71 % ) ( p = 0.05 ) . The percentage of children deteriorating between first and second tests was significantly lower in the zinc group ( 13 % vs 33 % , p = 0.03 ) . Regarding lymphocyte subsets , the zinc group had a significantly higher rise in the geometric means of CD3 ( 25 % , p = 0.02 ) , CD4 ( 64 % p = 0.001 ) , and CD4/CD8 ratio ( 73 % p = 0.004 ) with no difference in CD8 and CD20 . The rise in CD4 was significantly higher in the zinc as compared to the control group ; the ratio of geometric means was 1.45 ( 95 % CI , 1.03 - 2.01 ) . CONCLUSION Zinc supplementation improves cellular immune status , which may have been one of the mechanisms for observed impact of zinc supplementation on diarrheal morbidity Diarrhea and pneumonia are the 2 main causes of death in children under 5 y of age . Short courses of zinc administration are now recommended for treatment of childhood diarrhea and some studies have also shown its beneficial effect on treatment of pneumonia . The objective of our study was to assess the efficacy of zinc administration ( 10 mg/d for children 2 - 11 mo and 20 mg/d for > or= 12 mo of age ) for 14 d on preventing diarrheal and respiratory illnesses for 6 mo of follow-up . This was a r and omized , double-blind , placebo-controlled trial in children 2 - 35 mo of age with community-acquired pneumonia . The number of illness episodes and time until the first episode of various illnesses were compared between the 2 study groups . After 14 d of zinc supplementation , plasma zinc was significantly higher in the group receiving zinc . However , this difference was not detectable at 1 and 2.5 mo after the end of zinc administration . Of 2628 enrolled cases , a total of 2599 ( 99 % ) were available for assessment after the completion of zinc supplementation . The number of hospital visits and the median number of days until the first episode of pneumonia , diarrhea , and dysentery was similar in the 2 groups . The hazard ratios ( 95 % CI ) were 1.02 ( 0.92 , 1.14 ) for nonsevere pneumonia , 1.11 ( 0.72 , 1.73 ) for severe pneumonia , 1.07 ( 0.91 , 1.26 ) for diarrhea , and 0.96 ( 0.69 , 1.34 ) for dysentery . A short course of zinc supplementation given during an episode of pneumonia did not prevent diarrheal or respiratory illness over the next 6 mo Abstract We design ed a double-blinded r and omized clinical trial of zinc ( 10 or 20 mg of zinc sulphate for 2–5 month-old or 6–59 month-old children , respectively , during 10 days ) vs. placebo in otherwise healthy children aged 2 months to 5 years who presented with acute diarrhoea ( i.e. ≥3 stools/day for less than 72 h ) . Eighty-seven patients ( median age 14 months ; range 3.1–58.3 ) were analysed in an intention-to-treat approach . Forty-two patients took zinc and 45 placebo . There was no difference in the duration nor in the frequency of diarrhoea , but only 5 % of the zinc group still had diarrhoea at 120 h of treatment compared to 20 % in the placebo group ( P = 0.05 ) . Thirty-one patients ( 13 zinc and 18 placebo ) were available for per- protocol analyses . The median ( IQR ) duration of diarrhoea in zinc-treated patients was 47.5 h ( 18.3–72 ) and differed significantly from the placebo group ( median 76.3 ; IQR 52.8–137 ) ( P = 0.03 ) . The frequency of diarrhoea was also lower in the zinc group ( P = 0.02 ) . Conclusion : zinc treatment decreases the frequency and severity of diarrhoea in children aged 2 months to 5 years living in Switzerl and . However , the intention-to-treat analysis reveals compliance issues that question the proper duration of treatment and the choice of optimal pharmaceutical formulation . What is known• The effectiveness of zinc in childhood diarrhoea has been demonstrated in developing countries . It helps to decrease the duration and severity of diarrhoea . There is currently no sufficient data to justify its use in developed countries , where there is , theoretically , no zinc deficiency . What is new• We demonstrated the effectiveness of zinc in diarrhoea of children living in a developed country . This confirms the result of two studies ( Passariello 2011 , and Dalgic 2011 ) that also reported the positive impact of zinc in diarrhoea of children living in Italy and in Turkey . However , our population is wider in terms of age ( 2–60 months compared to 3–36 months for Passariello ’s study and 1–28 months for Dalgic ’s study ) and is not limited to a specific aetiology or to a certain degree of severity of the diarrhoea . Furthermore , it ’s the first study that uses a placebo for the control group . The main limitation of our study is the differences in the intention-to-treat and the per- protocol analyses that reveal big compliance problems . These could be dealt by changing the dosage form of the zinc formula and /or by diminishing the treatment duration OBJECTIVE To assess the effect of supplementation with iron or multiple micronutrients ( MM ) on the prevalence of anaemia in a malaria-endemic area . METHODS A community-based r and omized double-blind trial was conducted in rural Burkina Faso , including children aged 6 - 23 months with haemoglobin ( Hb ) concentrations of 70 - 109 g/l who were r and omized into an iron group ( Fe , n = 96 ) , an iron and zinc group ( IZ , n = 100 ) or an MM group ( MM , n = 100 ) , 5 days/week for 6 months . All children were provided with insecticide-treated bednets ; those who had a Plasmodium falciparum ( PF ) positive-smear at baseline and /or at each monthly checking received antimalarial therapy . RESULTS The mean ( SD ) endpoint Hb concentration was higher in the MM group [ 113.2 ( 13.6 ) g/l ] than in the IZ group [ 106.3 ( 15.6 ) g/l ] and the Fe group [ 107.1 ( 12.9 ) g/l ] ( P = 0.001 ) . Children in the MM group were more likely to recover from anaemia than those in the Fe group [ prevalence rate ratios , PRR ( 95 % confidence interval , CI ) = 1.62 ( 1.22 - 2.15 ) , P < 0.001 ] . The IZ group did not differ from the Fe group [ PRR ( 95 % CI ) = 0.94 ( 0.65 - 1.35 ) , P = 0.72 ] . None of the interactions on the effect of supplementation of baseline age ( 0.13 ) , or baseline height-for-age z-score ( P = 0.33 ) , or incident PF parasitemia ( P = 0.99 ) , was significant . CONCLUSION In this malaria-endemic area , in combination with malaria management , the MM supplement was more efficacious than the Fe supplement and the IZ supplement for reducing anaemia . Further investigation into limiting factors and amounts of micronutrients that would be more efficacious for reducing anaemia is recommended Our objective in this trial was to assess the impact of daily zinc supplementation on growth in young children . A double-blind , r and omized , placebo-controlled trial was conducted in New Delhi , India . We enrolled 2482 children aged 6 - 30 mo who were supplemented daily with placebo or zinc ( 10 mg elemental zinc to infants and 20 mg to older children ) for 4 mo . At enrollment , all children also received a single dose of vitamin A ( 104.7 micromol for infants and 209.4 micromol for older children ) . Weight and length were measured at enrollment and 4 mo later . Weekly visits were conducted by field workers to ascertain morbidity in the previous 7 d. Change in length , weight , length-for-age Z-scores ( LAZ ) , and weight-for-length Z-scores ( WLZ ) after 4 mo of supplementation were assessed in the zinc and placebo groups . After 4 mo of supplementation , the weight and length gains in the 2 groups did not differ and there was no impact on LAZ , weight-for-age , and WLZ in the 2 groups . There was no substantial effect in any of the subgroups defined for age , income , gender , zinc levels in the crude analysis nor after adjusting for age , gender , income , breast-feeding status , and baseline anthropometric status . Despite successful zinc supplementation reflected in increased plasma zinc concentration and a substantially reduced incidence of diarrhea and pneumonia in zinc-supplemented children , the intervention did not have a beneficial effect on growth Objective : To determine the effectiveness of combined iron and zinc over the iron or zinc-only supplementation in correcting deficiency and possible interactive effects in a group of adolescent school children . Subjects and methods : Schoolchildren ( n=821 ) of 12–16 years of age were r and omized into four groups and supplemented with iron ( 50 mg/day ) , zinc ( 14 mg/day ) , iron+zinc or placebo capsules 5 days per week for 24 weeks . Anthropometry , and haemoglobin ( Hb ) , serum zinc ( SZn ) and serum ferritin ( SF ) concentrations were determined before and after the intervention . Results : There were no significant effects between-groups in their weight , height and Hb concentrations with the intervention when compared with the placebo group . Iron-only and combination-supplemented groups had reached mean SF concentrations of 55.1 μg/l with no difference between them ( P=0.99 ) . The zinc-only group had a mean change of 4.3 μmol//l whereas the combine-supplemented group had a mean change of 4.0 μmol/l ( P=0.82 ) . The prevalence of anaemia was found to be 70.3 % in the iron group at baseline ; this was reduced to 14.5 % after the supplementation . In the combine-supplemented group anaemia , prevalence was reduced from 64.8 to 19.3 % . Conclusions : Zinc alone or in combination with iron has not shown a significant improvement in growth in adolescence . Severe and moderate forms of anaemia were successfully treated in children who received iron supplementation . Initial high prevalence of low SZn and iron stores was significantly improved with micronutrient supplementation BACKGROUND Intervention trials have shown that zinc may be efficacious in treating acute diarrhea in children of developing countries . A double-blind placebo-controlled study was design ed to evaluate the effects of zinc supplementation on the clinical course and duration of diarrhea in malnourished Turkish children . METHODS The study group comprised 40 subjects with low zinc levels ( Group 1a ) and 52 subjects with normal zinc levels ( Group 1b ) . The control group was also comprised of two subgroups : 36 subjects with low zinc levels ( Group 2a ) and 54 subject with normal zinc levels ( Group 2b ) . Forty-three percent of children in the study group and 40 % of controls had low serum zinc levels ( < 14 micromol/L ) , and 43 % of subjects in both groups had very low serum zinc concentrations ( < 10 micromol/L ) . The study group were given 20 mg zinc per day for 10 days and the control group were given 750 mg glucose per day as a placebo for 10 days . RESULTS The mean duration of diarrhea was shorter and the percentage of children with consistent diarrhea for more than 3 - 7 days was lower in the study subgroups than in the control subgroups . Prolonged diarrhea was present in 12 % of children in the study group , and in 44 % and 37 % of children in the hypozincemic and normozincemic control subgroups , respectively . The was no significant difference among the four subgroups of children in the number of cases with post-enrollment diarrhea of a duration of>14 days . Stool frequency over the first 4 days after enrollment was lower in children in the study group . CONCLUSION It was concluded that zinc supplementation in malnourished children with acute diarrhea may reduce the severity and duration of diarrhea , especially in children with low zinc levels Objective : To assess the impact of zinc supplementation on clinical recovery , weight gain and subsequent growth and morbidity in moderately malnourished children with shigellosis . Design : A r and omized , double-blind , controlled trial . Setting : Dhaka hospital of ICDDR , B : Centre for Health and Population Research , Dhaka , Bangladesh . Subjects : Fifty-six moderately malnourished children , aged 12–59 months with culture-proven shigellosis . Methods : Subjects were r and omly allocated to receive zinc ( 20 mg/day elemental ) in multivitamin syrup ( intervention ) or multivitamin syrup without zinc ( control ) in two equally divided doses daily for 2 weeks . All children received pivmecillinam in a dose of 15 mg/kg every 6 h for 5 days . After supplementation , children were followed in their respective homes every 2 weeks for 6 months . Results : Children receiving zinc recovered from acute illness significantly faster than the control children ( P<0.05 ) . The medians time ( days ) to recovery and disappearances of blood and mucous were significantly 50 % shorter in the zinc-supplemented group compared to the control group . The mean body weight of zinc supplemented children increased significantly from 8.8 kg on admission to 9.2 kg ( P<0.01 ) at recovery , which was not observed in the control children ( from 9.3 to 9.6 kg ; P=0.12 ) . During the 6-month follow-up period , zinc-supplemented children had significantly fewer mean episodes of diarrhoea compared to the control children ( 2.2 vs 3.3 ; P=0.03 ) . Conclusion : Zinc supplementation significantly shortens the duration of acute shigellosis , promotes better weight gain during recovery and reduces diarrhoeal morbidity during the subsequent 6 months Zinc is an important micronutrient for the overall health and development of infants and young children . But among children in the poorest countries , zinc deficiency is widespread and can result in higher rates of infectious diseases , including diarrhea . During diarrheal episodes , zinc is further depleted . Replacing this critical nutrient is an important way to help children recover from diarrhea and stay healthy BACKGROUND In developing countries the duration and severity of diarrheal illnesses are greatest among infants and young children with malnutrition and impaired immune status , both factors that may be associated with zinc deficiency . In children with severe zinc deficiency , diarrhea is common and responds quickly to zinc supplementation . METHODS To evaluate the effects of daily supplementation with 20 mg of elemental zinc on the duration and severity of acute diarrhea , we conducted a double-blind , r and omized , controlled trial involving 937 children , 6 to 35 months of age , in New Delhi , India . All the children also received oral rehydration therapy and vitamin supplements . RESULTS Among the children who received zinc supplementation , there was a 23 percent reduction ( 95 percent confidence interval , 12 percent to 32 percent ) in the risk of continued diarrhea . Estimates of the likelihood of recovery according to the day of zinc supplementation revealed a reduction of 7 percent ( 95 percent confidence interval , -9 percent to + 22 percent ) in the risk of continued diarrhea during days 1 through 3 and a reduction of 38 percent ( 95 percent confidence interval , 27 percent to 48 percent ) after day 3 . When zinc supplementation was initiated within three days of the onset of diarrhea , there was a 39 percent reduction ( 95 percent confidence interval , 7 percent to 61 percent ) in the proportion of episodes lasting more than seven days . In the zinc-supplementation group there was a decrease of 39 percent ( 95 percent confidence interval , 6 percent to 70 percent ) in the mean number of watery stools per day ( P = 0.02 ) and a decrease of 21 percent ( 95 percent confidence interval , 10 percent to 31 percent ) in the number of days with watery diarrhea . The reductions in the duration and severity of diarrhea were greater in children with stunted growth than in those with normal growth . CONCLUSION For infants and young children with acute diarrhea , zinc supplementation results in clinical ly important reductions in the duration and severity of diarrhea INTRODUCTION Iron deficiency is widespread in the developing world and is especially common in young children who live on the Indian subcontinent . Supplementation with iron and folic acid alleviates severe anaemia and enhances neurodevelopment in deficient population s , but little is known about the risks of mortality and morbidity associated with supplementation . METHODS We did a community-based , cluster-r and omised , double-masked , placebo-controlled , 2x2 factorial trial in children aged 1 - 36 months and residing in southern Nepal . We r and omly assigned children daily oral supplementation to age 36 months with : iron ( 12.5 mg ) and folic acid ( 50 microg ; n=8337 ) , zinc alone ( 10 mg ) , iron , folic acid , and zinc ( n=9230 ) , or placebo ( n=8683 ) ; children aged 1 - 11 months received half the dose . Our primary outcome measure was all-cause mortality , and our secondary outcome measures included cause-specific mortality and incidence and severity of diarrhoea , dysentery , and acute respiratory illness . Analyses were by intention to treat . This study is registered at , number NCT00109551 . FINDINGS The iron and folic acid-containing groups of the study were stopped early in November , 2003 , on the recommendation of the data and safety monitoring board ; mortality in these groups did not differ from placebo and there was low power to detect positive or negative effects by the time enrollment was completed . We continued to enroll children to the placebo and zinc alone groups . 25,490 children participated and analyses are based on 29,097.3 person-years of follow-up . There was no difference in mortality between the groups who took iron and folic acid without or with zinc when compared with placebo ( HR 1.03 , 95 % CI 0.78 - 1.37 , and 1.00 , 0.74 - 1.34 , respectively ) . There were no significant differences in the attack rates for diarrhoea , dysentery , or respiratory infections between groups , although all the relative risks except one indicated modest , non-significant protective effects . INTERPRETATION Daily supplementation of young children in southern Nepal with iron and folic acid with or without zinc has no effect on their risk of death , but might protect against diarrhoea , dysentery , and acute respiratory illness A controlled , r and omized trial was conducted in 50 infants with acute dehydrating diarrhea to evaluate the effect of oral zinc supplementation in acute diarrhea . After completion of rehydration , 25 infants in Group A received oral zinc sulfate ( 20 mg elemental zinc twice daily ) and an equal number in Group B were given placebo ( glucose ) . Both groups were comparable with respect to various initial characteristics including nutritional status , diarrheal disease , serum alkaline phosphatase , and serum and rectal mucosal zinc content . During therapy all the assessed parameters of zinc status ( serum alkaline phosphatase and serum and rectal zinc ) recorded significant elevation and reduction in Groups A and B , respectively . At recovery the zinc status of Group A was significantly better and was nearer that of healthy controls . The diarrheal duration and frequency in the zinc-supplemented group were lower , but the differences were not significant ( 0.05 less than p less than 0.1 ) . However , when only subjects with relatively severe initial zinc depletion ( rectal zinc lower than the 15th percentile of healthy controls ; 11 in Group A and 14 in Group B ) were considered , the diarrheal duration and frequency were significantly ( p less than 0.05 and p less than 0.01 , respectively ) lower in the zinc-supplemented cases . Weight gain in both groups was similar . It is concluded that oral zinc administration in acute diarrhea can replenish body zinc status and this may shorten the diarrheal duration and frequency in children with relatively severe zinc depletion A r and omized double blind clinical trial was conducted to assess the efficacy of a special infant formula containing Lactobacillus rhamnosus LMG P-22799 ( probiotic : 5 x 10(8 ) CFU/100mL ) , inulin ( prebiotic : 0.15 g/100mL ) , dietary fiber ( soy polysaccharides : 0.2 g/100mL ) and increased amounts of zinc+iron ( + 0.4 and + 0.6 mg/100mL , respectively ) as active ingredients for the early dietary management of 58 Indonesian well-nourished male infants aged 3 - 12 months suffering from acute diarrhea with moderate dehydration . After adequate oral rehydration , the patients were r and omly assigned to receive either a low lactose infant formula supplemented with added precooked rice ( 1.5 g/100mL ) with the above active ingredients ( study group ) or a low lactose infant formula with added precooked rice without the above active ingredient supplement ( control group ) . No antibiotic , anti-secretory drug or antiemetic was given at all . Both study and control groups showed similar outcomes for weight gain and stool weight . The duration of diarrhea was significantly shorter in the study group than in the control group ( 1.63 versus 2.45 days ; p<0.05 ; for the study and control group respectively ) . No treatment failure or other side effects were observed during the course of the study . The present study supports the evidence for the efficacy of a special anti-diarrhea infant formula containing probiotic , prebiotic , fiber and iron+zinc after oral rehydration by shortening the duration of infantile diarrhea in developing countries . However , from the results of our study we can not discern the individual contribution of the active ingredients and also not whether they may act independent from each other or in a synergistic way BACKGROUND The WHO and UNICEF recommend therapeutic zinc supplementation ( TZS ) for the treatment of diarrhea . In zinc-deficient population s , preventive zinc supplementation might provide greater benefits for reducing diarrhea and malaria incidence and increasing growth and plasma zinc ( pZn ) concentration . If effective , intermittent preventive zinc supplementation ( IPZS ) would cost less than daily preventive zinc supplementation ( DPZS ) . OBJECTIVE We assessed the effects of IPZS , DPZS , and TZS in children on the primary outcomes of diarrhea incidence , malaria incidence , growth , and pZn concentration compared with nonsupplemented control groups . METHODS Rural Burkinabe children ( n = 7641 ; 6 - 30 mo old ) in 36 clusters were r and omly assigned to 1 of 5 treatment groups for 16 , 32 , or 48 wk : 1 ) IPZS ( 10 mg Zn/d for 10 d every 16 wk ) ; 2 ) DPZS ( 7 mg Zn/d ) ; 3 ) TZS ( 20 mg Zn/d for 10 d for diarrhea ) ; 4 ) morbidity surveillance control ( MSC ) ; or 5 ) nonintervention control ( NIC ) . Supplemented groups remained masked until completion of primary analyses with mixed models . RESULTS At baseline , stunting ( 28.6 % ) and low pZn concentration ( < 65 μg/dL ; 43.5 % ) were common . After 48 wk , mean ± SE pZn increased more ( P = 0.008 ) in the DPZS group ( 3.9 ± 1.3 μg/dL ) than in the TZS ( -0.5 ± 1.2 μg/dL ) and NIC ( -1.2 ± 0.9 μg/dL ) groups . All supplemented groups had a moderately lower incidence of reported diarrhea ( 0.48 - 0.49 compared with 0.57 episodes/100 d , P = 0.001 ) and reported fever ( 1.1 - 1.2 compared with 1.5 episodes/100d , P < 0.001 ) and gained slightly less length ( 3.15 - 3.20 compared with 3.36 cm/16 wk , P < 0.001 ) than the MSC group , but did not differ from each other . Prevalence of diarrhea and incidences of confirmed fever and malaria were not different across study groups . CONCLUSIONS The preventive and TZS groups had reduced diarrhea incidence , but it is uncertain whether this result ed from a functional response to zinc or reporting bias . The comparison should be re-examined in population s known to respond to zinc supplementation . This trial was registered at www . clinical trials.gov as NCT00944359 BACKGROUND Adequate nutrition is necessary for the rapid brain development that occurs during infancy . OBJECTIVES We tested the hypothesis that the provision of small-quantity , lipid-based nutrient supplements ( SQ-LNSs ) plus malaria and diarrhea treatment positively affects infant development . We also tested the effect of various doses of zinc provided in SQ-LNSs or in a tablet . METHODS In a partially masked , cluster-r and omized controlled trial , communities in rural Burkina Faso were stratified by selected characteristics and then r and omly assigned within strata to the intervention ( IC ; 25 communities , 2435 children ) or the nonintervention ( NIC ; 9 communities , 785 children ) cohorts . IC children were r and omly assigned to 4 groups . As secondary outcomes , a sub sample of 3 of these 4 groups ( n = 747 ) and of the NIC ( n = 376 ) were assessed for motor , language , and personal-social development at age 18 mo by using the Developmental Milestones Checklist II . The 3 IC groups received 20 g SQ-LNSs/d containing 0 or 10 mg added zinc with a placebo tablet or 20 g SQ-LNSs/d containing 0 mg added zinc with a tablet containing 5 mg Zn . All IC groups received treatment of malaria and diarrhea from age 9 to 18 mo . Data collectors and participants were aware of allocation to the IC or NIC but did not know the particular IC subgroup . RESULTS Children in the IC scored 0.34 ( 95 % CI : 0.21 , 0.46 ) , 0.30 ( 95 % CI : 0.15 , 0.44 ) , and 0.32 ( 95 % CI : 0.16 , 0.48 ) SDs higher in motor , language , and personal-social development , respectively , than did children in the NIC ( All P < 0.001 ) . Children who received different amounts of zinc did not differ significantly in any of the scores . No effect on caregiver-child interaction was found . CONCLUSION In rural Burkina Faso , the provision of SQ-LNSs to infants from age 9 to 18 mo , regardless of added zinc content , plus malaria and diarrhea treatment positively affected motor , language , and personal-social development at age 18 mo . This trial was registered at clinical trials.gov as NCT00944281 OBJECTIVE To assess the impact of zinc supplementation on diarrheal morbidity and growth pattern of low birth weight ( LBW ) infants . METHODOLOGY In a r and omized , double-blind , placebo-controlled , community-based study conducted in the Tiljala slum of eastern Kolkata , India , between 1999 and 2001 , a birth cohort of 100 LBW infants was r and omly allocated into either an intervention group receiving 1 mL daily dose of 5 mg of elemental zinc as zinc sulfate in vitamin B complex-based syrup or a placebo group receiving an identical placebo of 1 mL of vitamin-based syrup from birth up to 1 completed year of age . Active weekly surveillance was conducted for detection of diarrhea . Anthropometric measurements of each child were recorded once every month as close to the child 's birth date as possible . Data were analyzed by using statistical software packages SPSSPC+ 4.0 ( SPSS , Inc , Chicago , IL ) and Epi Info 6.0 ( Centers for Disease Control and Prevention , Atlanta , GA ) . RESULTS Among the zinc-supplemented group , diarrheal incidence of 1.36 episodes per child per year were observed , whereas it was 1.93 episodes per child per year among the placebo group , giving a relative risk of 1.4 ( 95 % confidence interval : 1.02 - 2.00 ) . Linear growth and weight for age showed significant differences between the supplemented and placebo groups only at the end of 1 year . Interestingly , the impact of zinc supplementation was masked to a large extent by the protective action of breastfeeding . CONCLUSIONS The study showed that zinc supplementation had a beneficial impact on the incidence of diarrhea and also weight gain among LBW infants OBJECTIVES To determine whether continuing with zinc supplementation after zinc treatment ( ZT ) of an acute diarrhoea episode will result in additional clinical benefits beyond ZT alone . METHODS Children 6 - 23 months of age , living in an urban slum in Dhaka , Bangladesh with acute childhood diarrhoea ( ACD ) , were enrolled in a r and omized , double-blind field trial . All children received 10 days of ZT ( 20 mg/day ) and were then r and omized to zinc ( 10 mg/day ) or placebo supplementation for 3 months . Weekly follow-up of all children occurred over a period of 9 months . RESULTS A total of 353 subjects were enrolled , with 93 % of the zinc supplemented and 96 % of the placebo children followed for 9 months . The incidence density of ACD among those receiving zinc supplementation compared to those receiving placebo was reduced by 28 % ( 2.64 vs.3.66 episodes/p-y follow-up ) over the 3 months while on supplementation and by 21 % ( 2.05 vs.2.59 episodes/p-y follow-up ) over the 9 months of follow-up . There was no observed effect on the incidence of acute respiratory infections ( ARIs ) or on growth . CONCLUSIONS Zinc supplementation after treatment provides additional preventive ACD benefits to children in early childhood . Larger , effectiveness trials of this strategy are warranted Objectives : To study the different responses by sex to zinc supplementation among young children . Study Children and Methods : Double-blind r and omized controlled trial of zinc supplementation in 686 children aged 6–30 months , conducted in Nouna , a rural area of Burkina Faso . Children received either a 12.5-mg zinc sulfate tablet or a placebo every day for about 6 months . Outcomes were morbidity , nutritional status , and mortality . Results : Results revealed significant differences between boys and girls in their responses to zinc supplementation . Boys who received the zinc preparation had fewer days with diarrhea than did control boys ( RR = 0.88 , P = 0.05 ) , especially less nonfebrile diarrhea ( RR = 0.72 , P < 0.001 ) and less dysentery ( RR = 0.65 , P = 0.05 ) , but more ear infections ( RR = 4.00 , P < 0.001 ) . By contrast , girls who received the zinc supplement had the same prevalence of diarrhea as did control girls , but more dysentery ( RR = 3.70 , P < 0.001 ) , fewer ear infections ( RR = 0.39 , P < 0.001 ) , and fewer eye infections ( RR = 0.41 , P < 0.001 ) . The effect of supplementation on nutritional status was not detectable in boys , but girls who received supplementation experienced a faster growth velocity in height than did control girls ( P = 0.004 ) and a faster growth velocity for weight and height if they were wasted and not stunted at baseline ( P = 0.003 ) . Conclusions : Zinc supplementation had positive , nil , or negative effects depending on pathological condition , and the effects were different for boys than for girls Summary Zinc has been shown to enhance intestinal mucosal repair in patients suffering from acrodermatitis enteropathica ; but the impact on mucosal integrity during acute ( AD ) or persistent ( PD ) diarrhoea is unknown . One hundred eleven children with AD and 190 with PD aged between 3 and 24 months received , r and omly and blind to the investigators , either an elemental zinc supplement of 5 mg/kg body wt/day or placebo in multivitamin syrup for 2 weeks while intestinal permeability and , biochemical and anthropometric markers were serially monitored . The permeability test was administered as an oral dose of 5 g lactulose/1 g mannitol in a 20-ml solution followed by a 5-h urine collection . The ratio of the urinary probe sugars was correlated to clinical , biochemical , and microbiological parameters . At presentation , lactulose excretion was increased and mannitol excretion decreased in both AD and PD as compared with age-matched asymptomatic children . The lactulose/mannitol ratio ( L/M ) was higher in subjects with mucosal invasive pathogens ( rotavirus and enteropathogenic Escherichia coli ) compared with children excreting Vibrio cholera and enterotoxigenic . coli . Two-week zinc supplementation significantly reduced lactulose excretion in both AD and PD , whereas the change in mannitol excretion and L/M was similar between study groups in both studies . Changes in lactulose excretion were significantly influenced by zinc supplementation in children with E. coli , Shigella sp. , and Campylobacter jejuni stool isolates . The greatest reduction in total lactulose excretion was seen in supplemented children who on presentation were lighter ( wt/age < 80 % ) , thinner ( wt/ht < 85 % ) , and undernourished [ middle upper arm circumference ( MUAC ) < 12.5 cm ] or with hypozincaemia ( < 14 μmlmol/L ) . The results suggest zinc supplementation improves intestinal permeability in certain groups of children with AD or PD syndrome and contributes to their recovery . This effect may indirectly reflect enhanced mucosal recovery . Further studies on the mechanisms of mucosal repair following zinc supplementation are recommended AIMS To describe the incidence of parentally reported illness in otherwise healthy South Isl and toddlers ; characterise the predictors of illness ; and determine whether there was a relationship between teething and illness in this population . METHODS A 20-week r and omised controlled trial was conducted on 1-year-old children ( n=225 ) from Otago and Southl and between February 2004 and December 2005 . Information on symptoms of morbidity , occurrence of teething , and childcare attendance were recorded daily throughout the intervention period . Morbidity symptoms were categorised into respiratory illness ( RI ) , gastrointestinal illness ( GII ) , ear infection , and total illness , and the number and duration of events were determined . RESULTS The mean ( SD ) number of total illnesses was 3.4 ( 2.3 ) per 20 weeks , with an average duration of 4.5 days . Episodes of RI were most common ( 50 % of total illness events ) , and tended to be the longest in duration ( mean of 3.7 days ) . Having siblings aged less than 5 years ( 23 % increase , 95%CI 6%-42 % , p=0.007 ) and attending childcare ( 72 % increase , 95%CI 38%-113 % , p<0.001 ) ) , were positively associated with the number of total illness events but not duration . In addition , teething was positively associated with total events ( OR 1.94 , 95%CI 1.45 - 2.60 , p<0.001 ) , RI events ( OR 2.03 , 95%CI 1.41 - 2.93 , p<0.001 ) and GII events ( OR 1.90 , 95%CI 1.36 - 2.67 , p<0.001 ) . CONCLUSION This study has shown that illness ( particularly RI ) is common in the second year of life . It has also confirmed that attending childcare and having siblings aged under 5 years increases the number of illness events . An association between teething and the occurrence of illness was also seen but the exact nature of this relationship requires verification Aim : To determine the role of zinc supplementation in reducing diarrhoeal morbidity in children . Methods : A r and omized , double‐blind , community‐based intervention study was conducted in 280 rural children aged between 6 and 41 mo . Children were r and omly allocated into three groups . One group received a daily dose of 10 mg zinc for 5 d wk−1 , another group received 50 mg zinc once weekly and the remaining group received placebo . Zinc was supplemented for 16 wk from November 1999 . Diarrhoeal episodes were detected by weekly surveillance during the supplementation period . Results : Eighty diarrhoeal episodes were detected among 59 children in all 3 groups . The groups were compared with each other at baseline and as regard to the outcome variable ( incidence of diarrhoea ) . The proportion of children suffering from diarrhoea during the period was significantly lower in the zinc‐supplemented groups ( 15.8 % in daily and 16.5 % in weekly group ) than in the placebo group ( 30.8 % ) . The incidence of diarrhoea in the daily and weekly zinc‐supplemented groups was 0.68 and 0.69 episodes child−1 y−1 , and that in the placebo group was 1.67 episodes child−1 y−1 ( relative risk 0.41 , 95 % confidence interval 0.24–0.71 ) . Diarrhoeal incidence of > 4d duration was found to occur significantly less often in the supplemented groups . There was no difference in diarrhoeal incidence between the daily and weekly zinc‐supplemented children . There were no detected adverse reactions in any of the supplemented groups The childhood diarrhoea-management guidelines of the World Health Organization/United Nations Children 's Fund ( WHO/UNICEF ) now include zinc treatment , 20 mg per day for 10 days . To determine if a dispersible zinc sulphate tablet formulation is associated with increased risk of vomiting or regurgitation following the initial , first treatment dose , a double-blind , placebo-controlled r and omized clinical trial was carried out in the Dhaka hospital of ICDDR , B : Centre for Health and Population Research ( n=800 ) and in an adjacent NGO outpatient clinic ( n=800 ) . Children were r and omized to one of three groups : no treatment , placebo , or zinc sulphate tablet ( 20 mg ) . They were then observed for 60 minutes , and all vomiting or regurgitation episodes were recorded . When compared with placebo , zinc treatment result ed in an attributable risk increase of 14 % for vomiting and 5.2 % for regurgitation . The median time to vomiting among those receiving zinc was 9.6 minutes and was limited to one episode in 91.2 % of the cases . Overall , the proportion of 60-minute post-treatment vomiting attributable to zinc , placebo , and the illness episode was estimated to be 40 % , 26 % , and 34 % respectively . The dispersible zinc sulphate tablet formulation at a dose of 20 mg is associated with increased risks of vomiting and regurgitation . Both are transient side-effects In rural Mexico and in many developing countries micronutrient deficiencies , growth stunting , and morbidity from infectious diseases are highly prevalent in young children . We assessed the extent to which growth stunting could be reversed and the number of infectious disease episodes reduced by zinc and /or iron supplementation . In a double-blind , r and omized community trial 219 Mexican preschoolers were supplemented with either 20 mg Zn as zinc methionine , 20 mg Fe as ferrous sulfate , 20 mg Zn + 20 mg Fe , or a placebo . After 12 mo , plasma zinc increased significantly in the two zinc-treated groups , and plasma ferritin was significantly higher in the two iron-treated groups . There was no effect of treatments on growth velocity or body composition . Children in both zinc-supplemented groups had fewer episodes of disease ( zinc alone , 3.9 + /- 0.3 ; zinc+iron , 3.7 + /- 0.4 ; placebo , 4.6 + /- 0.5 ; P < 0.03 ) , including diarrhea ( zinc alone , 0.7 + /- 0.1 ; zinc+iron , 0.8 + /- 0.1 ; placebo , 1.1 + /- 0.2 ; P < 0.01 ) . Zinc and zinc+iron supplements reduced morbidity but had no effect on growth or body composition Diarrhoea remains one of the leading killers of young children . A recent meta- analysis demonstrated that a two-week course of zinc tablets once daily significantly reduces the severity and duration of diarrhoea and mortality in young children ( Bhutta et al. , 2000 . Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries : Pooled analysis of r and omized controlled trials . American Journal of Clinical Nutrition , 72(6 ) , 1516 - 1522 ) . Formative research is being conducted in a number of countries to prepare for the large-scale promotion of this new treatment . In-depth and semi-structured interviews with parents , community health workers , and traditional healers were conducted to examine the household management of diarrhoea in the Sikasso region of southern Mali in preparation for the introduction of a short-course of daily zinc for childhood diarrhoea at the community level . Supporting data from a subsequent household survey are also presented . Although nearly all parents knew oral rehydration solution ( ORS ) could replace lost fluids , its inability to stop diarrhoea caused parents to seek antibiotics from local markets , traditional medicines or anti-malarials to cure the illness . The notion of combining multiple treatments to ensure the greatest therapeutic benefit was prevalent , and modern medicines were often administered simultaneously with traditional therapies . As parents often deem ORS insufficient and judge that an additional treatment should be combined with ORS to cure diarrhoea , the concept of joint therapy of zinc and ORS should be well accepted in the community . Mothers-in-law and fathers , who play a significant role in decisions to seek treatment for sick children , as well as traditional healers , should also be considered when design ing new programs to promote zinc . Similarities with formative research conducted for a previous generation of diarrhoea control programmes are discussed OBJECTIVE To determine whether supplemental zinc , with or without additional micronutrients , affects the severity and duration of persistent childhood diarrhea and the rate of nutritional recovery . DESIGN The study was a community-based , double-blind , r and omized trial implemented in a shanty town in Lima , Peru . Children aged 6 to 36 months with persistent ( > /=14 days ) diarrhea received daily , for 2 weeks , a placebo ( group P , n = 136 ) or a supplement of 20 mg of zinc , either with ( group Z+VM , n = 137 ) or without ( group Z , n = 139 ) additional vitamins and minerals . Symptoms of illness were recorded daily , and biochemical and anthropometric assessment s were completed at baseline and on day 15 . RESULTS The treatment groups were similar at baseline with regard to the characteristics of the presenting episode , anthropometric data , and plasma zinc concentration . The children consumed , on average , 95 % ( group P ) , 94 % ( group Z ) , or 88 % ( group Z+VM ) of the supplement ( P < .001 ) . The plasma zinc concentration did not change significantly from baseline to day 15 in group P ( 4 microg/dL ) but increased by 38 microg/dL in group Z and 14 microg/dL in group Z+VM . The median duration of diarrhea after starting treatment was 1 day ; among children who continued to have diarrhea , there was a significant effect of treatment on diarrheal duration ( P = .04 , analysis of covariance ) . Specifically , the duration of illness was significantly reduced by 28 % in children in group Z ( P = .01 ) and by 33 % in girls in group Z+VM ( P = .04 ) . There were no differences in the severity of the episode by treatment group . CONCLUSION There was a significant reduction in the duration of persistent diarrhea in selected subgroups of zinc-supplemented ambulatory patients in this population Objective To compare the effect of oral zinc supplementation on growth of preterm infants . Design R and omized controlled trial . Setting Dhaka Shisu Hospital ( Tertiary care hospital).Subjects100 appropriate for date preterm infants weighing between 1000 to 2500 g were r and omized to receive zinc and multivitamin supplement ( Group I ; n=50 ) or only multivitamin supplement ( Group II).InterventionZinc supplementation was given 2mg/kg/day for 6 weeks along with multivitamin in Group I and only multivitamin to Group II . Primary outcome variableIncrement of weight and length . Results At enrollment , serum zinc ( 62.1±12.4μg/dL in Group I and 63.1±14.6μg/dL in Group II ) and hemoglobin levels ( 14.9±2.4g/dL in Group I and 14.4±1.7g/dL in Group II ) were almost similar in both groups . Serum zinc levels were in lower limit of normal range . After supplementation , serum zinc and hemoglobin levels were significantly higher in Group I ( 105±16.5μg/dL ) than Group II ( 82.2±17.4μg/dL ) ( P<0.05 ) . Weight , length and head circumference were comparable in both groups at enrollment . Significant differences in weight gain and increment in length were found in first and second follow up between two groups but OFC increments were not significant ( P>0.05 ) . Reduction of morbidity was apparent in zinc supplemented group . No serious adverse effect was noted related to supplementation therapy . Conclusion Zinc supplementation for preterm low birth weight babies is found effective to enhance the growth in early months of life Background / Objectives : Many children have diets deficient in both iron and zinc , but there has been some evidence of negative interactions when they are supplemented together . The optimal delivery approach would maximize clinical benefits of both nutrients . We studied the effectiveness of different iron and zinc supplement delivery approaches to improve diarrhea and anemia in a rural Bangladesh population . Study Design : R and omized , double blind , placebo-controlled factorial community trial . Results : Iron supplementation alone increased diarrhea , but adding zinc , separately or together , attenuated these harmful effects . Combined zinc and iron was as effective as iron alone for iron outcomes . All supplements were vomited < 1 % of the time , but combined iron and zinc were vomited significantly more than any of the other supplements . Children receiving zinc and iron ( together or separately ) had fewer hospitalizations . Separating delivery of iron and zinc may have some additional benefit in stunted children . Conclusions : Separate and combined administration of iron and zinc are equally effective for reducing diarrhea , hospitalizations and improving iron outcomes . There may be some benefit in separate administration in stunted children Objective : We investigated whether there was a growth or morbidity response to zinc supplementation . Design : The study was r and omized , placebo-controlled , and double-blind . Setting : Children were recruited at clinics in Kingston , Jamaica , and supplemented at home . Subjects : Children selected were singletons aged 6–24 months , and stunted ( < –2.0 s.d . length for age , NCHS references ) . They were stratified by sex and age and r and omly assigned to receive zinc supplement ( n=31 ) or placebo ( n=30 ) . Four children were excluded because of hospitalization ; all others had all measurements . Adequately nourished children ( n=24 ) were recruited from a well-baby clinic . Interventions : The supplement provided 5 mg elemental zinc in a syrup daily for 12 weeks ; the placebo comprised the syrup only . Main outcome measures : Caretakers were interviewed to obtain social background data , number of clinic visits and hospitalizations . Anthropometric measurements were done on enrolment , and after 6 weeks , 12 weeks and 12 months . Children 's health was determined by weekly question naire to caretakers of the undernourished groups during the supplementation period . Results : The supplemented and placebo groups were similar on enrolment . The adequately nourished children were from significantly better socio-economic circumstances . Mean initial hair zinc content was 5.5±4.8μmol/g ( supplemented group ) and 6.7±12.1 μmol/g (placebo)(n.s . ) . Regression analyses showed that there were no significant effects of supplementation on length , height or head circumference , nor on the incidence of any morbidity symptom . Mean duration of the episodes was significantly shorter for skin rashes in the supple-mented group compared with the control group ( ANCOVA , P=0.02 ) , and longer for vomiting ( P=0.02 ) . The incidence of hospitalization was significantly greater in the control group ( Fisher 's exact test , P=0.02 ) . Conclusions : Zinc supplementation reduced the hospitalizations which probably reflect severity of morbidity , but did not improve growth . Sponsorship : The study was funded by the Commonwealth Caribbean Medical Research Council and a Research and Publications Grant , University of the West Indies , Mona . Tropivite Vitamin Drops were donated by Federated Pharmaceutical Co. Ltd , Jamaica ; and zinc sulphate donated by Lascelles Laboratories Ltd. , Jamaica To evaluate the impact of zinc supplementation on the clinical recovery and body weight of children with persistent diarrhoea , a r and omized , double‐blind , controlled trial was conducted in 190 children with persistent diarrhoea aged between 3 and 24 months . Children were r and omly allocated to receive either zinc ( 20 mg d−1 ) syrup with multivitamin ( 2 × RDA ) or multivitamin alone in three divided daily doses for 2 weeks . The trial was conducted in a diarrhoeal disease hospital in Dhaka , Bangladesh . Duration until clinical recovery ( d ) , impact on body weight and serum zinc level after 2 weeks of zinc supplementation were recorded . The duration of illness was significantly reduced ( 33 % ) with zinc supplementation among children who were underweight ( ≤70 % wt/age , p= 0:03 ) . Supplemented male children also had a significant reduction ( 27 % ) in duration for recovery compared with unsupplemented children ( p= 0:05 ) . From baseline to convalescence , zinc‐supplemented children maintained their serum zinc concentration ( 13.4 vs 13.6/μmol l−1 ) , whereas unsupplemented children had a decrease in serum zinc after the 2 weeks of diarrhoea ( 13.6 vs 11.8 μmol l−1 , p < 0:03 ) . The mean body weight of the children in the supplemented group was maintained ( 5.72 vs 5.70 kg , p= 0:62 ) during hospitalization , unlike that of the control group , in which there was a reduction in body weight ( 5.75 vs 5.67 kg , p= 0:05 ) . Five children in the unsupplemented group and one child in the zinc‐supplemented group died during the 2 weeks of supplementation ( p= 0:06 ) . Zinc supplementation in persistent diarrhoea significantly reduced the length of the recovery period in malnourished children and prevented a fall in body weight and serum zinc concentration , indicating that zinc is a beneficial therapeutic strategy in this high‐risk childhood illness BACKGROUND Pneumonia and diarrhoea cause much morbidity and mortality in children younger than 5 years . Most deaths occur during infancy and in developing countries . Daily regimens of zinc have been reported to prevent acute lower respiratory tract infection and diarrhoea , and to reduce child mortality . We aim ed to examine whether giving zinc weekly could prevent clinical pneumonia and diarrhoea in children younger than 2 years . METHODS 1665 poor , urban children aged 60 days to 12 months were r and omly assigned zinc ( 70 mg ) or placebo orally once weekly for 12 months . Children were assessed every week by field research assistants . Our primary outcomes were the rate of pneumonia and diarrhoea . The rates of other respiratory tract infections were the secondary outcomes . Growth , final serum copper , and final haemoglobin were also measured . Analysis was by intention to treat . FINDINGS 34 children were excluded before r and om assignment to treatment group because they had tuberculosis . 809 children were assigned zinc , and 812 placebo . After treatment assignment , 103 children in the treatment group and 44 in the control group withdrew . There were significantly fewer incidents of pneumonia in the zinc group than the control group ( 199 vs 286 ; relative risk 0.83 , 95 % CI 0.73 - 0.95 ) , and a small but significant effect on incidence of diarrhoea ( 1881 cases vs 2407 ; 0.94 , 0.88 - 0.99 ) . There were two deaths in the zinc group and 14 in the placebo group ( p=0.013 ) . There were no pneumonia-related deaths in the zinc group , but ten in the placebo group ( p=0.013 ) . The zinc group had a small gain in height , but not weight at 10 months compared with the placebo group . Serum copper and haemoglobin concentrations were not adversely affected after 10 months of zinc supplementation . INTERPRETATION 70 mg of zinc weekly reduces pneumonia and mortality in young children . However , compliance with weekly intake might be problematic outside a research programme Objective Zinc deficiency is very common in developing countries and is more pronounced during an episode of diarrhea . Supplementation with zinc improves diarrhea and might correct zinc deficiency in both the short and longer term . Method .We conducted a nested study within a cluster r and omized treatment trial . Fifty children with diarrhea living in the zinc treated clusters , 50 children with diarrhea living in control clusters , and 50 healthy children living in the control clusters were enrolled . We assessed serum zinc at the start of the diarrhea episode , which was 1–3 days after supplementation began in zinc treated children , and again one week after the diarrhea ended and supplementation ceased . Baseline characteristics and serum zinc concentration were assessed . Results .Serum zinc was low in 44 % of healthy children at the first blood draw . Compared to healthy controls , serum zinc was 3.1 mmol/L higher among children with diarrhea who were supplemented with zinc at first blood draw and 1.3mmol/L higher 3 weeks later . Conclusion .Zinc supplementation enhances serum zinc concentration when given as a treatment for diarrhea and helps children maintain a more adequate zinc status during the convalescent period Objective : Assess the impact of zinc supplementation with locally developed culturally specific educational statements ( messages ) on oral rehydration solution ( ORS ) and antibiotics or antidiarrheal use in children with acute watery diarrhea as well as to assess adherence and side effects of zinc . Methods : This was a r and omized effectiveness trial conducted in outpatient health facilities of six sites in five countries , namely , Fortaleza ( Brazil ) , Addis Adaba ( Ethiopia ) , Cairo ( Egypt ) , Lucknow and Nagpur ( India ) , and Manila ( Philippines ) . Participants were 2,002 children aged 2 to 59 months . Intervention was zinc ( 20 mg orally , once daily for 14 days ) with ORS ( zinc group ) compared with ORS alone ( control group ) . Primary outcomes were ORS use on day 3 to 5 ; adherence to zinc ; and any use of an antibacterial/antidiarrheal up to day 14 . Results : One thous and ten and 992 children enrolled in zinc and control groups , respectively . Loss to follow-up on days 3 to 5 and 15 to 17 was 1.2 % and 2.8 % in the zinc group and 0.8 % and 1.7 % in the control group . In five of six sites , ORS use in cases with continued diarrhea on days 3 to 5 was the same in the two groups or higher in zinc group . Overall adherence to zinc supplementation was 83.8 % ( 95 % confidence interval [ CI ] 81 - 86 ) . There was no difference in vomiting by group . In consideration of the six countries overall , less antibiotic/antidiarrheal use occurred in the zinc group ( absolute difference , 3.8 % [ 95 % CI 1.7 - 5.9 ] ) . Conclusions : In the management of acute watery diarrhea , zinc plus ORS along with culturally appropriate , site-specific messages in local language does not affect overall ORS use generally and decreases antibiotic/antidiarrheal use ; children had good adherence without side effects OBJECTIVE To test whether zinc supplementation during pregnancy would reduce infant morbidity rates . STUDY DESIGN A double-blind , r and omized controlled trial of prenatal zinc supplementation was conducted from 1995 to 1997 in a periurban slum of Lima , Peru . Participants were r and omly assigned to receive daily supplementation with zinc ( 15 mg zinc + 60 mg iron + 250 microg folic acid ) or placebo ( 60 iron + 250 microg folic acid ) from 10 to 24 weeks gestation until 1 month postpartum . Anthropometry was measured monthly from birth through age 12 months , and morbidity and dietary intake were measured weekly from 6 to 12 months ( n = 421 ) . RESULTS The average percentage of observation days with diarrhea among infants prenatally treated with zinc ( 5.8 % ) was reduced compared with infants in the control group ( 7.7 % ) ( P = .01 ) . Prenatal zinc supplementation reduced the likelihood of an infant experiencing diarrheal episodes of acute diarrhea lasting longer than 7 days ( OR 0.66 , 95 % CI 0.43 , 0.99 , P = .04 ) and mucus in the stool ( OR 0.65 95 % CI 0.46 , 0.92 , P = .01 ) adjusting for infant age , breastfeeding , season , and hygiene and sanitation covariates . No treatment effects on respiratory illnesses , fever , or skin conditions were detected . CONCLUSIONS Improving prenatal zinc nutrition protected against diarrheal morbidity in infant offspring through 12 months of age BACKGROUND Rotavirus is the world 's leading cause of childhood diarrheal death . Despite successes , oral rotavirus vaccines are less effective in developing countries . In an urban slum of Dhaka , we performed active diarrhea surveillance to evaluate monovalent G1P[8 ] rotavirus vaccine ( RV1 ) efficacy and underst and variables contributing to risk of rotavirus diarrhea ( RVD ) . METHODS We performed a r and omized controlled trial of monovalent oral rotavirus vaccine ( RV1 ) . Seven hundred healthy infants received RV1 or no RV1 ( 1:1 ) using delayed dosing ( 10 and 17 weeks ) and were followed for 1 year . Intensive diarrhea surveillance was performed . The primary outcome was ≥1 episode of RVD . Nutritional , socioeconomic , and immunologic factors were assessed by logistic regression best-subsets analysis for association with risk of RVD and interactions with vaccine arm . RESULTS Incidence of all RVD was 38.3 cases per 100 person-years . Per- protocol RV1 efficacy was 73.5 % ( 95 % confidence interval [ CI ] , 45.8%-87.0 % ) against severe RVD and 51 % ( 95 % CI , 33.8%-63.7 % ) against all RVD . Serum zinc level ( odds ratio [ OR ] , 0.77 ; P = .002 ) and lack of rotavirus immunoglobulin A ( IgA ) seroconversion ( OR , 1.95 ; P = .018 ) were associated with risk of RVD , independent of vaccination status . Water treatment and exclusive breastfeeding were of borderline significance . Factors not associated with RVD included height for age at 10 weeks , vitamin D , retinol binding protein , maternal education , household income , and sex . CONCLUSIONS In an urban slum with high incidence of RVD , the efficacy of RV1 against severe RVD was higher than anticipated in the setting of delayed dosing . Lower serum zinc level and lack of IgA seroconversion were associated with increased risk of RVD independent of vaccination . CLINICAL TRIALS REGISTRATION NCT01375647 Objectives : Supplementation of probiotics and supplementation of zinc during acute gastroenteritis in children have been shown to exert positive effects on diarrhea duration and severity . Our aim was to evaluate a new diet enriched with zinc and probiotic bacteria in the treatment of acute gastroenteritis in young children . Methods : In a double blind prospect i ve study , 65 children aged 6–12 months were r and omized to receive 6 × 109 colony forming units of Streptococcus thermophilus , Bifidobacterium lactis , Lactobacillus acidophilus ( 2 × 109 of each strain ) , 10 mg of zinc/day , and 0.3 grams of fructo-oligosaccharides in the supplemented group ( n = 33 ) or placebo ( n = 32 ) , given in a soy protein based rice cereal . For each child , age , sex , weight , degree of dehydration , the presence of fever or vomiting , stool frequency and consistency were recorded daily until diarrhea resolution . Results : Diarrhea resolution occurred after 1.43 ± 0.71 days in the supplemented group vs. 1.96 ± 1.24 in the control group ( p = 0.017 ) . In the subset of children who presented with vomiting , time to vomiting resolution was 0.27 ± 0.59 vs. 0.81 ± 0.91 days in the supplemented and control groups , respectively ( p = 0.06 ) . On day 3 , there was only 1 child with watery stools in the supplemented group versus 10 children in the control group ( p = 0.02 ) . Conclusions : In our series , the feeding of a cereal containing Streptococcus thermophilus , Bifidobacterium lactis , Lactobacillus acidophilus and zinc , reduced the severity and duration of acute gastroenteritis in young children . However , whether this combination is better than either the addition of probiotics or zinc alone is yet to be determined In a double‐blind , controlled trial with a factorial design , 684 patients ( aged 6 months to 2 y ; excludes 6 early dropouts ) with acute watery diarrhoea of 3 d or less and some dehydration , who were attending a hospital , were r and omly assigned to 4 groups to receive : ( a ) vitamin A 4500 μg retinol equivalent daily for 15 d ; ( b ) 14.2 mg elemental zinc as acetate for the first 417 patients and 40 mg of the remaining 273 patients r and omized to this group for 15 d ; ( c ) both vitamin A 4500 μg retinol equivalent and zinc at the above doses daily for 15 d ; or ( d ) placebo mixtures for 15 d. Patients were observed in the hospital for 24 h and followed up at home for 15 d. All received ascorbic acid 30 mg with each dose of medicine or placebo . Zinc supplementation was associated with a reduced duration of diarrhoea ( 13 % , p= 0.03 ) and markedly reduced rate ( 43 % , p= 0.017 ) of prolonged diarrhoea ( < 7 d ) . Vitamin A supplementation was associated with a nonsignificant trend for reduced rate of prolonged diarrhoea ( p= 0.089 ) . In conclusion , zinc supplementation as adjunct therapy had a substantial impact on the rate of prolonged diarrhoea and some impact on duration and may be beneficial in children with diarrhoea in developing countries Aims : To examine the effect of the daily use of micronutrients ( including zinc ) or the same micronutrients plus heat inactivated lactic acid bacteria ( LAB ) , on diarrhoea in children compared to placebo . Methods : A triple blind r and omised clinical trial in an urban slum of Karachi , Pakistan . Micronutrients ( including zinc ) , micronutrients ( including zinc and LAB ) , or placebo , were provided daily for two months to 75 young children ( aged 6–12 months ) identified at high risk for diarrhoea related mortality on the basis of history of at least one episode of diarrhoea in the preceding two weeks . The longitudinal prevalence of diarrhoea was defined as the percentage of days a child had diarrhoea out of the days the child was observed . Results : Mean longitudinal prevalence of diarrhoea in the micronutrient – zinc group was 15 % ( SD = 10 % ) child-days compared to 26 % ( SD = 20 % ) child-days in the placebo group and 26 % ( SD = 19 % ) child-days in the micronutrient – zinc – LAB group . The difference between the micronutrient – zinc – LAB and placebo groups was not significant . Conclusion : The daily provision of micronutrients ( including zinc ) reduces the longitudinal prevalence of diarrhoea and thus may also reduce diarrhoea related mortality in young children ; heat inactivated LAB has negative effects in these children Objective : To assess the impact of zinc supplementation during acute diarrhoea on subsequent growth and morbidity in malnourished young children . Design : Double blind r and omized controlled clinical trial Setting : International Centre for Diarrhoeal Disease Research , Bangladesh . Subjects : Sixty-five children aged 3–24 months with acute diarrhoea for less than 3 d . Intervention : Either elemental zinc ( 20 mg/d ) in a multivitamin syrup or multivitamin syrup alone divided in three divided daily doses for a period of two weeks . Children were followed up weekly at home to assess subsequent growth and morbidity for a period of eight weeks . Main outcome measures : Gain in length and body weight and reduction in diarrhoea and respiratory tract infection . Results : During the follow-up , zinc supplemented children showed significantly greater cumulative length gain ( 18.9 mm vs 14.5 mm , P<0.03 ) and comparable body weight gain than the children of the control group . Subsequent length gain was not correlated with initial height in the zinc-supplemented group ( r=−0.13 ) , P=0.5 ) , but was significantly correlated in the control group ( r=-0.6 , P<0.0007 ) . Zinc-supplemented and stunted children ( ≤ 90 % length for age n=18 ) experienced significantly fewer episodes of diarrhoea ( 0.07 vs 0.6 , P 0.05 ) and respiratory illness ( 1.0 vs 2.4 , P<0.01 ) compared to the control group . The underweight children ( ≤ 71 % weight/age n=38 ) receiving zinc-supplementation also had fewer episodes of diarrhoea ( 0.4 vs 1.0 , P<0.04 ) and shorter duration of diarrhoeal episodes ( 1.0 vs 3.0 d , P<0.04 ) compared to their counterparts in the control group . Conclusion : These results suggest that a short course of zinc supplementation to malnourished children during acute diarrhoea reduces growth-faltering and diarrhoeal and respiratory morbidity during subsequent two months . Sponsorship : Wellcome Trust BACKGROUND Zinc supplementation can reduce subsequent morbidity in children recovering from diarrhoea and respiratory illness in developing countries . However , whether routine supplementation would decrease morbidity and mortality in population s with zinc deficiency is unclear . We assessed the effect of daily zinc supplementation on children in southern Nepal . METHODS We did a community-based , cluster-r and omised , double-masked , placebo-controlled , 2x2 factorial trial in children aged 1 - 35 months . Treatment groups were placebo , iron and folic acid , zinc , and iron and folic acid with zinc , with daily doses of 12.5 mg iron , 50 microg folic acid , and 10 mg zinc . Study staff gave children tablets on 2 days each week and left tablets with caregivers for other days . All children received vitamin A supplementation twice per year . Results of the iron arm of the trial have been reported previously . Between October , 2001 , and January , 2006 , 41,276 children were enrolled into the placebo ( n=20,308 ) or zinc ( n=20,968 ) groups and were followed-up for 60,636.3 person-years . The primary outcome was child mortality , and analyses were by intention to treat . Daily reports of signs and symptoms of common morbidities in stratified r and om sub sample s of children were assessed every week for 12 months . This study is registered at Clinical Trials.gov , number NCT00109551 . FINDINGS 2505 children refused to continue the trial and 3219 children were lost to follow-up . There was no significant difference in mortality between the zinc and placebo groups ( 316 vs 333 deaths ; hazard ratio 0.92 , 95 % CI 0.75 - 1.12 ) . Zinc had no effect on mortality in children younger than 12 months ( 181 vs 168 deaths ; 1.04 , 0.83 - 1.31 ) ; mortality was lower , but not statistically significantly so , in older children receiving zinc ( 135 vs 165 ; 0.80 , 0.60 - 1.06 ) . The frequency and duration of diarrhoea , persistent diarrhoea , dysentery , and acute lower respiratory infections did not differ between the groups . INTERPRETATION Total mortality of children receiving zinc supplementation was not significantly different from that of children receiving placebo . Further data are needed from other population s with endemic zinc deficiency to confirm the potential age-specific effects reported in this study BACKGROUND The low micronutrient content of complementary foods is associated with growth faltering in many population s. A potential low-cost solution is the home fortification of complementary foods with Sprinkles ( SP ) powder , crushable Nutritabs ( NT ) tablets , or energy-dense ( 108 kcal/d ) , fat-based Nutributter ( NB ) . OBJECTIVE The objective was to test the hypothesis that multiple micronutrients added to home-prepared complementary foods would increase growth and that the effect would be greatest in the presence of added energy from fat . DESIGN We r and omly assigned 313 Ghanaian infants to receive SP , NT , or NB containing 6 , 16 , and 19 vitamins and minerals , respectively , daily from 6 to 12 mo of age . We assessed anthropometric status at 6 , 9 , and 12 mo ; micronutrient status at 6 and 12 mo ; motor development at 12 mo ; and morbidity weekly . Infants ( n = 96 ) not r and omly selected for the intervention ( nonintervention ; NI ) were assessed at 12 mo . RESULTS The groups did not differ significantly at baseline , except that the NB group had a higher proportion of boys and weighed slightly more . The dropout rate ( 15/313 ) was low . At 12 mo , after control for initial size , the NB group had a significantly greater weight-for-age z score ( WAZ ) ( -0.49 + /- 0.54 ) and length-for-age z score ( LAZ ) ( -0.20 + /- 0.54 ) than did the NT group ( WAZ : -0.67 + /- 0.54 ; LAZ : -0.39 + /- 0.54 ) and the NT and SP groups combined ( WAZ : -0.65 + /- 0.54 ; LAZ : -0.38 + /- 0.54 ) ; the difference with the NI group ( WAZ : -0.74 + /- 1.1 ; LAZ : -0.40 + /- 1.0 ) was not significant . A lower percentage of the NI infants ( 25 % ) than of the intervention groups ( SP : 39 % ; NT : 36 % ; NB : 49 % ) could walk independently by 12 mo . CONCLUSION All 3 supplements had positive effects on motor milestone acquisition by 12 mo compared with no intervention , but only NB affected growth Protein-energy malnutrition ( PEM ) remains one of the common causes of morbidity and mortality among children throughout the world . The supplementation of 10 mg elemental zinc , as zinc sulphate , was evaluated in the management of PEM in a r and omized , controlled double-blind clinical trial in 300 children , aged 6 - 60 months ( zinc , n = 150 ; control , n = 150 ) admitted to the Queen Elizabeth II Hospital , Maseru , Lesotho . Supplementation and follow-up were done for 3 months post-discharge from the hospital . Mortality during hospitalization was significantly lower in the zinc supplemented group ( 4.7 per cent ) , compared with 16.7 per cent in the control group . The prevalence of morbidity was significantly higher in the control group at 1 , 2 , and 3 month 's follow-up . In the zinc supplemented group 58 per cent of the children were above the 80th percentile of expected weight-for-age 3 months after discharge , compared with 27.6 per cent in the control group . Dietary zinc supplementation result ed in a significant reduction in diarrhoeal disease , respiratory morbidity , and episodes of clinical anaemia , skin infections , and fever as well as vomiting in children with PEM . These findings suggest that interventions to improve zinc intake in their management may be of benefit to Basotho children in Lesotho with PEM Protein-energy malnutrition ( PEM ) remains one of the common causes of morbidity and mortality among children throughout the world . The supplementation of 10 mg elemental zinc , as zinc sulphate , was evaluated in the management of PEM in a r and omized , controlled , double-blind clinical trial in 300 children , aged 6 - 60 months ( zinc , n = 150 ; control , n = 150 ) admitted to the Queen Elizabeth II Hospital , Maseru , Lesotho . Supplementation and follow-up were done for 3 months post-discharge from the hospital . Both the supplemented and the control groups presented with biochemically determined zinc deficiency on presentation . Despite supplementation the treated group only began to show evidence of biochemical increase in serum zinc at 60 days post-discharge from hospital . This may represent the period of replacement of the total body zinc . Zinc deficiency was more severe in those children in the control group that died after admission to hospital than those that survived , suggesting that low serum levels in children with PEM are associated with a poor prognosis . Zinc did not emerge as a predicator of poor prognosis in the supplemented group as very few children died in this group . The supplemented group also made significant gains as far as albumin levels were concerned , which probably reflects rehabilitation of their malnutrition . The associated improvement in haematological parameters has not been described before and may be secondary to the decreased burden of disease in the supplemented group . These findings suggest that not only were significant benefits of zinc supplementation shown for morbidity in mortality of children in Lesotho with PEM , but these trends were also demonstrated on biochemical profiles OBJECTIVE . Gastrointestinal parasites continue to be an important cause of morbidity and stunting among children in developing countries . We evaluated the effect of vitamin A and zinc supplementation on infections by Giardia lamblia , Ascaris lumbricoides , and Entamoeba histolytica . METHODS . A r and omized , double-blind , placebo-controlled trial was conducted among 707 children who were 6 to 15 months of age and from periurban areas of Mexico City , Mexico , between January 2000 and May 2002 . Children , who were assigned to receive either vitamin A every 2 months , a daily zinc supplement , a combined vitamin A and zinc supplement , or a placebo , were followed for 1 year . The primary end points were the 12-month rates and duration s of infection for the 3 parasites and rates of parasite-associated diarrheal disease as determined in stools collected once a month and after diarrheal episodes . RESULTS . G lamblia infections were reduced and A lumbricoides infections increased among children in the combined vitamin A and zinc group or the zinc alone group , respectively . Duration s of Giardia infections were reduced among children in all 3 treatment arms , whereas Ascaris infections were reduced in the vitamin A and zinc group . In contrast , E histolytica infection duration s were longer among zinc-supplemented children . Finally , E histolytica– and A lumbricoides – associated diarrheal episodes were reduced among children who received zinc alone or a combined vitamin A and zinc supplement , respectively . CONCLUSIONS . We found that vitamin A and zinc supplementation was associated with distinct parasite-specific health outcomes . Vitamin A plus zinc reduces G lamblia incidence , whereas zinc supplementation increases A lumbricoides incidence but decreases E histolytica – associated diarrhea OBJECTIVE To determine the efficacy of zinc-fortified oral rehydration salts solution ( ORS ) in comparison to ORS without zinc in 6- to 35-month-old urban children with acute diarrhea not sick enough to be hospitalized . DESIGN Double-blind , r and omized , controlled trial . METHODS Children ( n = 1219 ) with acute diarrhea were r and omly assigned to one of 3 groups . The first group received a zinc syrup ( 15 mg zinc to 6- to 11-month-old children and 30 mg to 12- to 35-month-old children ) , the second group received zinc premixed with ORS ( 40 mg/L ) , and the control children received ORS only . Households were visited twice weekly until recovery . RESULTS The total number of stools was lower in the zinc-ORS group ( rate ratio , 0.83 ; 95 % CI , 0.71 - 0.96 ) , as was the proportion of children with watery stools ( odds ratio , 0.61 ; 95 % CI , 0.39 - 0.95 ) , compared with the control group ; there was no significant effect on diarrheal duration . ORS intake and proportion of children with vomiting were not significantly different between the zinc-ORS and control groups . The zinc syrup group had lower diarrheal duration ( relative hazards , 0.89 ; 95 % CI , 0.80 - 0.99 ) and total stools ( rate ratio , 0.73 ; 95 % CI , 0.70 - 0.77 ) than control children . CONCLUSIONS Zinc-ORS was moderately efficacious in reducing the severity of acute diarrhea without increasing vomiting or reducing ORS intake OBJECTIVE To determine if educating caregivers in providing zinc supplements to infants < 6 months old with acute diarrhoea is effective in treating diarrhoea and preventing acute lower respiratory infections ( ALRIs ) , and whether it leads to a decrease in the use of oral rehydration salts ( ORS ) . METHODS In this retrospective subgroup analysis of infants aged < 6 months , six clusters were r and omly assigned to intervention or control sites . Care providers were trained to give zinc and ORS to children with acute diarrhoea at intervention sites , and only ORS at control sites . Surveys were conducted at 3 and 6 months to assess outcomes . Differences between intervention and control sites in episodes of diarrhoea and ALRI in the preceding 24 hours or 14 days and of hospitalizations in the preceding 3 months were analysed by logistic regression . FINDINGS Compared with control sites , intervention sites had lower rates of acute diarrhoea in the preceding 14 days at 3 months ( odds ratio , OR : 0.60 ; 95 % confidence interval , CI : 0.43 - 0.84 ) and 6 months ( OR : 0.72 ; 95 % CI : 0.54 - 0.94 ) ; lower rates of acute diarrhoea in the preceding 24 hours at 3 months ( 0.66 ; 95 % CI : 0.50 - 0.87 ) and of ALRI in the preceding 24 hours at 6 months ( OR : 0.59 ; 95 % CI : 0.37 - 0.93 ) ; and lower rates of hospitalization at 6 months for all causes ( OR : 0.40 ; 95 % CI : 0.34 - 0.49 ) , diarrhoea ( OR : 0.34 ; 0.18 - 0.63 ) and pasli chalna or pneumonia ( OR : 0.36 ; 95 % CI : 0.24 - 0.55 ) . CONCLUSION Educating caregivers in zinc supplementation and providing zinc to infants < 6 months old can reduce diarrhoea and ALRI . More studies are needed to confirm these findings as these data are from a subgroup analysis BACKGROUND Low-birth-weight infants may have impaired zinc status , but little is known about the effect of zinc supplementation . OBJECTIVE The objective was to investigate the effect of daily zinc supplementation on morbidity and anthropometric status in hospital-born , low-birth-weight infants . DESIGN In a double-blind , r and omized , placebo-controlled trial , 2052 hospital-born term infants with a birth weight < or = 2500 g were r and omly assigned to receive zinc or placebo . The zinc group received elemental zinc : 5 mg/d for those infants between ages 2 wk and 6 mo and 10 mg/d for those infants aged > 6 mo . All-cause hospitalizations , prevalence of diarrhea , acute lower respiratory tract infections , visits to health care providers , weights , and lengths were ascertained at 3 , 6 , 9 , and 12 mo of age . RESULTS The supplement was consumed for > 85 % of the follow-up period . Mean plasma zinc at 12 mo of age was higher in the zinc group ( 100.2 microg/dL ) than in the control group ( 73.3 microg/dL ) ( difference in means : 26.9 ; 95 % CI : 19.6 , 34.2 ) . The 24-h and 7-d prevalence of diarrhea and acute lower respiratory tract infections was similar at 3 , 6 , 9 , and 12 mo . Care-seeking for illness was significantly lower in the zinc group ( difference in proportions : -5.7 ; 95 % CI : -9.9 , -1.4 ; P < 0.05 ) at 9 mo . The numbers of hospitalizations , weights , and lengths were all similar at all 4 assessment s. CONCLUSION Hospital-born , term , low-birth-weight infants do not seem to benefit substantially from zinc supplementation that meets the Recommended Dietary Allowance for zinc in terms of morbidity or physical growth during infancy in this setting . This trial was registered at www . clinical trials.gov as NCT00272142 Iron and zinc deficiencies are common in developing countries and supplementation is one way of reversing these deficiencies . The objective of this r and omized , placebo-controlled clinical trial was to identify the effect of daily supplementation with iron , zinc , and iron plus zinc on the morbidity experience of 855 children 0.5 - 15 years of age in Peru . Single nutrient supplementation with zinc reduced diarrhea morbidity by 23 % in all children . In older children ( more than five years of age ) , iron supplementation increased morbidity due to Plasmodium vivax and diarrhea . In younger children , iron combined with zinc provided protection against P. vivax malaria , but also interfered with some of the diarrhea protection associated with zinc supplementation . No statistically significant effect was observed of either supplement on incidence of respiratory infection or anthropometric indices . Iron and zinc deficiencies should be remedied , and combined supplementation may be a good option , particularly in younger children in P. vivax malaria-endemic areas , although local endemicity and species-specific prevalence should be considered carefully when design ing any supplementation program involving iron in a malaria-endemic area Objective : Zinc deficiency is prevalent in children in developing countries . Supplemental zinc provides therapeutic benefits in diarrhoea . Our aim was to evaluate the effect of daily zinc supplementation for 14 days on diarrhoea duration , severity , and morbidity in children . Methods : In a r and omised , open label non-placebo controlled trial , we assessed the efficacy of providing zinc sulfate to 6–60 month old children with acute diarrhoea for 2 weeks followed by 3 months of morbidity surveillance . Children were r and omly assigned to zinc ( n = 150 ) and control ( n = 130 ) groups and received 15–30 mg elemental zinc daily . Results : Supplemented children had significantly improved plasma zinc levels by day 14 of therapy . Zinc deficiency was observed in 2.6 % of the treatment and 3.3 % of the control group . The mean duration of diarrhoea after starting supplementation was 3.02±2 days in the zinc group and 3.67±3.2 days in the control group . There was no significant difference in diarrhoea duration by treatment group ( p>0.05 ) . The number of stools after starting supplementation was 5.8±3.7 and 5.1±3.9 on day 1 , 2.9±1.6 and 3.0±2.2 on day 2 , and 1.8±1.1 and 1.6±0.9 on day 3 in the zinc and control groups , respectively . There was no significant difference in diarrhoea severity by treatment group ( p>0.05 ) . No significant effect was found on the incidence and prevalence of diarrhoea in the zinc compared with the control group . Conclusion : Our data indicate that supplementing children with acute diarrhoea in Turkey with 3 RDA of elemental zinc for 14 days improved neither diarrhoea duration nor severity despite significant increments in plasma zinc Objective : This r and omized , placebo controlled trial was design ed to assess the safety and efficacy of 10-mg zinc supplementation for the treatment of acute diarrhea in infants . Methods : A total of 1110 infants aged 28 days to 5 months with acute diarrhea were enrolled and r and omized to receive either zinc ( n = 554 ) or placebo ( n = 556 ) for 14 days . Diarrhea history , anthropometric status , breast-feeding status and socioeconomic indicators were assessed at baseline . The homes of all infants were visited every 3 days until the diarrhea episode was over . The number of stools , presence of blood and additional illnesses were recorded daily . Results : The geometric mean duration of the diarrhea episode was 0.21 days longer among infants receiving zinc versus those receiving placebo , but this was not statistically significant and no difference was observed after controlling for sex , exclusive breast-feeding and length for age Z score . There were no differences in any subgroup ( ie , sex , baseline length for age Z score , exclusive breast-feeding or site after controlling for the remaining subgroup variables ) . There were no differences in reported stool frequency or among the proportion of episodes lasting longer than 7 days . Rates of vomiting were similar in the zinc and placebo groups . Conclusions : Young infants do not appear to benefit from zinc supplementation for the treatment of diarrhea Zinc is recommended for the treatment of acute diarrhea in children but the effect of its introduction on drug and oral rehydration solution use is unclear . Government care providers , private practitioners and community workers were trained to distribute zinc and oral rehydration solution to children seeking care for diarrhea . Periodic surveys showed that village-based workers became a common source of diarrhea treatment and private practitioners were used less . Zinc was used in approximately half of the episodes ; the prescription and use rates of oral rehydration solution packets increased from 7 % at baseline to 44.9 % 6 months later . Reduction in use of drugs during diarrhea ranged from 34 % for tablets to 64 % for injections 6 months later . The cost of treatment to families declined significantly . These findings need confirmation in a r and omized controlled trial OBJECTIVE To determine whether zinc with oral rehydration solution ( ORS ) is more cost effective than ORS alone in the treatment of acute diarrhea . STUDY DESIGN AND SETTING Cost-effectiveness analysis among patients consulting the emergency room of a government institution . METHOD Cost of treatment and outcome of participants of a r and omized trial of zinc+ORS vs. ORS alone for acute diarrhea were investigated . Included were subjects 2 - 59 months with diarrhea < 7 days and no dehydration . The direct medical , nonmedical and indirect costs were obtained , using the societal perspective . The incremental cost-effectiveness ratio ( ICER ) was calculated . RESULTS Sixty patients were given zinc+ORS and 57 were given ORS alone . Mean duration of diarrhea was 17 hours shorter and mean total cost of treatment was 5 % cheaper in the zinc than ORS group . The ICER showed that with use of zinc , the society saves $ 2.4 per day of diarrhea < 4 days and spends $ 0.03 per case of diarrhea averted < 4 days from consult , although the confidence interval included the null value of zero . CONCLUSION Use of zinc with ORS reduced the total cost and duration of acute diarrhea . The ICER suggests cost effectiveness of zinc supplementation but there is a need to further assess the role of zinc supplementation in a larger population BACKGROUND Zinc deficiency is associated with impaired immune function and an increased risk of infection . Supplementation can decrease the incidence of diarrhoea and pneumonia in children in re source -poor countries . However , in children with HIV-1 infection , the safety of zinc supplementation is uncertain . We aim ed to assess the role of zinc in HIV-1 replication before mass zinc supplementation is recommended in regions of high HIV-1 prevalence . METHODS We did a r and omised double-blind placebo-controlled equivalence trial of zinc supplementation at Grey 's Hospital in Pietermaritzburg , South Africa . 96 children with HIV-1 infection were r and omly assigned to receive 10 mg of elemental zinc as sulphate or placebo daily for 6 months . Baseline measurements of plasma HIV-1 viral load and the percentage of CD4 + T lymphocytes were established at two study visits before r and omisation , and measurements were repeated 3 , 6 , and 9 months after the start of supplementation . The primary outcome measure was plasma HIV-1 viral load . Analysis was per protocol . FINDINGS The mean log(10 ) HIV-1 viral load was 5.4 ( SD 0.61 ) for the placebo group and 5.4 ( SD 0.66 ) for the zinc-supplemented group 6 months after supplementation began ( difference 0.0002 , 95 % CI -0.27 to 0.27 ) . 3 months after supplementation ended , the corresponding values were 5.5 ( SD 0.77 ) and 5.4 ( SD 0.61 ) , a difference of 0.05 ( -0.24 to 0.35 ) . The mean percentage of CD4 + T lymphocytes and median haemoglobin concentrations were also similar between the two groups after zinc supplementation . Two deaths occurred in the zinc supplementation group and seven in the placebo group ( p=0.1 ) . Children given zinc supplementation were less likely to get watery diarrhoea than those given placebo . Watery diarrhoea was diagnosed at 30 ( 7.4 % ) of 407 clinic visits in the zinc-supplemented group versus 65 ( 14.5 % ) of 447 visits in the placebo group ( p=0.001 ) . INTERPRETATION Zinc supplementation of HIV-1-infected children does not result in an increase in plasma HIV-1 viral load and could reduce morbidity caused by diarrhoea . RELEVANCE TO PRACTICE Programmes to enhance zinc intake in deficient population s with a high prevalence of HIV-1 infection can be implemented without concern for adverse effects on HIV-1 replication . In view of the reductions in diarrhoea and pneumonia morbidity , zinc supplementation should be used as adjunct therapy for children with HIV-1 infection OBJECTIVE A community-based , r and omized , double-blind intervention trial was conducted to measure the impact of zinc supplementation on young Guatemalan children 's morbidity from diarrhea and respiratory infections . METHODS Children aged 6 to 9 months were r and omly assigned to receive 4 mL of a beverage containing 10 mg of zinc ( as zinc sulfate ) daily ( 7 d/wk ) for 7 months ( n = 45 ) or a placebo ( n = 44 ) . Morbidity data were collected daily . Diagnoses of diarrhea , fever , and anorexia were based on mothers ' definitions . Respiratory infections were defined as the presence of at least two of the following symptoms : runny nose , cough , wheezing , difficulty breathing , or fever . RESULTS High rates of diarrhea and respiratory infections were reported . Children from the placebo group had a 20 % episodic prevalence of diarrhea , with 8 episodes/100 d , and a 7 % episodic prevalence of respiratory infections , with 3 episodes/100 d. The median incidence of diarrhea among children who received zinc supplementation was reduced by 22 % ( Wilcoxon rank test ) , with larger reductions among boys and among children with weight-for-length at baseline lower than the median of the sample ( 39 % reductions in both subgroups ) . Zinc supplementation also produced a 67 % reduction in the percentage of children who had one or more episodes of persistent diarrhea ( chi2 test ) . No significant effects were found on the episodic prevalence of diarrhea , the number of days per episode , or the episodic prevalence or incidence of respiratory infections . CONCLUSIONS The large impact of zinc supplementation on diarrhea incidence suggests that young , rural Guatemalan children may be zinc deficient and that zinc supplementation may be an effective intervention to improve their health and growth A double-blind , r and omized , controlled clinical trial was conducted on 80 malnourished children with acute dehydrating diarrhoea to evaluate the efficacy of oral supplementation of zinc as an adjunct therapy to oral rehydration solution ( ORS ) . After decoding it was observed that 44 children received zinc sulphate ( 177 mg/kg/day in three divided doses equivalent to 40 mg elemental zinc ) in a syrup form and 36 children received only syrup placebo . Clinical parameters and microbiological findings of stool sample s were comparable in the two groups at the time of enrollment . All the children ( 100 per cent ) in the zinc supplemented group and 32 ( 89 per cent ) children in the placebo group recovered within 5 days of hospitalization ( p = 0.04 ) . The zinc supplemented group had a significantly shorter duration of diarrhoea ( 70.4 + /- 10.0 vs. 103.4 + /- 17.1 h ; p = 0.0001 ) , passed less liquid stool ( 1.5 + /- 0.7 vs. 2.4 + /- 0.7 kg ; p=0.0001 ) , consumed less oral rehydration solution ( 2.5 + /- 1.0 vs. 3.6 + /- 0.8 litre ; p = 0.0001 ) and other liquids ( 867.0 + /- 466.1 vs. 1354.7 + /- 675.6 ml ; p = 0.0001 ) as compared to the placebo group . Our findings suggest that zinc supplementation as an adjunct therapy to ORS has beneficial effects on the clinical course of dehydrating acute diarrhoea OBJECTIVE To investigate the therapeutic effects of oral zinc supplement in infants and young children with rotavirus enteritis , and its preventive effects against diarrhea recurrence within 3 months after treatment . METHODS A total of 103 infants and young children with rotavirus enteritis were r and omly divided into zinc supplement group ( n=51 ) and conventional treatment group ( n=52 ) . Both groups were equally treated with a comprehensive therapy , besides which the zinc supplement group received zinc gluconate granules for 10 days . The treatment outcomes were examined at 72 hours after treatment , and the time required for the disappearance of positive symptoms and the recovery of injured extra-intestinal organs were determined . In addition , these patients were followed up for 3 months to determine the incidence of diarrhea recurrence after treatment . RESULTS The overall response rate in the zinc supplement group was significantly higher than that in the conventional treatment group ( 90 % vs 75 % ; P<0.05 ) . The duration s of diarrhea , high fever , and vomiting in the zinc supplement group were significantly shorter than that in the conventional treatment group ( P<0.05 ) . In addition , the recurrence rate of diarrhea and the incidence of severe diarrhea within 3 months after treatment in the zinc supplement group were significantly lower than in the conventional treatment group ( P<0.05 ) . CONCLUSIONS Oral zinc supplement as adjunctive therapy is effective in treating infants and young children with rotavirus enteritis , and reducing the incidence and severity of diarrhea recurrence in the subsequent 3 months Concurrent micronutrient deficiencies are prevalent among Vietnamese school children . A school-based program providing food fortified with multiple micronutrients could be a cost-effective and sustainable strategy to improve health and cognitive function of school children . However , the efficacy of such an intervention may be compromised by the high prevalence of parasitic infestation . To evaluate the efficacy of school-based intervention using multi-micronutrient-fortified biscuits with or without deworming on anemia and micronutrient status in Vietnamese schoolchildren , a r and omized , double-blind , placebo-controlled trial was conducted among 510 primary schoolchildren , aged 6 - 8 y , in rural Vietnam . Albendazole ( Alb ) ( 400 mg ) or placebo was given at baseline . Nonfortified or multi-micronutrient-fortified biscuits including iron ( 6 mg ) , zinc ( 5.6 mg ) , iodine ( 35 microg ) , and vitamin A ( 300 microg retinol equivalents ) were given 5 d/wk for 4 mo . Multi-micronutrient fortification significantly improved the concentrations of hemoglobin ( + 1.87 g/L ; 95 % CI : 0.78 , 2.96 ) , plasma ferritin ( + 7.5 microg/L ; 95 % CI : 2.8 , 12.6 ) , body iron ( + 0.56 mg/kg body weight ; 95 % CI : 0.29 , 0.84 ) , plasma zinc ( + 0.61 micromol/L ; 95 % CI : 0.26 , 0.95 ) , plasma retinol ( + 0.041 micromol/L ; 95 % CI : 0.001 , 0.08 ) , and urinary iodine ( + 22.49 micromol/L ; 95 % CI : 7.68 , 37.31 ) . Fortification reduced the risk of anemia and deficiencies of zinc and iodine by > 40 % . Parasitic infestation did not affect fortification efficacy , whereas fortification significantly enhanced deworming efficacy , with the lowest reinfection rates in children receiving both micronutrients and Alb . Multi-micronutrient fortification of biscuits is an effective strategy to improve the micronutrient status of Vietnamese schoolchildren and enhances effectiveness of deworming Objectives The authors evaluated the effect of zinc treatment as an adjunct to oral rehydration therapy on stool output and diarrheal duration in children with acute noncholera diarrhea with dehydration . Methods This double-blind , r and omized , controlled trial was conducted at two urban hospitals in New Delhi . A total of 287 dehydrated male patients , ages 3 to 36 months , with diarrhea for ≤ 72 hours were enrolled . They were assigned to zinc or placebo by a r and omization scheme stratified by age ( ≤ or > 12 months ) and weight for height ( 65%–80 % or > 80 % National Centre for Health Statistics median ) . Participants in the zinc group received 15 mg ( ≤12 months ) or 30 mg ( > 12 months ) elemental zinc daily in three divided doses for 14 days . The main outcome measures were stool output and diarrheal duration . Results Zinc treatment reduced total stool output ( ratio of geometric means , 0.69 ; 95 % confidence interval [ CI ] : 0.48 , 0.99 ) and stool output per day of diarrhea ( ratio of geometric means , 0.76 ; 95 % CI : 0.59 , 0.98 ) . The risk of continued diarrhea was lower ( relative hazards , 0.76 ; 95 % CI : 0.59 , 0.97 ) and the proportion of diarrheal episodes lasting ≥ 5 days ( odds ratio , 0.49 ; 95 % CI : 0.25 , 0.97 ) or ≥ 7 days was less ( odds ratio , 0.09 ; 95 % CI : 0.01 , 0.73 ) in the zinc group . Conclusions This study demonstrates a beneficial effect of zinc administered during acute diarrhea on stool output , diarrheal duration , and proportion of episodes lasting more than 7 days . The effects are large enough to merit routine use of zinc during acute diarrhea in developing countries BACKGROUND The rates of anemia in children in southern Israel are high despite the current prevention strategy . A daily dose of " Sprinkles " ( SuppleForte , Heinz , Canada ) , a micronutrient home supplementation , was proven effective for the treatment of anemia worldwide . OBJECTIVES To assess the efficacy of Sprinkles , a novel supplementation formulation , in the primary prevention of anemia in infants who have free access to health care services . METHODS A two-arm open-labeled cluster r and omized controlled clinical trial was performed in 6 month old Bedouin and Jewish infants . The Sprinkles arm received sachets with iron , vitamins A and C , folic acid and zinc , and the control arm received st and ard treatment ( liquid iron and vitamins A and D ) . The infants were from families attending Mother and Child Health clinics during 2005 - 2007 . Intervention and follow-up were conducted for babies aged 6 - 12 months . Health outcomes ( hematologic and nutritional indicators , growth parameters , morbidity rates ) were evaluated at 12 and 18 months . RESULTS The final study population numbered 621 infants ( 328 Bedouin and 293 Jewish ) ; of the parents approached 88.5 % agreed to participate . Hemoglobin > 11 g/dl was found in 55 % of Bedouin and 40 % of Jewish infants ( P < 0.01 ) . Bedouin infants had significantly lower serum concentration of iron , folic acid and zinc . All background , hematologic and micronutrient indicators were similar in the two study arms except for a slightly but not clinical ly significant difference in hemoglobin and hematocrit levels in Bedouins . CONCLUSIONS Our findings indicate the need to improve the micronutrient status of infants living in the Negev . A cluster r and omized trial in MCH clinics is a feasible option BACKGROUND In Nigeria , diarrhoeal disease is second only to malaria as a cause of death the under 5 age group . This study was aim ed at assessing the benefit or otherwise of zinc supplement in acute diarrhoea . SUBJECTS AND METHODS This was a multi-centred r and omized double blind controlled study . Children with acute diarrhoea aged between 6 and 24 months were r and omized into zinc supplemented and placebo groups . Plasma zinc levels were analyzed at enrollment and at the end of the study . The children were review ed for the next three months from the time of enrollment . RESULTS The mean plasma zinc levels at baseline and at the end of the study were 0.06 + /- 0.04 and 0.067 + /- 0.03 ppm in the zinc supplemented group and 0.11 + /- 0.02 and 0.05 + /- 0.03 ppm in the control group . The differences were not statistically significant . The zinc supplemented group had an average weight gain of 1.1 kg as against 0.73 kg ( p = 0.00 ) for the control group in the study period . No adverse effect was reported on account of zinc supplementation . CONCLUSION Zinc supplementation is beneficial in acute diarrhoea as observed in this study OBJECTIVE As HIV has spread through sub-Saharan Africa , persistent diarrhoea has emerged as a major problem in hospitals and in the community in severely affected areas . We have previously demonstrated that antiprotozoal therapy with albendazole reduces diarrhoea in AIDS patients in urban Zambia . This trial was design ed to test the hypothesis that the clinical response to albendazole might be improved by oral micronutrient supplementation . DESIGN R and omized , placebo-controlled trial . SETTING Home care service of Ndola Central Hospital , Zambia . PATIENTS HIV-seropositive patients with persistent diarrhoea . INTERVENTION Patients were r and omized to albendazole plus vitamins A , C and E , selenium and zinc orally or albendazole plus placebo , for 2 weeks . MAIN OUTCOME MEASURES Time with diarrhoea following completion of treatment ; mortality ; adverse events . RESULTS Serum vitamin A and E concentrations before treatment were powerful predictors of early mortality , but supplementation did not reduce time with diarrhoea or mortality during the first month , even after taking into account initial vitamin A or E concentrations , CD4 cell count or clinical markers of illness severity . Serum concentrations of vitamins A and E did not increase significantly in supplemented patients compared with those given placebo , and there were no changes in CD4 cell count or haematological parameters . No adverse events were detected except those attributable to underlying disease . CONCLUSIONS Although micronutrient deficiency is predictive of early death in Zambian patients with the diarrhoea-wasting syndrome , short-term oral supplementation does not overcome it nor influence morbidity or mortality BACKGROUND Among the preventive strategies for lowering the incidence of upper respiratory tract infections ( URTI ) and acute diarrhoea episodes , two of the most common diseases in children , zinc supplementation has received special interest . However , there is a need for additional studies that determine the preventive effects of different doses of zinc on URTI and diarrhoeal disease episodes in children . METHODS In a r and omised , triple-blind clinical trial , we evaluated the efficacy of 12 months of daily zinc supplementation in the incidence of URTI and acute diarrhoea in a population of healthy children aged between 6 and 12 months living in Bogota , Colombia . The outcomes analysed were incidence of URTI , acute diarrhoeal disease episodes , and side effects of the interventions . RESULTS Between 2010 and 2013 , a total of 355 children underwent r and omisation , with 174 assigned to the zinc supplementation group and 181 to the control group . In the multivariate analyses , having been r and omised to the non-supplemented control group ( IRR 1.73 , 95 % CI 1.52 - 1.97 , p<0.001 ) , and nursery attendance ( IRR 1.41 , 95 % CI 1.07 - 1.87 , p=0.016 ) were independently linked to the number of URTI . Likewise , having been r and omised to the non-supplemented group ( IRR 1.43 , 95 % CI 1.20 - 1.71 , p<0.001 ) , and lower socioeconomic status ( IRR 1.86 , 95 % CI 1.11 - 3.13 , p=0.018 ) were independently associated to the number of diarrhoeal disease episodes . CONCLUSIONS Daily supplementation of 5 mg of zinc during 12 months significantly decreased the incidence of URTI and diarrhoeal disease episodes in a healthy population of children aged between 6 and 12 months Our objective was to evaluate the effect of zinc and copper supplementation in acute diarrhea on morbidity and growth during 12 weeks of follow-up . In a double-blind r and omized controlled clinical trial of 724 children aged 6–59 months , none of the 11 evaluated outcomes showed significant association with zinc or zinc and copper supplementation . Thus , therapeutic zinc supplementation may not always yield short-term benefits Objectives : We assessed the effect of zinc for the treatment of diarrhoea implemented at the community level on physical growth among children 6 to 35 months of age . Methods : The service areas of 30 community health workers in the Matlab field site of International Centre for Diarrhoeal Disease Research , Bangladesh , were r and omly allocated to the intervention or comparison study arm . Between November 1998 and October 2000 , caretakers of 3- to 59-month-old children with diarrhoea in both intervention and comparison areas were offered oral rehydration solution and feeding advice , and severe episodes were referred for facility-based care . The caretakers of the children in the intervention area were additionally offered 20 mg/day elemental zinc for 14 days as adjunct treatment for each diarrhoea episode . Weight and length of children who were 6 to 11 months of age at the beginning of the study were measured every 2 months for 2 years . Rates of length and weight gains were compared between children living in intervention and control arms using a latent growth model . Results : Characteristics of children living in control and intervention areas were similar , except that more children living in intervention areas were underweight at baseline ( 44 vs 35 % ; P = 0.02 ) . Children living in intervention clusters gained slightly more weight and length than children in the control clusters ( 86.4 g/year and 2.8 mm/year , respectively ) . Conclusions : The therapeutic use of zinc along with oral rehydration solution for community-based diarrhoea management may have a small positive benefit on the rates of growth among children younger than 3 years of age OBJECTIVE Improvement of hemoglobin and serum retinol and facilitation of the mobilization of iron storage were achieved with a multiple-micronutrient-fortified diet in preschoolers for 6 mo in a suburb of Chongqing , China . We investigated whether fortification with multiple micronutrients in a diet for preschool children results in changes in children 's infectious morbidity compared with diets fortified solely with vitamin A and with vitamin A plus iron . METHODS From December 2005 to June 2006 , 226 2- to 6-y-old preschool children were recruited from three nurseries r and omly assigned to three different fortified-diet groups for 6 mo . Group I was fortified with vitamin A ; groups II and III were fortified with vitamin A plus iron and vitamin A plus iron , thiamine , riboflavin , folic acid , niacinamide , zinc , and calcium , respectively . The secondary functional outcomes , morbidity of diarrhea and respiratory infection , were collected during supplementation . RESULTS The groups were comparable concerning compliance and loss to follow-up . There was evidence of a lower incidence rate of respiratory-related illnesses , diarrhea-related illness , fewer symptoms of runny nose , cough , and fever , and shorter duration of respiratory-related illnesses and cough for children in group III compared with children in groups I and II . However , there was no significantly or clinical ly important difference between children in groups I and II . CONCLUSION The beneficial effects on infectious morbidity over 6 mo , in addition to some biochemical improvements , highlight the potential of this micronutrient-fortified seasoning powder supplied in a diet for preschool children We conducted a r and omized , double-blind placebo controlled , community trial in rural Bangladesh in children 4 - 59 mo of age to compare the efficacy of a 5- and 10-d course of zinc therapy on the incidence and duration of diarrhea over the subsequent 90-d follow-up after initial treatment for an acute childhood diarrheal ( ACD ) episode . Children ( n = 1622 ) with ACD were r and omly allocated to either 5 or 10 d of zinc treatment . Female field workers visited each child daily , supervised the administration of zinc , recorded the duration of current episode , and the occurrence and duration of diarrhea over the subsequent 3 mo . The incidence of diarrhea over the 90 d of follow-up did not differ between the 5-d ( 1.08 ± 1.38 episodes ) and 10-d ( 1.02 ± 1.35 episodes ) groups ( P = 0.35 ) . Children in both groups experienced a comparable duration of diarrheal episodes ( 3.1 ± 5.6 d vs. 2.9 ± 5.6 d , 5-d vs. 10-d , respectively ; P = 0.64 ) with a mean difference between groups within the defined range of equivalence . Time to onset of the first episode and the proportion children experiencing diarrhea during the 90-d follow-up also did not differ between groups . These findings suggest that among Bangladeshi children , a 5-d zinc treatment for ACD is as efficacious as 10 d in preventing diarrhea in the subsequent 3 mo |
13,608 | 19,635,044 | In the ONTARGET trial in patients with hypertension at high cardiovascular risk , ACE inhibitor/ARB combination therapy provided no significant clinical outcome benefits over monotherapy , and was associated with a worse safety and tolerability profile .
In patients with hypertension , ACE inhibitor/ARB combinations provided limited additional reductions in blood pressure ( BP ) over monotherapy .
Outcomes benefits were unclear : VALIANT and ONTARGET demonstrated no enhanced outcome benefit of combination therapy over monotherapy ; Val-HeFT and CHARM-Added showed reduced morbidity/mortality in patients with heart failure , but at the expense of poorer tolerability .
Combination therapy with the DRI aliskiren and an ACE inhibitor or ARB provided significant additional BP reductions over monotherapy in patients with mild-to-moderate hypertension , and reduced surrogate markers of organ damage in patients with heart failure or diabetic nephropathy , with generally similar safety and tolerability to the component monotherapies .
CONCLUSIONS ACE inhibitor/ARB combinations showed equivocal effects on clinical outcomes .
DRI/ACE inhibitor and DRI/ARB combinations reduced markers of organ damage , but longer-term trials are required to establish whether more complete renin -- angiotensin -- aldosterone system control with aliskiren-based therapy translates into improved outcome benefits | BACKGROUND Clinical trials have shown organ-protective effects of angiotensin-converting enzyme ( ACE ) inhibitors and angiotensin receptor blockers ( ARBs ) ; however , cardiovascular mortality and morbidity rates , and decline in renal function remain high .
These results raise the question of whether ACE inhibitor/ARB , direct renin inhibitor (DRI)/ACE inhibitor and DRI/ARB combinations are of clinical value . | CONTEXT Incidence of end-stage renal disease due to hypertension has increased in recent decades , but the optimal strategy for treatment of hypertension to prevent renal failure is unknown , especially among African Americans . OBJECTIVE To compare the effects of an angiotensin-converting enzyme ( ACE ) inhibitor ( ramipril ) , a dihydropyridine calcium channel blocker ( amlodipine ) , and a beta-blocker ( metoprolol ) on hypertensive renal disease progression . DESIGN , SETTING , AND PARTICIPANTS Interim analysis of a r and omized , double-blind , 3 x 2 factorial trial conducted in 1094 African Americans aged 18 to 70 years with hypertensive renal disease ( glomerular filtration rate [ GFR ] of 20 - 65 mL/min per 1.73 m(2 ) ) enrolled between February 1995 and September 1998 . This report compares the ramipril and amlodipine groups following discontinuation of the amlodipine intervention in September 2000 . INTERVENTIONS Participants were r and omly assigned to receive amlodipine , 5 to 10 mg/d ( n = 217 ) , ramipril , 2.5 to 10 mg/d ( n = 436 ) , or metoprolol , 50 to 200 mg/d ( n = 441 ) , with other agents added to achieve 1 of 2 blood pressure goals . MAIN OUTCOME MEASURES The primary outcome measure was the rate of change in GFR ; the main secondary outcome was a composite index of the clinical end points of reduction in GFR of more than 50 % or 25 mL/min per 1.73 m(2 ) , end-stage renal disease , or death . RESULTS Among participants with a urinary protein to creatinine ratio of > 0.22 ( corresponding approximately to proteinuria of more than 300 mg/d ) , the ramipril group had a 36 % ( 2.02 [ SE , 0.74 ] mL/min per 1.73 m(2)/y ) slower mean decline in GFR over 3 years ( P = .006 ) and a 48 % reduced risk of the clinical end points vs the amlodipine group ( 95 % confidence interval [ CI ] , 20%-66 % ) . In the entire cohort , there was no significant difference in mean GFR decline from baseline to 3 years between treatment groups ( P = .38 ) . However , compared with the amlodipine group , after adjustment for baseline covariates the ramipril group had a 38 % reduced risk of clinical end points ( 95 % CI , 13%-56 % ) , a 36 % slower mean decline in GFR after 3 months ( P = .002 ) , and less proteinuria ( P<.001 ) . CONCLUSION Ramipril , compared with amlodipine , retards renal disease progression in patients with hypertensive renal disease and proteinuria and may offer benefit to patients without proteinuria The study was design ed to assess the antihypertensive effect of combined angiotensin-converting enzyme ( ACE ) inhibition and angiotensin II type 1 receptor ( AT1 ) antagonism in patients with essential hypertension . Twenty patients with uncontrolled ambulatory diastolic blood pressure ( BP ) after 6 weeks of ACE inhibitor monotherapy ( benazepril , 20 mg , o.d . ) were r and omized to receive double-blind valsartan , 80 mg , o.d . ( AT1 antagonist ) or matching placebo for 5 weeks while continuing to receive background benazepril . Then patients crossed over to the alternative regimen for a second 5-week period . The 24-h ambulatory BP was monitored on the final day of the benazepril monotherapy period and on the final day of each double-blind treatment period . Valsartan added to benazepril produced a significant antihypertensive effect with a benefit over placebo of 6.5 + /- 12.6/4.5 + /- 8.0 mm Hg ( systolic/diastolic ) for average awake ambulatory BP ( p < 0.05 ) , 7.1 + /- 9.4/5.6 + /- 6.5 mm Hg for asleep BP ( p < 0.01 ) , and 6.8 + /- 9.7/4.9 + /- 6.8 mm Hg for average 24-h ambulatory BP ( p < 0.01 ) . Pulse rate was unaffected . Plasma active renin was higher on the benazepril-valsartan combination compared with benazepril-placebo ( p < 0.05 ) . There was no change in routine biochemical variables when valsartan was added to benazepril . Six patients reported mild dizziness or fatigue ( three also with placebo ) . These data suggest that in hypertensive patients uncontrolled with an ACE inhibitor , the addition of an AT1 antagonist provides a powerful and safe antihypertensive drug combination BACKGROUND Treatment of hypertension with diuretics , beta-blockers , or both leads to improved outcomes . It has been postulated that agents that inhibit the renin-angiotensin system confer benefit beyond the reduction of blood pressure alone . We compared the outcomes in older subjects with hypertension who were treated with angiotensin-converting-enzyme ( ACE ) inhibitors with the outcomes in those treated with diuretic agents . METHODS We conducted a prospect i ve , r and omized , open-label study with blinded assessment of end points in 6083 subjects with hypertension who were 65 to 84 years of age and received health care at 1594 family practice s. Subjects were followed for a median of 4.1 years , and the total numbers of cardiovascular events in the two treatment groups were compared with the use of multivariate proportional-hazards models . RESULTS At base line , the treatment groups were well matched in terms of age , sex , and blood pressure . By the end of the study , blood pressure had decreased to a similar extent in both groups ( a decrease of 26/12 mm Hg ) . There were 695 cardiovascular events or deaths from any cause in the ACE-inhibitor group ( 56.1 per 1000 patient-years ) and 736 cardiovascular events or deaths from any cause in the diuretic group ( 59.8 per 1000 patient-years ; the hazard ratio for a cardiovascular event or death with ACE-inhibitor treatment was 0.89 [ 95 percent confidence interval , 0.79 to 1.00 ] ; P=0.05 ) . Among male subjects , the hazard ratio was 0.83 ( 95 percent confidence interval , 0.71 to 0.97 ; P=0.02 ) ; among female subjects , the hazard ratio was 1.00 ( 95 percent confidence interval , 0.83 to 1.21 ; P=0.98 ) ; the P value for the interaction between sex and treatment-group assignment was 0.15 . The rates of nonfatal cardiovascular events and myocardial infa rct ions decreased with ACE-inhibitor treatment , whereas a similar number of strokes occurred in each group ( although there were more fatal strokes in the ACE-inhibitor group ) . CONCLUSIONS Initiation of antihypertensive treatment involving ACE inhibitors in older subjects , particularly men , appears to lead to better outcomes than treatment with diuretic agents , despite similar reductions of blood pressure BACKGROUND Patients with type 2 diabetes are at increased risk of macro- and microvascular disease , and the presence of albuminuria and /or reduced kidney function further enhances macrovascular risk . Angiotensin-converting-enzyme inhibitors reduce both macro- and microvascular events , yet the residual renal and cardiovascular risk still remains high . Aliskiren a novel oral direct renin inhibitor that unlike ACEi and ARBs , lowers plasma renin activity , angiotensin I and angiotensin II levels , may thereby provide greater benefit compared to ACEi or ARB alone . METHODS The primary objective of the ALTITUDE trial is to determine whether aliskiren 300 mg once daily , reduces cardiovascular and renal morbidity and mortality compared with placebo when added to conventional treatment ( including ACEi or ARB ) . ALTITUDE is an international , r and omized , double-blind , placebo-controlled , parallel-group study , which will include three categories of high-risk patients with type 2 diabetes ( aged > or = 35 years ) : those with either urinary albumin/creatinine ratio ( UACR ) > or = 200 mg/g ; microalbuminuria ( UACR ) > or = 20 < 200 mg/g and eGFR > or = 30 < 60 mL/min/1.73 m2 ; and thirdly , those with a history of cardiovascular disease and eGFR > or = 30 < 60 mL/min/1.73 m2 with or without microalbuminuria . ALTITUDE is an event driven trial that aims to r and omize 8600 patients with a planned follow-up time of 48 months . The primary outcome measure is time to first event for the composite endpoint of cardiovascular death , resuscitated death , myocardial infa rct ion , stroke , unplanned hospitalization for heart failure , onset of end-stage renal disease or doubling of baseline serum creatinine concentration . Secondary endpoints include a composite CV endpoint and a composite renal endpoint . CONCLUSION ALTITUDE will determine whether dual RAAS blockade with the direct renin inhibitor aliskiren in combination with an ACEi or ARB will reduce major morbidity and mortality in a broad range of high-risk patients with type 2 diabetes BACKGROUND Angiotensin II exerts a number of harmful effects in patients with chronic heart failure ( CHF ) and , through an increase in oxidative stress , is thought to be critical in the development of endothelial dysfunction . Angiotensin II may be elevated in CHF despite treatment with angiotensin converting enzyme ( ACE ) inhibitors , producing a rationale for adjunctive angiotensin receptor blockade . We investigated whether the addition of angiotensin antagonism to ACE inhibition would reduce oxidative stress and improve endothelial function and exercise tolerance in patients with chronic heart failure . METHODS AND RESULTS Twenty-eight heart failure patients , who were on stable ACE inhibitor therapy , were r and omised to receive adjunctive therapy with c and esartan or placebo . Plasma lipid-derived free radicals , TBARS and neutrophil O2-generation , markers of oxidative stress , were measured in venous blood . Arterial endothelial function was assessed as the response of the brachial artery to flow-related shear stress . Exercise capacity was determined by cardiopulmonary exercise testing . Compared with placebo , c and esartan had no effect on changes in lipid derived free radicals ( -0.1+/-1.2 vs. -0.1+/-1.0 units , respectively , P = NS ) , TBARS ( -2.2+/-1.1 vs. -2.6+/-2.2 micromol/l , respectively , P = NS ) or neutrophil O2-generating capacity ( -7.3+/-5.1 vs. -8.4+/-7.9 mV/5x10(5 ) neutrophils , respectively , P = NS ) . There was no effect on changes in brachial artery flow-mediated dilatation ( 0.5+/-1.0 vs. 0.8+/-1.3 % , respectively , P = NS ) nor peak VO2 ( 1.6+/-0.7 ml/kg per min vs. 1.8+/-0.6 ml/kg per min ; P = NS ) . CONCLUSION The addition of the c and esartan to ACE inhibitor therapy had no effect on oxidative stress and did not improve endothelial function or exercise capacity in patients with CHF BACKGROUND We evaluated the renoprotective effects of dual blockade of renin-angiotensin system ( RAS ) by using a low-dose combination of ACE inhibiter and angiotensin II receptor blocker in type 2 diabetic patients with advanced kidney disease . The amount of proteinuria and the urinary levels of bioassayable TGF-beta1 were used as surrogate markers of renal injury and sclerosis . METHODS We performed a prospect i ve double-blinded r and omized crossover trial consisting of three 16-week treatment periods with ramipril alone ( 10 mg/day ) , c and esartan alone ( 16 mg/day ) , and ramipril ( 5 mg/day ) plus c and esartan ( 8 mg/day ) combination therapy . Twenty-one type 2 diabetic patients with overt nephropathy with a 24 h urinary protein excretion rate ( UPER ) of > 1.0 g/24 h and creatinine clearance ( Ccr ) of 30 to 59 ml/min/1.73 m2 completed the entire study . RESULTS Subjects consisted of 10 female and 11 male patients with a mean age of 49 + /- 8 years and duration of diabetes ranging from 4 to 13 years . At baseline , 24-h blood pressures ( BPs ) were 133 + /- 6/81 + /- 7 mmHg , Ccr 40.6 + /- 4.1 ml/min/1.73 m2 , 24-h UPER 4.1 + /- 1.9 g/24 h , and urinary TGF-beta1 level 28.4 + /- 16.1 pg/mg creatinine ( cr ) . Although there was no comparable change in BP and plasma/urinary biochemical parameters , 24-h UPER was significantly reduced by the combination therapy ( 2.9 + /- 1.4 g/24 h ) compared with that of ramipril ( 3.5 + /- 1.8 g/24 h ) and of c and esartan ( 3.3 + /- 2.0 g/24 h ) single therapy ( P < 0.05 ) . Urinary TGF-beta1 level was reduced in all three therapies compared with that of the control ( 28.4 + /- 16.1 pg/mg cr ) ( P < 0.05 ) . However , the combination therapy showed the most significant change ( combination 19.6 + /- 10.6 pg/mg cr ; ramipril 24.7 + /- 13.3 pg/mg cr ; c and esartan ; 23.4 + /- 11.7 pg/mg cr ) . No significant or irreversible adverse effect was observed in the 21 patients who completed the entire study . CONCLUSIONS The dual blockade of RAS with low-dose ramipril plus c and esartan was found to be safe and offered additive benefits with respect to reducing proteinuria and urinary TGF-beta1 excretion in diabetic patients with advanced kidney disease . These benefits were evident as compared with single ramipril and c and esartan therapies at doses two-fold greater . Further study on the dose-titration is m and atory in terms of safety and especially for maximizing renoprotection in this patient population Background —Loss of negative feedback inhibition of renin release during chronic treatment with an angiotensin-converting enzyme ( ACE ) inhibitor leads to a compensatory rise in renin secretion and downstream components of the renin-angiotensin-aldosterone ( RAAS ) cascade . This may overcome ACE inhibition but should be blocked by a direct renin inhibitor . We studied the effects of adding the direct renin inhibitor aliskiren to an ACE inhibitor in patients with heart failure . Methods and Results — Patients with New York Heart Association class II to IV heart failure , current or past history of hypertension , and plasma brain natriuretic peptide ( BNP ) concentration > 100 pg/mL who had been treated with an ACE inhibitor ( or angiotensin receptor blocker ) and β-blocker were r and omized to 3 months of treatment with placebo ( n=146 ) or aliskiren 150 mg/d ( n=156 ) . The primary efficacy outcome was the between-treatment difference in N-terminal pro-BNP ( NT-proBNP ) . Patients ’ mean age was 68 years , mean ejection fraction was 31 % , and mean±SD systolic blood pressure was 129±17.4 mm Hg . Sixty-two percent of the patients were in New York Heart Association functional class II , and 33 % were taking an aldosterone antagonist . Plasma NT-proBNP rose by 762±6123 pg/mL with placebo and fell by 244±2025 pg/mL with aliskiren ( P=0.0106 ) . BNP and urinary ( but not plasma ) aldosterone were also reduced by aliskiren . Clinical ly important differences in blood pressure and biochemistry were not seen between aliskiren and placebo . Conclusions —Addition of aliskiren to an ACE inhibitor ( or angiotensin receptor blocker ) and β-blocker had favorable neurohumoral effects in heart failure and appeared to be well tolerated Angiotensin-converting enzyme ( ACE ) inhibitors have favourable effects on hypertension and diabetic nephropathy , but persistent use may result in incomplete blockade of the renin-angiotensin system . Long-term effects of dual blockade using the ACE inhibitor lisinopril and the long-acting angiotensin II receptor blocker ( ARB ) telmisartan on blood pressure and albumin excretion rate ( AER ) were evaluated . Patients with type 2 diabetes mellitus , hypertension ( systolic blood pressure [ SBP ] > or=140 mmHg or diastolic blood pressure [ DBP ] > or=90 mmHg ) and microalbuminuria ( AER 30 - 300 mg/24h ) received 20 mg of lisinopril or 80 mg of telmisartan once a day for 24 weeks . Patients were then r and omised to continuing treatment with the respective monotherapy or with lisinopril plus telmisartan for a further 28 weeks . Significant ( P<0.001 ) declines in SBP ( 11.1 mmHg versus 10.0 mmHg ) , DBP ( 5.6 mmHg versus 5.3 mmHg ) and AER ( 98 mg/24 h versus 80 mg/24 h ) were achieved with lisinopril ( n=95 ) or telmisartan ( n=97 ) , respectively , after 24 weeks . Subsequent treatment with lisinopril plus telmisartan for 28 weeks result ed in further significant reductions ( P<0.001 ) in SBP , DBP and AER compared with either monotherapy . All treatments were well tolerated . Lisinopril plus telmisartan thus provides superior blood pressure and AER control than either monotherapy . We conclude that use of dual blockade may provide a new approach to prevention of diabetic nephropathy in patients with type 2 diabetes , hypertension and microalbuminuria BACKGROUND Angiotensin II type 1 receptor blockers have favourable effects on haemodynamic measurements , neurohumoral activity , and left-ventricular remodelling when added to angiotensin-converting-enzyme ( ACE ) inhibitors in patients with chronic heart failure ( CHF ) . We aim ed to find out whether these drugs improve clinical outcome . METHODS Between March , 1999 , and November , 1999 , we enrolled 2548 patients with New York Heart Association functional class II-IV CHF and left-ventricular ejection fraction 40 % or lower , and who were being treated with ACE inhibitors . We r and omly assigned patients c and esartan ( n=1276 , target dose 32 mg once daily ) or placebo ( n=1272 ) . At baseline , 55 % of patients were also treated with beta blockers and 17 % with spironolactone . The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF . Analysis was done by intention to treat . FINDINGS The median follow-up was 41 months . 483 ( 38 % ) patients in the c and esartan group and 538 ( 42 % ) in the placebo group experienced the primary outcome ( unadjusted hazard ratio 0.85 [ 95 % CI 0.75 - 0.96 ] , p=0.011 ; covariate adjusted p=0.010 ) . C and esartan reduced each of the components of the primary outcome significantly , as well as the total number of hospital admissions for CHF . The benefits of c and esartan were similar in all predefined subgroups , including patients receiving baseline beta blocker treatment . INTERPRETATION The addition of c and esartan to ACE inhibitor and other treatment leads to a further clinical ly important reduction in relevant cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction Renin is the main determinant of angiotensin ( Ang ) II levels . It , therefore , always appeared desirable to reduce Ang II levels by direct inhibition of renin . So far , specific renin inhibitors lacked potency and /or oral availability . We tested the new orally active nonpeptidic renin inhibitor SPP100 ( Aliskiren , an octanamide with a 50 % inhibitory concentration [ IC50 ] in the low nanomolar range ) in 18 healthy volunteers on a constant 100 mmol/d sodium diet using a double-blind , 3-way crossover protocol . In 3 periods of 8 days , separated by wash-outs of 6 days , each volunteer received 2 dosage levels of Aliskiren ( low before high ; 40 and 80 or 160 and 640 mg/d ) and r and omized placebo or 20 mg enalapril . Aliskiren was well tolerated . Not surprisingly , blood pressure and heart rate remained unchanged in these normotensive subjects . There was a dose-dependent decrease in plasma renin activity , Ang I , and Ang II following single doses of Aliskiren starting with 40 mg . Inhibition was still marked and significant after repeated dosing with maximal decreases in Ang II levels by 89 % and 75 % on Days 1 and 8 , respectively , when the highest dose of Aliskiren was compared with placebo . At the same time , mean plasma active renin was increased 16- and 34-fold at the highest dose of Aliskiren . Plasma drug levels of Aliskiren were dose-dependent with maximal concentrations reached between 3 to 6 hours after administration ; steady state was reached between 5 and 8 days after multiple dosing . Less than 1 % of dose was excreted in the urine . Plasma and urinary aldosterone levels were decreased after doses of Aliskiren ≥80 mg and after enalapril . Aliskiren at 160 and 640 mg enhanced natriuresis on Day 1 by + 45 % and + 62 % , respectively , compared with placebo ( 100 % , ie , 87±11 mmol/24h ) and enalapril ( + 54 % ) ; kaliuresis remained unchanged . In conclusion , the renin inhibitor Aliskiren dose-dependently decreases Ang II levels in humans following oral administration . The effect is long-lasting and , at a dose of 160 mg , is equivalent to that of 20 mg enalapril . Aliskiren has the potential to become the first orally active renin inhibitor that provides a true alternative to ACE-inhibitors and Ang II receptor antagonists in therapy for hypertension and other cardiovascular and renal diseases BACKGROUND Proteinuria and hypertension have independent deleterious effects on the progression of chronic renal disease . The objectives of this study were to determine whether the addition of C and esartan , an angiotensin II receptor antagonist , would reduce proteinuria and blood pressure in normotensive patients with chronic renal disease already receiving an angiotensin converting enzyme inhibitor ( ACEI ) . METHODS This was an open r and omized controlled crossover study conducted in a private consultant practice in Melbourne . Sixty patients , aged 23 - 75 , who had chronic renal disease and stable proteinuria over 0.5 g in 24 h and were receiving an ACEI , were enrolled in the study . The patients were r and omized to have 8 mg of C and esartan added in the first or second of two 12-week study periods . The primary end point was urine protein excretion , which was measured every 2 weeks for the 24-week period . Secondary end points included systolic and diastolic blood pressure , serum creatinine , urea and potassium levels . C and esartan was added against a background of st and ard care , which included other blood pressure lowering therapy . RESULTS Lower urine protein excretion 2.4 vs 2.0 g in 24 h ( P<0.04 , difference 0.45 , CI 0.01 , 0.9 ) and lower levels of systolic blood pressure 134 vs 128 mmHg ( P<0.001 , difference 6.4 , CI 3.2 , 9.6 ) and diastolic blood pressure 82 vs 80 mmHg ( P<0.008 , difference 2.7 , CI 0.7 , 4.6 ) were observed when C and esartan , 8 mg , was added to a regimen , which included an ACEI . No rise in serum creatinine occurred but there was a significant rise in urea , during the C and esartan arm of the study , from 12.3 to 13.8 mmol/l ( P<0.001 ) . The addition of 8 mg of C and esartan in normotensive patients with chronic renal disease receiving ACEI appeared safe and was not accompanied by adverse effects apart from postural hypotension in three patients and a serum potassium level of 6.3 mmol/l in one . CONCLUSIONS In a private consulting practice setting , the addition of 8 mg of C and esartan in normotensive patients with chronic renal disease and proteinuria receiving an ACEI reduced proteinuria and blood pressure . The combination of C and esartan and ACEI appeared safe in this setting and may offer additional protection in preventing progression in chronic renal disease . Although the reduction of proteinuria was small ( 0.45 g/24 h ) this reflected in part a lack of response in diabetic nephropathy and in part a marked rise in proteinuria after ceasing C and esartan in patients who did not complete the C and esartan arm of the study BACKGROUND In patients who have vascular disease or high-risk diabetes without heart failure , angiotensin-converting-enzyme ( ACE ) inhibitors reduce mortality and morbidity from cardiovascular causes , but the role of angiotensin-receptor blockers ( ARBs ) in such patients is unknown . We compared the ACE inhibitor ramipril , the ARB telmisartan , and the combination of the two drugs in patients with vascular disease or high-risk diabetes . METHODS After a 3-week , single-blind run-in period , patients underwent double-blind r and omization , with 8576 assigned to receive 10 mg of ramipril per day , 8542 assigned to receive 80 mg of telmisartan per day , and 8502 assigned to receive both drugs ( combination therapy ) . The primary composite outcome was death from cardiovascular causes , myocardial infa rct ion , stroke , or hospitalization for heart failure . RESULTS Mean blood pressure was lower in both the telmisartan group ( a 0.9/0.6 mm Hg greater reduction ) and the combination-therapy group ( a 2.4/1.4 mm Hg greater reduction ) than in the ramipril group . At a median follow-up of 56 months , the primary outcome had occurred in 1412 patients in the ramipril group ( 16.5 % ) , as compared with 1423 patients in the telmisartan group ( 16.7 % ; relative risk , 1.01 ; 95 % confidence interval [ CI ] , 0.94 to 1.09 ) . As compared with the ramipril group , the telmisartan group had lower rates of cough ( 1.1 % vs. 4.2 % , P<0.001 ) and angioedema ( 0.1 % vs. 0.3 % , P=0.01 ) and a higher rate of hypotensive symptoms ( 2.6 % vs. 1.7 % , P<0.001 ) ; the rate of syncope was the same in the two groups ( 0.2 % ) . In the combination-therapy group , the primary outcome occurred in 1386 patients ( 16.3 % ; relative risk , 0.99 ; 95 % CI , 0.92 to 1.07 ) ; as compared with the ramipril group , there was an increased risk of hypotensive symptoms ( 4.8 % vs. 1.7 % , P<0.001 ) , syncope ( 0.3 % vs. 0.2 % , P=0.03 ) , and renal dysfunction ( 13.5 % vs. 10.2 % , P<0.001 ) . CONCLUSIONS Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema . The combination of the two drugs was associated with more adverse events without an increase in benefit . ( Clinical Trials.gov number , NCT00153101 [ Clinical Trials.gov ] . ) Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients . This study tested whether dual blockade of the renin-angiotensin system ( RAS ) with both an angiotensin-converting enzyme ( ACE ) inhibitor ( ACE-I ) and an Angiotensin-II receptor blocker ( ARB ) is superior to either drug alone in type I diabetic patients with diabetic nephropathy ( DN ) . A r and omized double-blind crossover trial was performed with 8-wk treatment with placebo , 20 mg of benazepril once daily , 80 mg of valsartan once daily , and the combination of 20 mg of benazepril and 80 mg of valsartan . Twenty type I diabetic patients with DN were included . At the end of each treatment period , albuminuria , 24-h BP , and GFR were measured . Eighteen patients completed the study . Placebo values were : albuminuria [ mean ( 95 % CI ) ] , 701 ( 490 to 1002 ) mg/24 h ; BP [ mean ( SEM ) ] , 144 (4)/79 ( 2 ) mmHg , and GFR [ mean ( SEM ) ] , 82 ( 7 ) ml/min per 1.73 m(2 ) . Treatment with benazepril , valsartan , or dual blockade significantly reduced albuminuria and BP compared with placebo . Benazepril and valsartan were equally effective . Dual blockade induced an additional reduction in albuminuria of 43 % ( 29 to 54 % ) compared with any type of monotherapy , and a reduction in systolic BP of 6 ( 0 to 13 ) mmHg and 7 ( 1 to 14 ) mmHg ( versus benazepril and valsartan , respectively ) and a reduction of 7 ( 4 to 10 ) mmHg diastolic compared with both monotherapies . GFR was reversibly reduced on dual blockade compared with monotherapy and placebo . All treatments were safe and well tolerated . In conclusion , dual blockade of the RAS may offer additional renal and cardiovascular protection in type I diabetic patients with DN Background Additive hemodynamic effects of combined blockade of the renin – angiotensin system by an angiotensin I converting enzyme inhibitor and an angiotensin II antagonist have been observed in sodium-depleted normotensive volunteers and in patients with congestive heart failure . Objective To investigate whether the same additive hemodynamic effects occur in patients with hypertension and to verify the safety of such an approach . Design Multicenter , r and omized , double-blind , parallel-group , pilot study . Patients 177 patients with mild-to-moderate hypertension [ diastolic blood pressure ( DBP ) : 95–115 mmHg after a 4-week placebo run-in period ] were included in the study . Intervention Combination therapy consisting of 50 mg losartan daily and 10 mg enalapril daily was administered for 6 weeks . The effects of this therapeutic regimen was compared with similar groups of patients who received either 50 mg losartan daily or 10 mg enalapril daily Main outcome measures 24-hour ambulatory mean DBP and clinic DBP measured at trough after 6 weeks of treatment . Results 24-hour ambulatory mean DBP did not significantly differ between treatment groups although the combination tended to lower BP more . The combination therapy was more effective on clinic DBP measured at trough than was losartan by 3.2 mmHg [ confidence interval ( 95 % , CI ) 0.7–5.7 mmHg , P = 0.012 ] , and more effective than enalapril by 4.0 mmHg ( 95 % CI , 1.5–6.4 mmHg , P = 0.002 ) . In a subgroup of 28 patients , higher plasma active renin and angiotensin I levels during blockade by the combination therapy were observed . This finding confirmed that the combination of the two agents inhibited the renin – angiotensin system to a greater extent than did either agent alone . Conclusion A combination of 10 mg enalapril daily and 50 mg losartan daily safely induces a supplementary , although modest , fall in clinic DBP in patients with mild-to-moderate essential hypertension BACKGROUND The antiproteinuric effect of combining the angiotensin-converting enzyme ( ACE ) inhibitor lisinopril and the angiotensin II ( Ang II ) antagonist losartan was compared to that of the optimal antiproteinuric doses of monotherapy . METHODS To this purpose , lisinopril and losartan were studied in 9 nondiabetic renal patients with median proteinuria 4.5 g/day ( 95 % CI , 3.5 , 6.4 ) , creatinine clearance of 80 mL/min ( 95 % CI , 66 , 96 ) , and mean arterial pressure ( MAP ) of 102 mm Hg ( 95 % CI , 93 , 112 ) . First , in two protocol s with six-week treatment periods per dose , the optimal antiproteinuric dose of each drug was established in each patient . Losartan and lisinopril were used in r and omized order , each preceded by a baseline period without medication . The doses of losartan ( mg/day ) were 50 , 100 , 150 , and again 50 . The lisinopril doses were 10 , 20 , 40 , and again 10 . After the second protocol , patients were treated with a combination , using the optimal antiproteinuric doses established for the individual drugs . RESULTS The antiproteinuric response by losartan was optimal at 100 mg ( -46 % ; 95 % CI , -60 , -24 % ) , being larger than at the 50 mg dose ( -27 % ; 95 % CI , -42 , -4 % , P < 0.05 ) , but not different from the 150 mg dose ( -46 % ; 95 % CI , -58 ; -20 % ) . Proteinuria decreased further at each up-titration step of lisinopril to -75 % ( 95 % CI , -85 , -43 % ) at the 40 mg dose . Combination therapy reduced proteinuria more effectively ( -85 % ; 95 % CI , -96 , -58 ) than monotherapy with losartan , and to a lesser extent than with lisinopril . Optimal blood pressure responses were obtained at similar doses . CONCLUSIONS Dose-titration with a renin-angiotensin system blocker , followed by add-on therapy is highly effective in order to reduce proteinuria . The safety of this regimen needs to be addressed in future studies Microalbuminuria independently predicts increased cardiovascular risk in hypertensive patients , especially in those with concomitant diabetes or established cardiovascular disease . Drugs that target the renin-angiotensin-aldosterone system reduce microalbuminuria regardless of diabetic status . The Irbesartan in the Management of PROteinuric patients at high risk for Vascular Events was a multicenter , r and omized , double-blind , placebo-controlled paralleled group study in which hypertensive patients with microalbuminuria and increased cardiovascular risk were r and omized to 20 weeks treatment with ramipril plus irbesartan or to ramipril plus placebo . Patients discontinued or tapered previous antihypertensive therapy during a 14-day placebo lead-in period . Change in albumin excretion rate from baseline to week 20 was the primary end point . Adjusted week 20 baseline geometric ratios for ramipril plus irbesartan and ramipril plus placebo were not significantly different . Although differences in blood pressure reductions were observed between the two treatments , these changes did not affect microalbuminuria . More patients on dual therapy achieved target blood pressure goals at week 20 than with monotherapy . The incidence of adverse effects and treatment-related adverse effects was similar in both groups . Our results suggest that patients with cardiovascular risk and relatively low albumin excretion rates in early-stage disease may only require monotherapy with renin-angiotensin-aldosterone blocking agents BACKGROUND It is unknown whether either the angiotensin-II-receptor blocker irbesartan or the calcium-channel blocker amlodipine slows the progression of nephropathy in patients with type 2 diabetes independently of its capacity to lower the systemic blood pressure . METHODS We r and omly assigned 1715 hypertensive patients with nephropathy due to type 2 diabetes to treatment with irbesartan ( 300 mg daily ) , amlodipine ( 10 mg daily ) , or placebo . The target blood pressure was 135/85 mm Hg or less in all groups . We compared the groups with regard to the time to the primary composite end point of a doubling of the base-line serum creatinine concentration , the development of end-stage renal disease , or death from any cause . We also compared them with regard to the time to a secondary , cardiovascular composite end point . RESULTS The mean duration of follow-up was 2.6 years . Treatment with irbesartan was associated with a risk of the primary composite end point that was 20 percent lower than that in the placebo group ( P=0.02 ) and 23 percent lower than that in the amlodipine group ( P=0.006 ) . The risk of a doubling of the serum creatinine concentration was 33 percent lower in the irbesartan group than in the placebo group ( P=0.003 ) and 37 percent lower in the irbesartan group than in the amlodipine group ( P<0.001 ) . Treatment with irbesartan was associated with a relative risk of end-stage renal disease that was 23 percent lower than that in both other groups ( P=0.07 for both comparisons ) . These differences were not explained by differences in the blood pressures that were achieved . The serum creatinine concentration increased 24 percent more slowly in the irbesartan group than in the placebo group ( P=0.008 ) and 21 percent more slowly than in the amlodipine group ( P=0.02 ) . There were no significant differences in the rates of death from any cause or in the cardiovascular composite end point . CONCLUSIONS The angiotensin-II-receptor blocker irbesartan is effective in protecting against the progression of nephropathy due to type 2 diabetes . This protection is independent of the reduction in blood pressure it causes Objective To compare the effects of combined therapy of an angiotensin II receptor blocker ( ARB ; valsartan ) and an angiotensin converting enzyme inhibitor ( ACEI ; perindopril ) on blood pressure ( BP ) , metabolic profiles , plasma brain natriuretic peptide ( BNP ) levels , echocardiographic findings , and aortic pulse wave velocity ( PWV ) with those of respective monotherapy in never-treated patients with essential hypertension . Methods This was a prospect i ve r and omized trial , in which there were 31 patients with essential hypertension and left ventricular hypertrophy ( LVH ) who visited the outpatient clinic of Oita Red Cross Hospital ( 14 women and 17 men ; mean±SD age , 59±5 years ) . Each patient was r and omly assigned to receive valsartan ( 160 mg/day , V group , n=10 ) , perindopril ( 8 mg/day , P group , n=11 ) , or a combination of valsartan ( 80 mg/day ) and perindopril ( 4 mg/day , V+P group , n=10 ) for 40 weeks . Ambulatory BP monitoring ( ABPM ) , echocardiographic findings , metabolic findings , plasma BNP levels , and brachial-ankle PWV ( baPWV ) were evaluated before and after the 40-week therapy . Results The baseline and post-therapeutic BP levels were similar among the three groups . At baseline ABPM , non-dipping was observed in 80 , 82 , and 80 % in the V , P , and V+P groups , respectively . Each 40-week therapy regimen comparably reduced ABP . The plasma BNP levels ( P<0.0001 for each ) , left ventricular mass index ( LVMI ) ( P<0.01 for each ) , and PWV values ( P<0.0001 for each ) were also reduced . However , when compared with either V or P group , the percentage reduction in LVMI ( P<0.05 and P<0.005 , respectively ) , BNP ( P<0.05 for each ) , and baPWV values ( P<0.005 and P<0.001 , respectively ) was greater in the V+P group . Conclusions Our findings suggest that , when compared with each monotherapy , perindopril and valsartan combination therapy exerts greater beneficial effects regarding the regression of LVH , reduction in BNP , and improvement of PWV in a selected group of essential hypertensive patients with LVH and high prevalence of non-dipping patterns BACKGROUND ACE inhibitors may not adequately suppress deleterious levels of angiotensin II in patients with heart failure . An angiotensin receptor blocker added to an ACE inhibitor may exert additional beneficial effects . METHODS AND RESULTS Eighty-three symptomatic stable patients with chronic heart failure receiving long-term ACE inhibitor therapy were r and omly assigned to double-blind treatment with valsartan 80 mg BID , valsartan 160 mg BID , or placebo while receiving their usual ACE inhibitor therapy . Studies were performed before and after the first dose of the test drug and again after 4 weeks of therapy . A single dose of lisinopril was administered during study days to ensure sustained ACE inhibition . Compared with placebo , the first dose of valsartan 160 mg result ed in a significantly greater reduction in pulmonary capillary wedge pressure at 3 , 4 , and 8 hours and during the prespecified 4- to 8-hour interval after the dose and in systolic blood pressure at 2 , 3 , 6 , 8 , and 12 hours and 4 to 8 hours after the dose . A pressure reduction from valsartan 80 mg did not achieve statistical significance . After 4 weeks of therapy , net reductions in 0-hour trough pulmonary capillary wedge pressure ( -4.3 mm Hg ; P=0 . 16 ) , pulmonary artery diastolic pressure ( -4.7 mm Hg ; P=0.013 ) , and systolic blood pressure ( -6.8 mm Hg ; P=0.013 ) were observed in the valsartan 160 mg group compared with placebo . After 4 weeks of therapy , plasma aldosterone was reduced by valsartan 80 mg BID ( -52 . 1 pg/mL ; P=0.001 ) and 160 mg BID ( -47.8 pg/mL ; P<0.001 ) compared with placebo , and there was a trend for a reduction in plasma norepinephrine ( -97 pg/mL ; P=0.10 ) . Seventy-four of the 83 patients completed the trial . CONCLUSIONS Physiologically active levels of angiotensin II persist during st and ard long-term ACE inhibitor therapy BACKGROUND Proteinuria predicts renal disease progression , and its reduction by angiotensin-converting enzyme inhibitors ( ACEi ) or angiotensin II receptor antagonists ( ARA ) is renoprotective . METHODS In this prospect i ve , r and omized , cross-over study of 24 patients with nondiabetic , chronic nephropathies , we compared the effects on proteinuria , renal hemodynamics , and glomerular permselectivity of 8 weeks with comparable blood pressure control achieved by benazepril ( 10 mg/day ) and valsartan ( 80 mg/day ) combined therapy with those achieved by benazepril ( 20 mg/day ) or valsartan ( 160 mg/day ) alone . RESULTS Despite comparable changes in blood pressure and glomerular filtration rate ( GFR ) , combined therapy decreased proteinuria more than benazepril ( -56 % vs. -45.9 % , P=0.02 ) and valsartan ( -41.5 % , P=0.002 ) . Changes in urinary protein to creatinine ratio followed the same trend . Filtration fraction and renal vascular resistances ( RVR ) decreased more with combined ( -14.7%,-23.7 % ) or benazepril ( -12.4 % , -20.5 % ) than with valsartan ( -2.7 % , -12.5 % , P < 0.05 vs. both ) . RVR changes , adjusted for GFR changes , were associated with those in proteinuria ( P < 0.05 ) . Changes in glomerular permeability were comparable and did not predict different changes in proteinuria in the three groups . CONCLUSION At comparable blood pressure , combined ACEi and ARA decreased proteinuria better than ACEi and ARA . The greater antiproteinuric effect most likely depended on an ACEi-related hemodynamic effect , in addition to glomerular size selectivity amelioration . Long-term combined ACEi and ARA therapy may be more renoprotective than treatment with each agent alone BACKGROUND Blood pressure reduction achieved with beta-blockers and diuretics is the best recorded intervention to date for prevention of cardiovascular morbidity and death in patients with hypertension . Left ventricular hypertrophy ( LVH ) is a strong independent indicator of risk of cardiovascular morbidity and death . We aim ed to establish whether selective blocking of angiotensin II improves LVH beyond reducing blood pressure and , consequently , reduces cardiovascular morbidity and death . METHODS We did a double-masked , r and omised , parallel-group trial in 9193 participants aged 55 - 80 years with essential hypertension ( sitting blood pressure 160 - 200/95 - 115 mm Hg ) and LVH ascertained by electrocardiography ( ECG ) . We assigned participants once daily losartan-based or atenolol-based antihypertensive treatment for at least 4 years and until 1040 patients had a primary cardiovascular event ( death , myocardial infa rct ion , or stroke ) . We used Cox regression analysis to compare regimens . FINDINGS Blood pressure fell by 30.2/16.6 ( SD 18.5/10.1 ) and 29.1/16.8 mm Hg ( 19.2/10.1 ) in the losartan and atenolol groups , respectively . The primary composite endpoint occurred in 508 losartan ( 23.8 per 1000 patient-years ) and 588 atenolol patients ( 27.9 per 1000 patient-years ; relative risk 0.87 , 95 % CI 0.77 - 0.98 , p=0.021 ) . 204 losartan and 234 atenolol patients died from cardiovascular disease ( 0.89 , 0.73 - 1.07 , p=0.206 ) ; 232 and 309 , respectively , had fatal or non-fatal stroke ( 0.75 , 0.63 - 0.89 , p=0.001 ) ; and myocardial infa rct ion ( non-fatal and fatal ) occurred in 198 and 188 , respectively ( 1.07 , 0.88 - 1.31 , p=0.491 ) . New-onset diabetes was less frequent with losartan . Interpretation Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated . Losartan seems to confer benefits beyond reduction in blood pressure OBJECTIVE Many patients with diabetic nephropathy ( DN ) have levels of albuminuria > 1 g/day and blood pressure > 135/85 mmHg , despite antihypertensive combination therapy , including recommended doses of ACE inhibitors , e.g. , lisinopril/enalapril at 20 mg daily . We tested the concept that such patients might benefit from dual blockade of the renin-angiotensin system ( RAS ) . RESEARCH DESIGN AND METHODS We performed a r and omized double-blind crossover study of 2 months treatment with c and esartan cilexetil 8 mg once daily and placebo in addition to previous antihypertensive treatment . We included 18 type 2 diabetic patients with DN fulfilling the above-mentioned criteria . All received recommended doses of ACE inhibitor and , in addition , 15 patients received diuretics , 11 received a calcium channel antagonist , and 3 received a beta-blocker . At the end of each treatment period , we measured the glomerular filtration rate ( GFR ) , 24-h blood pressure , albuminuria , and IgGuria . RESULTS The addition of c and esartan to usual antihypertensive therapy induced a mean ( 95 % CI ) reduction in albuminuria of 25 % ( 2 - 58 ) , P = 0.036 ( geometric mean [ 95 % CI ] from 1,764 mg/24 h [ 1,225 - 2,540 ] to 1,334 mg/24 h [ 890 - 1,998 ] ) . It also produced a mean reduction of 35 % ( 9 - 53 ) in the fractional clearance of albumin ( P = 0.016 ) , a reduction of 32 % ( 1 - 54 ) in fractional clearance of IgG ( P = 0.046 ) , a reduction in 24-h systolic blood pressure of 10 mmHg ( 2 - 18 ) ( P = 0.019 ) ( mean + /- + /- SE ) from 148 + /- 3 to 138 + /- 5 mmHg , and a mean reduction in GFR of 5 ml . min(-1 ) . 1.73 m(-2 ) ( 0.1 - 9 ) ( P = 0.045 ) . CONCLUSIONS Dual blockade of the RAS reduces albuminuria and blood pressure in type 2 diabetic patients with DN responding insufficiently to previous antihypertensive therapy , including ACE inhibitors in recommended doses BACKGROUND Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in patients with diabetes . Approximately 30 % of type 1 patients with diabetic nephropathy ( DN ) have albuminuria > 1 g/day , and blood pressure > 135 and /or > 85 mmHg despite antihypertensive therapy with recommended doses of ACE inhibitor ( ACEI ) and diuretics . We tested the effect of dual blockade of the renin-angiotensin system ( RAS ) in these patients . METHODS We performed a r and omised double blind crossover trial with 2 months treatment with Irbesartan 300 mg o.d . and placebo added on top of previous antihypertensive treatment . We included 21 type 1 patients with DN responding insufficiently to ACEI and diuretics , as defined above . At the end of each treatment period , albuminuria , 24-h blood pressure and glomerular filtration rate ( GFR ) were measured . RESULTS Addition of 300 mg Irbesartan to the patients ' usual antihypertensive therapy induced a mean reduction in albuminuria of 37 % ( 95 % CI 20 - 49 , P<0.001 ) ; from 1574 mg/24 h ( 95 % CI 1162 - 2132 ) to 996 mg/24 h ( 95 % CI 699 - 1419 ) , a reduction in 24-h blood pressure of 8 mmHg systolic ( 95 % CI -2 to 18 ) and 5 mmHg diastolic ( 95 % CI 1 - 9 ) ( P=0.11 and 0.01 , respectively ) ( from placebo , mean ( SE ) 146 (4)/80 ( 2 ) mmHg ) . GFR remained unchanged . Serum potassium increased ( mean 4.3 to 4.6 mmol/l , P=0.02 ) . Intervention to reduce serum potassium was needed in two patients with GFR < 35 ml/min/1.73 m(2 ) . Otherwise the dual blockade with Irbesartan was safe and well tolerated . CONCLUSIONS Dual blockade of the RAS may offer additional renal and cardiovascular protection in type 1 patients with DN responding insufficiently to conventional antihypertensive therapy , including recommended doses of ACEI and diuretics OBJECTIVE We evaluated the renoprotective effects as reflected by short-term changes in albuminuria of dual blockade of the renin-angiotensin system ( RAS ) by adding an angiotensin II receptor blocker ( ARB ) to treatment with maximal recommended doses of an ACE inhibitor ( ACEI ) in patients with type 2 diabetes and nephropathy . RESEARCH DESIGN AND METHODS A total of 20 patients ( 17 men and 3 women ) with type 2 diabetes along with hypertension and nephropathy were enrolled in this double-blind , r and omized , two-period , crossover trial of 8 weeks of treatment with the ARB c and esartan 16 mg daily and placebo added in r and om order to existing treatment with lisinopril/enalapril 40 mg daily or captopril 150 mg daily . At the end of each treatment period , we evaluated albuminuria in three 24-h urinary collection s by turbidimetry , 24-h ambulatory blood pressure ( ABP ) using the Takeda-TM2420 , and glomerular filtration rate ( GFR ) by the (51)Cr-EDTA plasma-clearance technique . RESULTS During monoblockade of the RAS by ACEI treatment , albuminuria was 706 ( 349 - 1,219 ) mg/24 h [ geometric mean ( IQR ) ] ; 24-h ABP was 138 + /- 3/72 + /- 2 mmHg ( mean + /- SE ) ; and GFR was 77 + /- 6 ml x min(-1 ) x 1.73 m(-2 ) ( mean + /- SE ) . During dual blockade of the RAS by addition of c and esartan 16 mg daily , there was a mean ( 95 % CI ) reduction in albuminuria of 28 ( 17 - 38 ) compared with ACEI alone ( P < 0.001 ) . There was a modest reduction in systolic/diastolic 24-h ABP of 3/2 mmHg ( -2 to 8 systolic , -2 to 5 diastolic ; NS ) . Changes in albuminuria did not correlate to changes in ABP . Addition of c and esartan 16 mg daily induced a small , insignificant decrease in GFR of 4 ( -1 to 9 ) ml x min(-1 ) x 1.73 m(-2 ) . CONCLUSIONS Dual blockade of the RAS provides superior short-term renoprotection independent of systemic blood pressure changes in comparison with maximally recommended doses of ACEI in patients with type 2 diabetes as well as nephropathy OBJECTIVE To assess and compare the long-term effects of the combination of c and esartan and lisinopril with high-dose lisinopril on systolic blood pressure in patients with hypertension and diabetes . RESEARCH DESIGN AND METHODS This was a prospect i ve , r and omized , parallel-group , double-blind , double-dummy study with a 12-month follow-up . Drug therapy was either lisinopril 40 mg once daily or dual-blockade treatment with c and esartan 16 mg once daily and lisinopril 20 mg once daily . The study comprised 75 type 1 and type 2 diabetic patients aged 35 - 74 years . The main outcome measures were seated and 24-h ambulatory systolic blood pressure . RESULTS Reduction in systolic blood pressure ( 24-h systolic blood pressure ) reduction was obtained in both treatment arms ( mean reduction at final follow-up : dual blockade 6 mmHg vs. lisinopril 2 mmHg ) , but no significant difference was found between dual-blockade and lisinopril 40 mg once daily ( P = 0.10 ) . Both treatments were generally well tolerated , and similar low rates of side effects were found in the two groups . CONCLUSIONS There was no statistically significant difference between lisinopril 40 mg once daily and lisinopril 20 mg in combination with c and esartan 16 mg once daily in reducing systolic blood pressure in hypertensive patients with diabetes Abstract Objectives : To assess and compare the effects of c and esartan or lisinopril , or both , on blood pressure and urinary albumin excretion in patients with microalbuminuria , hypertension , and type 2 diabetes . Design : Prospect i ve , r and omised , parallel group , double blind study with four week placebo run in period and 12 weeks ' monotherapy with c and esartan or lisinopril followed by 12 weeks ' monotherapy or combination treatment . Setting : Tertiary hospitals and primary care centres in four countries ( 37 centres ) . Participants : 199 patients aged 30 - 75 years . Interventions : C and esartan 16 mg once daily , lisinopril 20 mg once daily . Main outcome measures : Blood pressure and urinary albumin : creatinine ratio . Results : At 12 weeks mean ( 95 % confidence interval ) reductions in diastolic blood pressure were 9.5 mm Hg ( 7.7 mm Hg to 11.2 mm Hg , P<0.001 ) and 9.7 mm Hg ( 7.9 mm Hg to 11.5 mm Hg , P<0.001 ) , respectively , and in urinary albumin : creatinine ratio were 30 % ( 15 % to 42 % , P<0.001 ) and 46 % ( 35 % to 56 % , P<0.001 ) for c and esartan and lisinopril , respectively . At 24 weeks the mean reduction in diastolic blood pressure with combination treatment ( 16.3 mm Hg , 13.6 mm Hg to 18.9 mm Hg , P<0.001 ) was significantly greater than that with c and esartan ( 10.4 mm Hg , 7.7 mm Hg to 13.1 mm Hg , P<0.001 ) or lisinopril ( mean 10.7 mm Hg , 8.0 mm Hg to 13.5 mm Hg , P<0.001 ) . Furthermore , the reduction in urinary albumin : creatinine ratio with combination treatment ( 50 % , 36 % to 61 % , P<0.001 ) was greater than with c and esartan ( 24 % , 0 % to 43 % , P=0.05 ) and lisinopril ( 39 % , 20 % to 54 % , P<0.001 ) . All treatments were generally well tolerated . Conclusion : C and esartan 16 mg once daily is as effective as lisinopril 20 mg once daily in reducing blood pressure and microalbuminuria in hypertensive patients with type 2 diabetes . Combination treatment is well tolerated and more effective in reducing blood pressure This study investigates the ability of low doses of angiotensin-converting-enzyme inhibitors , in combination with angiotensin II receptor blockers , to exert antiproteinuric effects in normotensive and proteinuric out patients with immunoglobulin A ( IgA ) nephropathy confirmed by biopsy . We performed a prospect i ve , r and omized , 6-month study of the effects of temocapril 1 mg ( n=10 ) , losartan 12.5 mg ( n=10 ) , and both ( n=11 ) on mild-to-moderate proteinuria 0.76+/-0.35 g/day ( range , 0.4 to 1.6 g/day ) and renal function . The study subjects comprised 31 normotensive and proteinuric out patients with IgA nephropathy accompanied by normal , or mild-to-moderately reduced but stable renal function ( glomerular filtration rate>50 ml/min ) without steroid or immunosuppressive therapy . We prospect ively evaluated blood pressure , proteinuria , renal function and biochemical parameters before and after 6 months of therapy . The combination therapy significantly reduced proteinuria ( 63.2 % ) compared with either temocapril or losartan alone ( 41.3 % and 36.6 % , respectively , p=0.04 and 0.01 , respectively ) . Blood pressure was most decreased in the group that received combination therapy . The reduced proteinuria did not correlate with reduced systolic or diastolic blood pressure or mean arterial pressure in any of the groups . The glomerular filtration rate fell during the first 3 months of combined therapy , but became reversible after a further 3 months of therapy . The combination significantly decreased angiotensin II ( p < 0.01 ) , and this decrease was greater than that by either drug alone . In conclusion , the effectiveness of the combined therapy may have been at least partly due to the greater inhibition of the action of angiotensin II in patients with IgA nephropathy . This strategy apparently reduced mild-to-moderate proteinuria in patients with normotensive IgA nephropathy BACKGROUND We assessed the effects of c and esartan in addition to angiotensin-converting enzyme ( ACE ) inhibitors on N-terminal pro-type natriuretic peptide ( Nt-proBNP ) , systemic markers of inflammation and oxidative stress as well as on glucose regulation in patients with heart failure ( HF ) . METHODS AND RESULTS Eighty patients with HF ages 62.5 + /- 8.4 years presenting mostly with New York Heart Association class II symptoms ( class II = 57.5 % , III = 41.3 % ) , and mean left ventricular ejection fraction 27.1 + /- 7.3 % were recruited . The patients were r and omized to receive c and esartan titrated to 32 mg 1 per day versus placebo in double-blind fashion for 6 months . Nt-proBNP , markers of inflammation and oxidative stress , glucose , insulin , and fasting insulin resistance index were analyzed . C and esartan decreased Nt-proBNP ( median value = 12.4 % versus -20.4 % ; [ c and esartan ] P = .05 ) , and high-sensitivity C-reactive protein ( hsCRP ) ( + 5.32 % versus -20.3 % [ c and esartan ] ; P = 0.046 ) , without significantly influencing serum interleukin-6 , interleukin-18 , adhesion molecules , or markers of oxidative stress . Blood glucose decreased in patients treated with c and esartan with a significantly greater effect in patients with higher blood glucose levels ( P < .01 for interaction ) . CONCLUSIONS The addition of c and esartan to ACE inhibitor and beta-blocker decreases Nt-proBNP and hsCRP , but does not change the other markers of inflammation or oxidative stress in patients with heart failure . Dual angiotensin-II suppression also decreased blood glucose with a greater impact in patients with higher blood glucose level BACKGROUND Isosorbide dinitrate combined with hydralazine therapy compared with placebo in patients with heart failure result ed in a sustained increase in left ventricular ( LV ) ejection fraction ( EF ) indicative of regression of LV remodeling in the first Vasodilator-Heart Failure Trial ( V-HeFT-I ) in patients receiving only digoxin and diuretic . In the African-American Heart Failure Trial ( A-HeFT ) a fixed-dose combination result ed in a 43 % reduction in mortality in 1050 black patients with heart failure already treated with recommended neurohormonal inhibiting drugs . Whether the fixed-dose combination produces a further regression of LV remodeling when added to renin-angiotensin and sympathetic inhibitors has not been documented . METHODS AND RESULTS Echocardiograms at baseline and 6 months after r and omization to placebo or a fixed-dose combination of isosorbide dinitrate/hydralazine ( FDC I/H ) were analyzed in 678 A-HeFT participants in a core laboratory . LVEF rose by 2.8 EF units in the FDC I/H group versus 0.8 % in the control group ( P < .01 ) , LV mass index fell by 7.4 g/m2 in the FDC I/H group versus an increase of 1.4 g/m2 in the placebo group ( P < .05 ) , LV diastolic transverse diameter fell by 2.2 mm in FDC I/H and was unchanged in placebo ( P < .01 ) , and the LV systolic and diastolic sphericity indices improved in the FDC I/H group but remained unchanged in the placebo group . The mean plasma B-type natriuretic peptide ( BNP ) also measured in a core laboratory fell in the FDC I/H group by 39 pg/mL compared with 8 pg/mL in the placebo group ( P = .05 ) . CONCLUSIONS A fixed-dose combination of I/H produces regression of LV remodeling when added to background therapy with renin-angiotensin and sympathetic inhibitors in black patients with heart failure . This remodeling benefit may explain at least in part the mortality reduction in A-HeFT AIMS The therapeutic benefits of dual blockade of the renin-angiotensin system ( RAS ) have been inconsistent on renal function and proteinuria . To know the contribution of the heterogeneity of study subjects to such inconsistency , we evaluated the effects of dual blockade of RAS in 2 groups of selected renal diseases , IgA and diabetic nephropathy . To avoid confounding by the blood pressure-reducing effects , angiotensin II receptor antagonists ( ATRAs ) were added on the patients with long-term , optimally controlled blood pressure taking ACE inhibitors . Twenty-four-hour urinary protein excretion rate and urinary TGF-beta1 level were measured as surrogate markers of renal injury . METHODS We conducted a prospect i ve crossover trial with 14 IgA and 18 type-2-diabetic nephropathy patients showing moderate degree of proteinuria ( > or = 1.0 g/day ) and renal dysfunction ( creatinine clearance 25 - 75/ml/min ) . Four to 8 mg once-daily dose of c and esartan and placebo were alternatively added on ramipril dose of 5 - 7.5 mg/day for 16 weeks . RESULTS All baseline data except for the age factor were statistically the same between the 2 disease groups . Twenty-four-hour mean arterial blood pressures were 91.2 + /- 1.6 and 92.3 + /- 1.8 mmHg in IgA and diabetic nephropathy patients respectively at baseline ( p = NS ) . Mean arterial pressure did not change by the addition of c and esartan or placebo in both groups . The addition of c and esartan ( combination ) reduced 24-hour urinary protein excretion rate in IgA nephropathy patients with a mean change of -12.3 + /- 4.5 % , which is significantly greater compared to a mean change of -0.1 + /- 3.3 % after the addition of placebo ( placebo ) ( mean difference 12.4 + /- 5.0 , 95 % CI 1.2 - 23.5 ; p < 0.05 ) . Urinary TGF-beta1 level was reduced considerably by the combination therapy , with a -28.9 + /- 6.0 % decrease , which was significantly different to that by the placebo , with + 4.3 + /- 12.4 % ( 33.3 + /- 13.5 , 3.2 - 63.3 ; p < 0.05 ) . In diabetic nephropathy patients , the addition of c and esartan did not reduce 24-hour urinary protein excretion rate . Mean changes of 24-hour urinary protein excretion rate were -0.8 + /- 4.7 % by the combination therapy and + 0.5 + /- 6.1 % by placebo ( mean difference 1.3 + /- 4.7 , 95 % CI -6.8 - 13.5 ; p < NS ) . The level of urinary TGF-beta1 was reduced by the combination therapy , with -14.3 + /- 9.5 % decrease , but it did not reach statistical significance compared to placebo of + 0.7 + /- 15.5 % ( 15.0 + /- 13.5 , -14.4 - 44.5 ; p < NS ) . The changes in 24-hour urinary protein excretion rate and urinary TGF-beta1 level were neither correlated with each other , nor with the change in mean arterial pressure . Significant changes in the renal function were not detected during the study period . CONCLUSION Definite beneficial effects of dual blockade of RAS on proteinuria and TGF-beta1 excretion were found in IgA nephropathy patients , which was independent of blood pressure-reducing effect . With our 16-week trial , such benefits were not observed in type 2 diabetic nephropathy . The reduction in urinary TGF-beta1 level suggests that the combination therapy may provide additional renoprotection through the antisclerosing effects . Based on our results , for a proper interpretation the therapeutic effects of the combination therapy should be evaluated separately according to the underlying renal disease BACKGROUND Angiotensin-converting-enzyme inhibitors improve the outcome among patients with left ventricular dysfunction , whether or not they have heart failure . We assessed the role of an angiotensin-converting-enzyme inhibitor , ramipril , in patients who were at high risk for cardiovascular events but who did not have left ventricular dysfunction or heart failure . METHODS A total of 9297 high-risk patients ( 55 years of age or older ) who had evidence of vascular disease or diabetes plus one other cardiovascular risk factor and who were not known to have a low ejection fraction or heart failure were r and omly assigned to receive ramipril ( 10 mg once per day orally ) or matching placebo for a mean of five years . The primary outcome was a composite of myocardial infa rct ion , stroke , or death from cardiovascular causes . The trial was a two-by-two factorial study evaluating both ramipril and vitamin E. The effects of vitamin E are reported in a companion paper . RESULTS A total of 651 patients who were assigned to receive ramipril ( 14.0 percent ) reached the primary end point , as compared with 826 patients who were assigned to receive placebo ( 17.8 percent ) ( relative risk , 0.78 ; 95 percent confidence interval , 0.70 to 0.86 ; P<0.001 ) . Treatment with ramipril reduced the rates of death from cardiovascular causes ( 6.1 percent , as compared with 8.1 percent in the placebo group ; relative risk , 0.74 ; P<0.001 ) , myocardial infa rct ion ( 9.9 percent vs. 12.3 percent ; relative risk , 0.80 ; P<0.001 ) , stroke ( 3.4 percent vs. 4.9 percent ; relative risk , 0.68 ; P<0.001 ) , death from any cause ( 10.4 percent vs. 12.2 percent ; relative risk , 0.84 ; P=0.005 ) , revascularization procedures ( 16.3 percent vs. 18.8 percent ; relative risk , 0.85 ; P<0.001 ) , cardiac arrest ( 0.8 percent vs. 1.3 percent ; relative risk , 0.62 ; P=0.02 ) , [ corrected ] heart failure ( 9.1 percent vs. 11.6 percent ; relative risk , 0.77 ; P<0.001 ) , and complications related to diabetes ( 6.4 percent vs. 7.6 percent ; relative risk , 0.84 ; P=0.03 ) . CONCLUSIONS Ramipril significantly reduces the rates of death , myocardial infa rct ion , and stroke in a broad range of high-risk patients who are not known to have a low ejection fraction or heart failure The new ACE inhibitor tr and olapril was administered to normal volunteers at daily doses of 0.5 , 2 , and 8 mg for 10 days . Twenty-one volunteers , aged 21–30 years , were included in the study . To r and omly selected groups of seven subjects , each dose was administered in a single-blind fashion . None of the doses induced a consistent fall in blood pressure . Angiotensin-converting enzyme activity ( ACE ) was measured in vitro using three different synthetic substrates ( i.e. , Hip-Gly-Gly , ZPhe-His-Leu , or angiotensin I ) . Although the degree of ACE inhibition assessed with the three methods varied widely , all methods clearly indicated dose-dependent ACE inhibition . These in vitro results were confirmed by measuring ACE inhibition in vivo using the ratio of plasma angiotensin II ( ANG II ) to blood angiotensin I ( ANG I ) . The dose-dependent ACE inhibition was paralleled by a dose-dependent rise in active renin and blood angiotensin I levels , most evident on day 10 . In contrast , plasma ANG II levels on day 10 were not different whether the volunteers received 0.5 or 8 mg tr and olapril . Thus , whereas increasing doses of this new ACE inhibitor progressively enhanced the blockade of ACE activity , this was not reflected by additional reductions of plasma ANG II levels . The progressive enhancement of ACE inhibition seemed to be offset by the accentuation of the compensatory rise in renin and ANG I , which was still partially converted to ANG II . These data strongly suggest that , particularly with long-term administration , in-creasing the dose of an ACE inhibitor may further inhibit ACE activity but does not necessarily result in progressively lower levels of circulating ANG II BACKGROUND Blockade of the renin-angiotensin system ( RAS ) with angiotensin converting enzyme ( ACE ) inhibitors or with angiotensin II type 1 ( AT1 ) receptor blockers has been shown to reduce proteinuria and to slow down the progression of renal disease in diabetic and non-diabetic primary proteinuric nephropathies . Additionally , this beneficial effect is not dependent on blood pressure control . METHODS To assess and compare the effects of lisinopril ( up to 40 mg/day ) , c and esartan ( up to 32 mg/day ) and combination therapy ( lisinopril up to 20 mg/day plus c and esartan up to 16 mg/day ) on urinary protein excretion , 45 patients with primary proteinuric nephropathies ( urinary protein/creatinine ratio 3.8+/-2.4 g/g ) and normal or slightly reduced renal function ( CCr 95+/-33 mL/min ) were enrolled in a six month multicenter , prospect i ve , open , r and omized , active-controlled and parallel-group trial with 1:1:1 allocation . Blood pressure goal was set at or below 125/75 mm Hg for all patients , with additional antihypertensive medication prescribed if required . RESULTS Renal function , estimated by creatinine clearance , remained stable throughout the study . Hyperkalemia ( K>5.5 mmol/L ) was detected in 3.1 % of all measurements in follow-up , and was more frequent in patients treated with lisinopril alone or lisinopril plus c and esartan ( P<0.001 ) than in those on c and esartan alone . No other relevant adverse event was recorded . The blood pressure goal ( < 125/75 mm Hg ) was achieved by week 4 in all treatment groups ( P<0.005 when compared to baseline ) , and afterwards the mean systolic and diastolic blood pressure remained below these values until the end of the trial with no statistically significant differences between groups . Urinary protein/creatinine ratio ( percentage reduction 95 % confidence intervals CI ) decreased in patients treated with lisinopril alone to -33 % ( CI -12 - 56 ) to -31 % ( CI 0 - 68 ) and to -50 % ( CI -9 - 90 ) , in patients treated with c and esartan to -28 % ( CI -12 - 45 ) , to -41 % ( CI -30 - 52 ) and to -48 % ( CI -32 - 63 ) , in patients treated with the combination of both to -60 % ( CI -44 - 77 ) to -54 % ( CI -38 - 69 ) and to -70 % ( CI -57 - 83 ) at two , three , and six months , respectively . All comparisons with baseline achieved statistical significance and treatment with combination therapy was statistically more effective in proteinuria reduction than treatment with c and esartan alone at two and six months ( P=0.004 and P=0.023 , respectively ) and than treatment with lisinopril only at two months ( P=0.03 ) . CONCLUSION Dual blockade of the renin-angiotensin system with ACE inhibitors and AT1 receptor blockers produces a beneficial antiproteinuric effect that could not be explained only by the systemic blood pressure reduction . All treatments were well tolerated BACKGROUND We investigated the effects of c and esartan ( an angiotensin II antagonist ) alone , enalapril alone , and their combination on exercise tolerance , ventricular function , quality of life ( QOL ) , neurohormone levels , and tolerability in congestive heart failure ( CHF ) . METHODS AND RESULTS Seven hundred sixty-eight patients in New York Heart Association functional class ( NYHA-FC ) II to IV with ejection fraction ( EF ) < 0.40 and a 6-minute walk distance ( 6MWD ) < 500 m received either c and esartan ( 4 , 8 , or 16 mg ) , c and esartan ( 4 or 8 mg ) plus 20 mg of enalapril , or 20 mg of enalapril for 43 weeks . There were no differences among groups with regard to 6MWD , NYHA-FC , or QOL . EF increased ( P = NS ) more with c and esartan-plus-enalapril therapy ( 0.025+/-0.004 ) than with c and esartan alone ( 0.015+/-0.004 ) or enalapril alone(0.015+/-0.005 ) . End-diastolic ( EDV ) and end-systolic ( ESV ) volumes increased less with combination therapy ( EDV 8+/-4 mL ; ESV 1+/-4 mL ; P<0.01 ) than with c and esartan alone ( EDV 27+/-4 mL ; ESV 18+/-3 mL ) or enalapril alone ( EDV 23+/-7 mL ; ESV 14+/-6 mL ) . Blood pressure decreased with combination therapy ( 6+/-1/4+/-1 mm Hg ) compared with c and esartan or enalapril alone ( P<0.05 ) . Aldosterone decreased ( P<0.05 ) with combination therapy ( 23.2+/-5.3 pg/mL ) at 17 but not 43 weeks compared with c and esartan ( 0.7+/-7.8 pg/mL ) or enalapril ( -0.8+/-11 . 3 pg/mL ) . Brain natriuretic peptide decreased with combination therapy ( 5.8+/-2.7 pmol/L ; P<0.01 ) compared with c and esartan ( 4 . 4+/-3.8 pmol/L ) and enalapril alone ( 4.0+/-5.0 pmol/L ) . CONCLUSIONS C and esartan alone was as effective , safe , and tolerable as enalapril . The combination of c and esartan and enalapril was more beneficial for preventing left ventricular remodeling than either c and esartan or enalapril alone BACKGROUND Stratum 2 of the Ramipril Efficacy in Nephropathy ( REIN ) study has already shown that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h , angiotensin-converting enzyme ( ACE ) inhibition reduced the rate of decline in glomerular filtration and halved the combined risk of doubling of serum creatinine or end-stage renal failure ( ESRF ) found in controls on placebo plus conventional antihypertensives . In REIN stratum 1 , reported here , 24 h proteinuria was 1 g or more but less than 3 g per 24 h. METHODS In stratum 1 of this double-blind trial 186 patients were r and omised to a ramipril or a control ( placebo plus conventional antihypertensive therapy ) group targeted at achieving a diastolic blood pressure of less than 90 mm Hg . The primary endpoints were change in glomerular filtration rate ( GFR ) and time to ESRF or overt proteinuria ( > or = 53 g/24 h ) . Median follow-up was 31 months . FINDINGS The decline in GFR per month was not significantly different ( ramipril 0.26 [ SE 0.05 ] mL per min per 1.73m2 , control 0.29 [ 0.06 ] ) . Progression to ESRF was significantly less common in the ramipril group ( 9/99 vs 18/87 ) for a relative risk ( RR ) of 2.72 ( 95 % CI 1.22 - 6.08 ) ; so was progression to overt proteinuria ( 15/99 vs 27/87 , RR 2.40 [ 1.27 - 4.52 ] ) . Patients with a baseline GFR of 45 mL/min/1.73 m2 or less and proteinuria of 1.5 g/24 h or more had more rapid progression and gained the most from ramipril treatment . Proteinuria decreased by 13 % in the ramipril group and increased by 15 % in the controls . Cardiovascular events were similar . As expected , the rate of decline in GFR and the frequency of ESRF were much lower in stratum 1 than they had been in stratum 2 . INTERPRETATION In non-diabetic nephropathies , ACE inhibition confers renoprotection even to patients with non-nephrotic proteinuria BACKGROUND Angiotensin-converting enzyme ( ACE ) inhibitors are generally prescribed by physicians in doses lower than the large doses that have been shown to reduce morbidity and mortality in patients with heart failure . It is unclear , however , if low doses and high doses of ACE inhibitors have similar benefits . METHODS AND RESULTS We r and omly assigned 3164 patients with New York Heart Association class II to IV heart failure and an ejection fraction < or = 30 % to double-blind treatment with either low doses ( 2.5 to 5.0 mg daily , n=1596 ) or high doses ( 32.5 to 35 mg daily , n=1568 ) of the ACE inhibitor , lisinopril , for 39 to 58 months , while background therapy for heart failure was continued . When compared with the low-dose group , patients in the high-dose group had a nonsignificant 8 % lower risk of death ( P=0.128 ) but a significant 12 % lower risk of death or hospitalization for any reason ( P=0.002 ) and 24 % fewer hospitalizations for heart failure ( P=0.002 ) . Dizziness and renal insufficiency was observed more frequently in the high-dose group , but the 2 groups were similar in the number of patients requiring discontinuation of the study medication . Conclusions -These findings indicate that patients with heart failure should not generally be maintained on very low doses of an ACE inhibitor ( unless these are the only doses that can be tolerated ) and suggest that the difference in efficacy between intermediate and high doses of an ACE inhibitor ( if any ) is likely to be very small AIM The study was conducted to evaluate efficacy and tolerability of fixed dose combination ( FDC ) of Losartan and Ramipril in the management of mild to moderate hypertensive Native Asian Indian patients with associated diabetes mellitus . The secondary objective was to evaluate the efficacy of the combination in reducing microalbuminuria . MATERIAL AND METHODS The study was an open , non-comparative , multicentric clinical trial conducted in seven Indian centres in 315 eligible patients . All the patients were treated with Losartan 50 mg + Ramipril 2.5 mg or Losartan 50 mg + Ramipril 5 mg once a day in 12 weeks and consisted of a total of eight visits . RESULTS The mean age of patients was 52.93 years ( range 45 - 60 years ) . Of the total patients , 62.86 % were males and 37.14 % were females . The mean pre study systolic blood pressure was 160.56 + /- 14.44 which was significantly reduced to 126.85 + /- 9.78 at the end of 12 weeks ( P < 0.001 ) . Similarly the mean diastolic blood pressure was 98.91 + /- 8.33 at baseline ( stage I ) which was significantly reduced to 79.82 + /- 5.42 at the end of 12 weeks ( P < 0.001 ) . A mean fall of 33.72 mmHg in systolic blood pressure and the mean fall of 19.10 mmHg was observed in systolic and diastolic blood pressure respectively at the end of the treatment which was statistically highly significant ( P < 0.001 ) . The JNC-VII goal of blood pressure < 130/80 was achieved in 79.05 % patients after the treatment which losartan and ramipril combination only . Microalbuminuria ( urinary albumin excretion > 30 but < 300 mg/day ) was seen in 83/250 ( 33.2 % ) patients and 135 ( 54 % ) patients had clinical proteinuria ( albuminuria ) at baseline . At the end of the therapy 20.8 % patients achieved normoalbuminuria . Good to excellent efficacy response was reported in 98.09 % patients and 98.41 % patients reported good to excellent tolerability to the treatment . CONCLUSION The fixed dose combination of Losartan and Ramipril showed good to excellent efficacy response in 98.10 % patients and achieved a target blood pressure of 130/80 mmHg in 79.05 % patients in 12 weeks . The combination reduced the urinary albumin excretion in majority of the patients with microalbuminuria and proteinuria ( the major marker of nephropathy ) The AMAZE ( A Multicenter Trial Using Atac and and Zestril vs. Zestril to Evaluate the Effects on Lowering Blood Pressure ) program included two identical studies sponsored by AstraZeneca LP . The oral form of c and esartan is c and esartan cilexetil ; for simplicity , the term " c and esartan " is used throughout this manuscript . Two identical multicenter , r and omized , double-blind studies were performed to determine if addition of the angiotensin receptor blocker c and esartan was more effective in lowering blood pressure than up-titration of lisinopril . Hypertensive patients ( N=1,096 ) who were uncontrolled on lisinopril 20 mg daily were r and omized ( 1:1 ) to receive either 8 weeks of high-dose lisinopril ( 40 mg ) or the addition of c and esartan ( 16 mg ) for 2 weeks followed by 32 mg for 6 weeks . Study 1 ( n=538 ) demonstrated decreases in trough sitting systolic/diastolic blood pressures at Week 8 by 6.2/5.9 mm Hg , respectively , for the lisinopril up-titration treatment group and by 11.6/8.3 mm Hg , respectively , for the lisinopril plus c and esartan treatment group ( p<0.01 in comparing both blood pressures reductions between the two treatment groups ) . Corresponding results for Study 2 ( n=558 ) are reductions of 8.7/6.2 mm Hg and 9.5/7.4 mm Hg , respectively , for each of the two treatment groups . For Study 2 , comparisons of systolic/diastolic blood pressures between the two treatment groups were not statistically significantly different ( p=0.51/p=0.08 , respectively ) . Post hoc pooled analysis ( N=1,096 ) demonstrated a slightly greater blood pressure reduction with lisinopril plus c and esartan compared with lisinopril ( 3.1/1.7 mm Hg ) . A 95 % confidence interval limit for the difference in least squares mean change from baseline in systolic blood pressure between the two treatment groups is -4.8 to -1.5 and is -2.8 to -0.7 in mm Hg for diastolic blood pressure . The blood pressure control rates ( < 140/<90 mm Hg ) were 42.7 % and 36.9 % , respectively . Both treatment regimens were well tolerated in all groups . In conclusion , for hypertensive patients not controlled by lisinopril 20 mg once daily , addition of c and esartan ( 32 mg once daily ) or doubling the dose of lisinopril provides safe , additional reduction of blood pressure Objective Angiotensin-converting enzyme inhibitors ( ACEI ) show an antiproteinuric and thus nephroprotective effect in patients suffering from glomerulonephritis . Angiotensin II-receptor-antagonists ( AT1RA ) are also efficacious in reducing proteinuria . The study was performed to investigate the antiproteinuric effect of AT1RA c and esartan in patients diagnosed with chronic glomerulonephritis by biopsy , and who were already being treated with an ACEI . Methods A total of 12 patients with a persistent proteinuria of at least 1 g/day who were already being treated with an ACEI for more than 3 months were included . The study was performed using a double-blind , placebo-controlled and r and omized method with two treatment periods of 8 weeks ( placebo or c and esartan 8 mg/day ) and a wash-out period of 4 weeks in between . Glomerular filtration rate ( GFR ) and effective renal plasma flow ( ERPF ) were measured by inulin- and PAH-clearances at the beginning and the end of each treatment period . Results Proteinuria significantly decreased from 2 ± 0.4 g/day to 1.3 ± 0.3 g/day ( P < 0.05 ) with the addition of c and esartan treatment , whereas it remained unchanged ( from 1.8 ± 0.3 g/day to 1.9 ± 0.3 g/day ) under placebo . GFR ( c and esartan : from 66 ± 13 to 58 ± 11 ml/min per 1.73 m2 , placebo : from 64 ± 11 to 62 ± 13 ml/min per 1.73 m2 ) and ERPF ( c and esartan : from 329 ± 44 to 304 ± 37 ml/min per 1.73 m2 , placebo : from 362 ± 48 to 315 ± 46 ml/min per 1.73 m2 ) did not alter significantly after 8 weeks of treatment . The addition of c and esartan treatment significantly reduced systolic blood pressure ( from 129 ± 3 to 123 ± 2 mmHg , P < 0.05 ) and diastolic blood pressure ( from 79 ± 2 to 76 ± 2 mmHg , P < 0.05 ) compared with placebo ( systolic : 128 ± 3 to 127 ± 3 mmHg , diastolic : 79 ± 2 to 79 ± 2 mmHg ) . Conclusion C and esartan promotes a complementary antiproteinuric and a small antihypertensive effect after a treatment period of 8 weeks in patients with chronic glomerulonephritis when given in conjunction with an ACEI . Renal hemodynamics did not vary significantly BACKGROUND Present angiotensin-converting-enzyme inhibitor treatment fails to prevent progression of non-diabetic renal disease . We aim ed to assess the efficacy and safety of combined treatment of angiotensin-converting-enzyme inhibitor and angiotensin-II receptor blocker , and monotherapy of each drug at its maximum dose , in patients with non-diabetic renal disease . METHODS 336 patients with non-diabetic renal disease were enrolled from one renal outpatient department in Japan . After screening and an 18-week run-in period , 263 patients were r and omly assigned angiotensin-II receptor blocker ( losartan , 100 mg daily ) , angiotensin-converting-enzyme inhibitor ( tr and olapril , 3 mg daily ) , or a combination of both drugs at equivalent doses . Survival analysis was done to compare the effects of each regimen on the combined primary endpoint of time to doubling of serum creatinine concentration or end-stage renal disease . Analysis was by intention to treat . FINDINGS Seven patients discontinued or were otherwise lost to follow-up . Ten ( 11 % ) of 85 patients on combination treatment reached the combined primary endpoint compared with 20 ( 23 % ) of 85 on tr and olapril alone ( hazard ratio 0.38 , 95 % CI 0.18 - 0.63 , p=0.018 ) and 20 ( 23 % ) of 86 on losartan alone ( 0.40 , 0.17 - 0.69 , p=0.016 ) . Covariates affecting renal survival were combination treatment ( hazard ratio 0.38 , 95 % CI 0.18 - 0.63 , p=0.011 ) , age ( 1.30 , 1.03 - 2.29 , p=0.009 ) , baseline renal function ( 1.80 , 1.02 - 2.99 , p=0.021 ) , change in daily urinary protein excretion rate ( 0.58 , 0.24 - 0.88 , p=0.022 ) , use of diuretics ( 0.80 , 0.30 - 0.94 , p=0.043 ) , and antiproteinuric response to tr and olapril ( 0.81 , 0.21 - 0.91 , p=0.039 ) . Frequency of side-effects with combination treatment was the same as with tr and olapril alone . INTERPRETATION Combination treatment safely retards progression of non-diabetic renal disease compared with monotherapy . However , since some patients reached the combined primary endpoint on combined treatment , further strategies for complete management of progressive non-diabetic renal disease need to be research ed Combination of an angiotensin-converting enzyme inhibitor ( ACEI ) with an angiotensin II receptor blocker is advocated as a treatment option in diabetic patients with nephropathy and residual albuminuria while on antihypertensive therapy . Abrogation of albuminuria is a key treatment goal to prevent disease progression . The assumption is that albuminuria reduction is the result of more complete blockade of the renin angiotensin system ; thus , the ACEI-angiotensin II receptor blocker combination would have a greater albuminuria-lowering effect than the combination of an ACEI with a calcium channel blocker such as amlodipine , which causes similar reductions in BP but does not affect the renin angiotensin system . Twenty-eight patients who had type 1 diabetes and known diabetic renal disease and had a persistently elevated albumin creatinine ratio ( ACR ) > 10 mg/mmol despite office BP recordings < or = 140/80 mmHg on maximal recommended dose of the ACEI lisinopril were studied . Patients were allocated to receive either c and esartan ( 16 mg/d ) or amlodipine ( 10 mg/d ) in addition to preexisting ACEI inhibition and followed for 24 wk in a r and omized , double-blind , parallel-group trial . By week 24 , ACR fell by 56 % with c and esartan and 54 % with amlodipine ( P < 0.01 versus baseline for both ) with no significant difference between groups . Mean arterial BP fell between 3 and 6 mmHg similarly in both groups . In neither group was a significant correlation found between the change in ACR and the change in BP . C and esartan and amlodipine lowered ACR and BP by a similar degree . The fall in ACR was disproportionate to the fall of systemic BP and independent of it . The mechanism of the reduction in albuminuria seen with these agents in combination with an ACEI remains to be eluci date Introduction Patients with stage 2 hypertension require large absolute reductions in blood pressure ( BP ) to achieve recommended BP goals . Combination therapy with the direct renin inhibitor , aliskiren , and the angiotensin receptor blocker , valsartan , has been shown to produce greater BP reductions than either agent alone in a double-blind study in 1797 hypertensive patients . Methods This post-hoc analysis evaluated the BP-lowering efficacy of aliskiren in combination with valsartan in a subset of patients ( n=581 ) with stage 2 hypertension ( baseline mean sitting systolic BP [ msSBP ] ≥160 mmHg ) . Patients were r and omized to receive aliskiren/valsartan 150/160 mg , aliskiren 150 mg , valsartan 160 mg , or placebo once daily for 4 weeks followed by 4 weeks at double the initial dose . Mean changes from baseline in msSBP and mean sitting diastolic BP were assessed at week-8 endpoint ( intent-to-treat population ) . Results Aliskiren/valsartan 300/320 mg reduced BP from baseline by 22.5/11.4 mmHg at week-8 endpoint . BP reductions with combination therapy were significantly greater than with aliskiren 300 mg ( 17.3/8.9 mmHg , P<0.05 ) , valsartan 320 mg ( 15.5/8.3 mmHg , P<0.01 ) , or with placebo ( 7.9/3.7 mmHg , P<0.0001 ) . BP control rates ( < 140/90 mmHg ) were also significantly higher ( P<0.05 ) with aliskiren/valsartan 300/320 mg ( 29.8 % ) compared with either aliskiren 300 mg ( 19.0 % ) or valsartan 320 mg ( 13.8 % ) monotherapy , or placebo ( 8.9 % ) . All treatments were generally well tolerated . Conclusion Combination therapy with aliskiren and valsartan provided significantly greater BP reductions over aliskiren or valsartan monotherapy and is an appropriate option for management of BP in patients with stage 2 hypertension BACKGROUND Treatment with angiotensin-converting-enzyme ( ACE ) inhibitors reduces the rate of cardiovascular events among patients with left-ventricular dysfunction and those at high risk of such events . We assessed whether the ACE inhibitor perindopril reduced cardiovascular risk in a low-risk population with stable coronary heart disease and no apparent heart failure . METHODS We recruited patients from October , 1997 , to June , 2000 . 13655 patients were registered with previous myocardial infa rct ion ( 64 % ) , angiographic evidence of coronary artery disease ( 61 % ) , coronary revascularisation ( 55 % ) , or a positive stress test only ( 5 % ) . After a run-in period of 4 weeks , in which all patients received perindopril , 12218 patients were r and omly assigned perindopril 8 mg once daily ( n=6110 ) , or matching placebo ( n=6108 ) . The mean follow-up was 4.2 years , and the primary endpoint was cardiovascular death , myocardial infa rct ion , or cardiac arrest . Analysis was by intention to treat . FINDINGS Mean age of patients was 60 years ( SD 9 ) , 85 % were male , 92 % were taking platelet inhibitors , 62 % beta blockers , and 58 % lipid-lowering therapy . 603 ( 10 % ) placebo and 488 ( 8 % ) perindopril patients experienced the primary endpoint , which yields a 20 % relative risk reduction ( 95 % CI 9 - 29 , p=0.0003 ) with perindopril . These benefits were consistent in all predefined subgroups and secondary endpoints . Perindopril was well tolerated . INTERPRETATION Among patients with stable coronary heart disease without apparent heart failure , perindopril can significantly improve outcome . About 50 patients need to be treated for a period of 4 years to prevent one major cardiovascular event . Treatment with perindopril , on top of other preventive medications , should be considered in all patients with coronary heart disease BACKGROUND Treatment with agents interfering with the renin-angiotensin system retards the progressive course of proteinuric chronic renal disease . However , because of unwanted effects associated with such therapy , some patients can not be treated with these drugs at all or may be administered only very small doses . To find an optimal nephroprotective strategy for these patients , we compared antiproteinuric effects of combination therapy with an angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor antagonist in very small doses with treatment with either agent alone at greater , but not maximal , doses . We compared the concomitant use of benazepril , 5 mg , and losartan , 25 mg , and monotherapy with these agents in doses 2-fold greater . METHODS This is a r and omized , open , crossover study of 3 treatments in 3 periods of 4 months each . Twenty-four patients with primary glomerulonephritis and nonnephrotic proteinuria , recognized previously as not able to be administered high doses of drugs from these classes , completed the protocol . RESULTS Combined therapy decreased 24-hour proteinuria ( -45.54 % versus baseline ) more effectively than either losartan ( -28.17 % ; analysis of variance , P < 0.01 ) or benazepril ( -20.19 % ; analysis of variance , P < 0.001 ) alone . Subgroup analysis showed that antiproteinuric effects of combination therapy , as well as losartan or benazepril alone , were significantly greater in patients with basal proteinuria greater than 2 g/24 h than in those with proteinuria less than this value ( P < 0.001 , P < 0.01 , and P < 0.05 , respectively ) . All therapies significantly decreased blood pressure ( BP ) compared with baseline , but there were no differences between treatments in BP changes . CONCLUSION The study shows that combination therapy with very small doses of losartan and benazepril was more effective in reducing proteinuria than greater doses of either agent in monotherapy , and this greater antiproteinuric efficacy was independent of changes in BP AIM To evaluate the effects of valsartan ( Val ) with or without benazepril ( Ben ) on blood pressure and plasma levels of angiotensin ( Ang II ) and digoxin-immunoreactive factors ( endoxin ) in patients with essential hypertension . METHODS Ninety patients with essential hypertension were r and omly divided into 3 groups ( n=30 per group ) : Ben group ( Ben 10 mg/d , po ) ; Val group ( Val 80 mg/d , po ) ; combination drug therapy group ( Val 80 mg/d+Ben 10 mg/d , po ) ; all patients were treated for 12 weeks . Age and sex-matched 20 normal subjects were served as control group . RESULTS The levels of plasma endoxin and Ang II in patients with essential hypertension were remarkably higher than those in normal subjects . The levels of plasma Ang II and endoxin were all obvious positive correlation with systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ) ( Ang II : r=0.5151 , 0.7978 ; endoxin : r=0.4706 , 0.7274 , respectively ) . Within 6 weeks of drug intervene , SBP and DBP were remarkably decreased in 3 groups . After 6 weeks , SBP and DBP were continuously decreased in Ben group and Val+Ben group , but not in Val group . Level of plasma Ang II was remarkably decreased as SBP and DBP decreased in Ben group and Val+Ben group ; level of plasma Ang II was remarkably increased in Val group . CONCLUSION Val with or without Ben remarkably decreased SBP and DBP in patients with essential hypertension within 6 weeks . Antihypertensive efficacy was weakened after long-term use of Val alone . The antihypertensive effect of Val+Ben group was the most remarkable among 3 groups and could avoid the side effects of high plasma Ang II Interrupting the renin-angiotensin system ( RAS ) with a usual daily dose of a single-site RAS inhibitor does not achieve complete and long-lasting pharmacologic blockade . Hormonal and BP effects were compared for 48 h after administration of single oral doses of 300 mg ( high dose ) of the renin inhibitor aliskiren ( A300 ) and 160 mg ( st and ard antihypertensive dose ) of the AT1 receptor antagonist valsartan ( V160 ) and their combination each at half dose ( A150+V80 ) in 12 mildly sodium-depleted normotensive individuals . In this double-blind , placebo-controlled , r and omized , four-period crossover study , A300 decreased plasma renin activity and angiotensin I and II levels for 48 h , stimulated immunoreactive active renin release more strongly than V160 , and decreased urinary aldosterone excretion for a longer duration than V160 . In contrast to V160 , the A150+V80 combination did not increase plasma angiotensins . The renin and aldosterone effects of the A150+V80 combination were similar to those of A300 and greater than those of V160 . When plasma drug concentrations were taken into account , the A150 + V80 combination had a synergistic effect on renin release . The A150+V80 combination lowered BP at least as effectively as either higher dose monotherapy . In conclusion , in mildly sodium-depleted normotensive individuals , the long-lasting effects of aliskiren alone or in combination with valsartan on plasma immunoreactive active renin and urinary aldosterone effects demonstrate strong and prolonged blockade of angiotensin II at the kidney and the adrenal level . Moreover , a renin inhibitor and AT1R antagonist combination may provide synergistic effects on RAS hormone levels Objective The combination of an angiotensin-converting enzyme ( ACE ) inhibitor and an angiotensin II ( Ang II ) receptor antagonist ( ARB ) could provide a higher degree of blockade of the renin-angiotensin system(RAS ) than either agent alone . The primary aim of this study was to look at the effect of three therapeutic regimens ( titrated ACE inhibitor ( ACE-I ) versus titrated ARB versus the combination of an ACE-I and an ARB ) on the attainment of adequate blood pressure ( BP ) control and antiproteinuric effect . Both ACE-I and ARB were titrated as monotherapy up to the maximal recommended dose . Methods A pilot r and omised , parallel group open-label study was conducted in 36 patients with primary renal disease , proteinuria above 1.5 g/day and BP > 140/90 mmHg while on therapy with an ACE-I. Patients were r and omly assigned to ( 1 ) benazepril , n=12 ; ( 2 ) valsartan , n=12 ; or ( 3 ) benazepril plus valsartan , n=12 . Other antihypertensive therapies could also be added to attain goal BP ( < 140/90 mmHg ) . The primary endpoint was the change in proteinuria during six months of follow-up . Results In the presence of similar BP decreases and stable creatinine clearance values , mean proteinuria decreases were 0.5±1.7 , 1.2±2.0 and 2.5±1.8 g/day in groups 1 , 2 and 3 , respectively . When compared with baseline values , only the fall induced by the combination of ARB and ACE-I attained statistical significance ( p<0.05 ) . Conclusion The antiproteinuric capacity of monotherapy at recommended doses with either an ACE-I or an ARB is lower than that obtained with the combination of the two drugs BACKGROUND In patients with symptomatic congestive heart failure receiving optimal therapy with an angiotensin-converting enzyme ( ACE ) inhibitor and a beta-blocker , the impact of using an angiotensin receptor blocker on submaximal exercise capacity and on neurohumoral activation at rest and during stress has not been investigated . METHODS Thirty-three patients with congestive heart failure , New York Heart Association II or III symptoms , and left ventricular ejection fraction 25.5 % + /- 7.2 % treated with an ACE inhibitor and a beta-blocker were recruited . Patients were r and omly assigned to receive irbesartan 150 mg per day ( n = 22 ) or a placebo ( n = 11 ) for 6 months . Maximal exercise capacity was assessed using a ramp protocol . Submaximal exercise duration was assessed using a constant load protocol , and plasma norepinephrine and angiotensin II ( A-II ) were measured in resting state , at 6 minutes , and at peak exercise . RESULTS Patients treated with irbesartan presented a 26 % increase in submaximal exercise time ( + 281 seconds , P = .08 ) whereas exercise duration increased by only 7 % in patients treated with a placebo ( + 128 seconds , P = NS irbesartan vs placebo ) . Norepinephrine levels increased to a similar extent in both groups , whereas A-II levels did not increase or change in response to therapy . CONCLUSIONS Dual A-II suppression with an ACE inhibitor plus irbesartan provides a small but a significant increase in submaximal exercise capacity . This beneficial effect is observed despite no significant changes in maximal exercise capacity , and in resting or exercise-induced increase in neurohumoral activation A large-scale , 8-week , open-label , clinical experience trial evaluated the efficacy of the angiotensin II receptor ( AT1 subtype ) blocker c and esartan cilexetil ( 16 to 32 mg once daily ) either alone or as add-on therapy in 6465 hypertensive patients . The study population was 52 % female and 16 % African American with a mean age of 58 years . It included 5,446 patients who had essential hypertension ( HBP ) and 1,014 patients who had isolated systolic hypertension ( ISH ) . These patients had either untreated or uncontrolled hypertension ( systolic blood pressure [ SBP ] 140 to 179 mm Hg or diastolic blood pressure [ DBP ] 90 to 109 mm Hg inclusive at baseline ) despite a variety of antihypertensive medications including diuretics , calcium antagonists , angiotensin converting enzyme ( ACE ) inhibitors , and alpha- or beta-blockers , either singly or in combination . The mean baseline blood pressure for the HBP group was 156/97 mm Hg . C and esartan cilexetil as monotherapy ( in 51 % of HBP patients ) reduced mean SBP/DBP by 18.7/ 13.1 mm Hg . As add-on therapy ( in 49 % of HBP patients ) to various background therapies , c and esartan cilexetil consistently reduced mean SBP/DBP further , irrespective of the background therapy : diuretics ( 17.8/11.3 mm Hg ) , calcium antagonists ( 16.6/11.2 mm Hg ) , beta-blockers ( 16.5/ 10.4 mm Hg ) , ACE inhibitors ( 15.3/10.0 mm Hg ) , alpha-blockers ( 16.4/10.4 mm Hg ) . The mean baseline blood pressure for the ISH group was 158/81 mm Hg . C and esartan cilexetil , as monotherapy ( in 34 % of ISH patients ) , reduced SBP/DBP by 17.0/4.4 mm Hg . As add-on therapy ( in 66 % of ISH patients ) to various background therapies , c and esartan cilexetil consistently reduced mean SBP/DBP further , irrespective of the background therapy : diuretics ( 17.4/5.1 mm Hg ) , calcium antagonists ( 15.6/3.6 mm Hg ) , beta-blockers ( 14.0/4.8 mm Hg ) , ACE inhibitors ( 13.4/4.3 mm Hg ) , and alpha-blockers ( 11.6/4.5 mm Hg ) . The further blood pressure lowering effects of c and esartan cilexetil as add-on therapy were seen regardless of age , sex , and race . Overall , 6.8 % of the 6465 patients withdrew because of adverse events , most commonly headache ( 6.3 % ) and dizziness ( 5.0 % ) . Orthostatic hypotension was infrequent ; 0.2 % with c and esartan cilexetil alone , and 0.8 % with c and esartan cilexetil as add-on therapy . Thus , c and esartan cilexetil either alone or as add-on therapy was highly effective for the control of systolic or diastolic hypertension regardless of demographic background when used in typical clinical practice setting BACKGROUND By blocking the renin-angiotensin-aldosterone system ( RAAS ) at its rate-limiting step , renin inhibition may provide improved RAAS suppression . We investigated the blood pressure (BP)-lowering effects of the oral direct renin inhibitor aliskiren , alone or in combination with the angiotensin receptor blocker valsartan . METHODS In this multicenter , r and omized , placebo-controlled , 8-week trial , 1123 patients with mild-to-moderate hypertension underwent a 3 to 4 week single-blind placebo run-in and were then r and omized in a modified factorial study design to receive once-daily , double-blind oral treatment with placebo , aliskiren monotherapy ( 75 , 150 , or 300 mg ) , valsartan monotherapy ( 80 , 160 , or 320 mg ) , aliskiren and valsartan in combination , or valsartan/hydrochlorothiazide ( 160/12.5 mg ) . The primary efficacy variable was the change from baseline in mean sitting diastolic BP ( DBP ) at endpoint . RESULTS Once-daily oral treatment with aliskiren 300 mg significantly ( P < .0001 ) lowered mean sitting DBP and systolic BP ( SBP ) compared with placebo ; aliskiren monotherapy demonstrated a safety and tolerability profile comparable to placebo . Changes in DBP and SBP were fitted to a first-order dose-response surface ( lack-of-fit test , P = .65 ) , which showed that aliskiren and valsartan alone and in combination produced dose-related reductions in DBP and SBP . Coadministration of aliskiren and valsartan produced a greater antihypertensive effect than either drug alone , comparable in magnitude to the effect of valsartan/hydrochlorothiazide , with similar tolerability to the component monotherapies and to placebo . CONCLUSIONS Aliskiren monotherapy provides antihypertensive efficacy and placebo-like tolerability in patients with hypertension . Aliskiren and valsartan in combination may provide additive BP-lowering effects with maintained tolerability Objective — The efficacy of angiotensin-converting enzyme ( ACE ) inhibitors in the treatment of heart failure ( HF ) is well documented . However , ACE inhibitors may provide incomplete blockade of the renin-angiotensin-aldosterone system due to the alternative pathways for the production of angiotensin II ( Ang II).The aim of this study was to evaluate the efficacy of combined therapy of an ACE inhibitor and the Ang II receptor blocker losartan in patients with HF by using cardiopulmonary exercise testing ( CPET ) on a treadmill . Methods and results — Seventien patients ( ejection fraction ≤ 40 % ) were included in the study group . At the start of the study , all participants were on chronic ACE inhibitors therapy . Fifty mg losartan was added to the treatment and CPET was performed before and 6 - 8 months after starting losartan therapy . Sixteen patients with HF were included in the control group . CPET was performed once at the beginning and repeated 6 - 8 months later without any change in the treatment protocol . The change in CPET values ( walk-time ( WT ) , peak VO2 , anaerobic threshold ( AT ) , minute ventilation ( VE ) , VE/VO2 , peak heart rate ( HR ) , VO2/HR ) was investigated . In the losartan-treated group a significant increase was noted in WT ( 393 ± 157 vs. 507 ± 155 sec , p < 0.01 ) ; peak VO2 ( 1205 ± 240 vs. 1330 ± 253 ml/min , p < 0.05 ) ; and AT ( 794 ± 131 vs. 895 ± 177 ml/min , p < 0.05 ) . In the control group exercise parameters did not change significantly . The change from baseline to follow-up between the two groups is statistically significant for WT and peak VO2 ( 114 ± 94 vs. –58 ± 134 sec , p < 0.01 and 125 ± 183 vs. –116 ± 221 ml/min , p < 0.01 ) . Conclusions — Addition of losartan to the ACE inhibitor therapy in patients with HF improves functional capacity in the long run Background : The renin-angiotensin system is thought to be involved in progression of chronic renal diseases of both diabetic and nondiabetic origin . It is confirmed that angiotensin-converting enzyme inhibitors reduce urinary protein excretion ( UPE ) and attenuate the development of renal injury . The angiotensin II receptor blockers are an alternative class of drugs inhibiting the renin-angiotensin system activity with preliminarily confirmed renoprotective activity . However , there is lack of data concerning renoprotective action of very small doses of these drugs . Methods : Prospect i ve , r and omized , 3-month study of the effects of losartan 25 mg ( n = 17 ) vs. enalapril 10 mg ( n = 17 ) vs. combination of losartan 25 mg and enalapril 10 mg ( n = 15 ) on proteinuria , kidney function and metabolic profile in 51 patients with biopsy proven chronic glomerulonephritis with normal or slightly declined kidney function [ creatinine clearance ( CRCL ) between 36 and 93 ml/min ] was performed . Clinical evaluation and laboratory tests were estimated before treatment ( basal ) , during the first week and after 3 months of therapy . Results : Both , monotherpy with losartan and enalapril significantly reduced proteinuria by 25.35 and 45.07 % , respectively . There was no significant difference between groups . Combined therapy induced a more remarkable reduction of proteinuria ( 65.96 % ) than either of the drugs administered alone . This antiproteinuric effect was significantly more pronounced only in comparison with the losartan group ( p = 0.009 ) . Decreasing of blood pressure was most pronounced in the combined group . In all groups , no correlation between fall of UPE and reducing the systolic or diastolic blood pressure was found . Significant decline in CRCL was observed with enalapril treatment just after 1 week of therapy ( p = 0.039 ) and at the end of observation ( p = 0.043 ) . CRCL remained stable in losartan-treated subjects . No changes in serum creatinine level , metabolic profile and sodium excretion were observed during therapy in studied groups . Conclusions : These results indicated that even very small doses of losartan and enalapril reduce proteinuria in patients with primary glomerulonephritis . Combination of these drugs could cause significantly greater antiproteinuric effect than either of the agents in monotherapy . It is likely that the treatment with losartan , compared to enalapril , is associated with less risk of acute fall of glomerular filtration at the beginning of therapy Objective The aim of this open multicentric study was to investigate the efficacy and safety of the addition of an angiotensin converting enzyme ( ACE ) inhibitor ( benazepril , 10 mg/day ) or a diuretic ( hydrochlorothiazide , 12.5 mg/day ) for 4 weeks in patients with mild to moderate essential hypertension having been treated for 4 weeks by an angiotensin II antagonist ( valsartan , 80 mg/day ) but still having a diastolic blood pressure ( BP ) > 90 mmHg on this medication given alone . Methods A total of 327 patients were included in the trial and 153 patients ( 46 % ) had their diastolic BP ⩽ 90 mmHg after 4 weeks of valsartan monotherapy . These patients continued the same treatment regimen for the next 4 weeks , but no further blood pressure reduction was observed . The remaining patients were r and omized to either the valsartan – hydrochlorothiazide or the valsartan – benazepril combination . Results The two combinations induced an additional significant BP reduction , which was of similar magnitude for diastolic BP ( −4.5 during valsartan – hydrochlorothiazide treatment and −3.3 mmHg during valsartan – benazepril treatment ) , but of greater magnitude for systolic BP during valsartan – hydrochlorothiazide ( −6.77 mmHg ) than during valsartan – benazepril co-administration ( −3.2 mmHg ) . At the end of the trial , the BP of the responders to the valsartan monotherapy was lower than that of patients having required a combination therapy . Valsartan given alone or in association with hydrochlorothiazide or benazepril was well tolerated . Conclusion These data therefore show that in patients not responding sufficiently to angiotensin II receptor blockade BP can be further and safely lowered by adding a small dose of a diuretic or an ACE inhibitor , with the diuretic-containing combination tending to being more effective in controlling systolic BP BACKGROUND Angiotensin-converting-enzyme ( ACE ) inhibitors such as captopril reduce mortality and cardiovascular morbidity among patients with myocardial infa rct ion complicated by left ventricular systolic dysfunction , heart failure , or both . In a double-blind trial , we compared the effect of the angiotensin-receptor blocker valsartan , the ACE inhibitor captopril , and the combination of the two on mortality in this population of patients . METHODS Patients receiving conventional therapy were r and omly assigned , 0.5 to 10 days after acute myocardial infa rct ion , to additional therapy with valsartan ( 4909 patients ) , valsartan plus captopril ( 4885 patients ) , or captopril ( 4909 patients ) . The primary end point was death from any cause . RESULTS During a median follow-up of 24.7 months , 979 patients in the valsartan group died , as did 941 patients in the valsartan- and -captopril group and 958 patients in the captopril group ( hazard ratio in the valsartan group as compared with the captopril group , 1.00 ; 97.5 percent confidence interval , 0.90 to 1.11 ; P=0.98 ; hazard ratio in the valsartan- and -captopril group as compared with the captopril group , 0.98 ; 97.5 percent confidence interval , 0.89 to 1.09 ; P=0.73 ) . The upper limit of the one-sided 97.5 percent confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality ( P=0.004 ) and with regard to the composite end point of fatal and nonfatal cardiovascular events ( P<0.001 ) . The valsartan- and -captopril group had the most drug-related adverse events . With monotherapy , hypotension and renal dysfunction were more common in the valsartan group , and cough , rash , and taste disturbance were more common in the captopril group . CONCLUSIONS Valsartan is as effective as captopril in patients who are at high risk for cardiovascular events after myocardial infa rct ion . Combining valsartan with captopril increased the rate of adverse events without improving survival BACKGROUND We are investigating whether aldosterone breakthrough negatively impacts on the antiproteinuric effects of angiotensin-converting enzyme ( ACE ) inhibitors and /or angiotensin II receptor blockers ( ARB ) . METHODS We examine the role of aldosterone breakthrough in 43 normotensive , proteinuric ( 0.7 + /- 0.3 g/day ) out patients ( aged 41.5 + /- 10.9 years ) with immunoglobulin A nephropathy ( IgAN ) accompanied by stable renal function ( creatinine clearance > 50 mL/min ) . The patients were treated with temocapril ( 1 mg ; n = 14 ) , losartan ( 12.5 mg ; n = 16 ) , or a combination therapy ( n = 13 ) for 12 months . We prospect ively evaluated blood pressure ( BP ) , urinary protein excretion ( UPE ) , biochemical parameters and the renin-angiotensin-aldosterone system before and after 12 months of treatment . RESULTS Although the overall plasma aldosterone concentrations values did not change after any of the treatments administered for 12 months , they eventually increased in 23 ( temocapril , seven patients ; losartan , eight patients ; combination , seven patients ) of the 43 patients ( 53.4 % ; aldosterone breakthrough ) , and fell in the remainder ( 46.6 % ) . Blood pressure and renal function did not differ among the three groups at 12 months . In contrast , UPE was significantly higher in patients with , than without aldosterone breakthrough during temocapril and losartan administration . However , combination therapy induced a more remarkable reduction in UPE regardless of aldosterone breakthrough . CONCLUSIONS A combination of ACE inhibitors and ARB in normotensive patients with IgAN produces a more profound decrease in proteinuria than either monotherapy . This additive antiproteinuric effect is not dependent on aldosterone breakthrough . Additional larger , prospect i ve , r and omized studies will be needed for general acceptance of this strategy BACKGROUND Renal function declines progressively in patients who have diabetic nephropathy , and the decline may be slowed by antihypertensive drugs . The purpose of this study was to determine whether captopril has kidney-protecting properties independent of its effect on blood pressure in diabetic nephropathy . METHODS We performed a r and omized , controlled trial comparing captopril with placebo in patients with insulin-dependent diabetes mellitus in whom urinary protein excretion was > or = 500 mg per day and the serum creatinine concentration was < or = 2.5 mg per deciliter ( 221 mumol per liter ) . Blood-pressure goals were defined to achieve control during a median follow-up of three years . The primary end point was a doubling of the base-line serum creatinine concentration . RESULTS Two hundred seven patients received captopril , and 202 placebo . Serum creatinine concentrations doubled in 25 patients in the captopril group , as compared with 43 patients in the placebo group ( P = 0.007 ) . The associated reductions in risk of a doubling of the serum creatinine concentration were 48 percent in the captopril group as a whole , 76 percent in the subgroup with a baseline serum creatinine concentration of 2.0 mg per deciliter ( 177 mumol per liter ) , 55 percent in the subgroup with a concentration of 1.5 mg per deciliter ( 133 mumol per liter ) , and 17 percent in the subgroup with a concentration of 1.0 mg per deciliter ( 88.4 mumol per liter ) . The mean ( + /- SD ) rate of decline in creatinine clearance was 11 + /- 21 percent per year in the captopril group and 17 + /- 20 percent per year in the placebo group ( P = 0.03 ) . Among the patients whose base-line serum creatinine concentration was > or = 1.5 mg per deciliter , creatinine clearance declined at a rate of 23 + /- 25 percent per year in the captopril group and at a rate of 37 + /- 25 percent per year in the placebo group ( P = 0.01 ) . Captopril treatment was associated with a 50 percent reduction in the risk of the combined end points of death , dialysis , and transplantation that was independent of the small disparity in blood pressure between the groups . CONCLUSIONS Captopril protects against deterioration in renal function in insulin-dependent diabetic nephropathy and is significantly more effective than blood-pressure control alone BACKGROUND Persistent activation of the renin-angiotensin-aldosterone-system ( RAAS ) is known to occur in patients with chronic heart failure ( CHF ) despite treatment with angiotensin-converting enzyme inhibitor ( ACE ) therapy . When added to ACE inhibitors , angiotensin II type 1 ( AT1 ) antagonists may allow more complete blockade of the RAAS and preserve the beneficial effects of bradykinin accumulation not seen with AT1 receptor blockade alone . METHODS Thirty-six patients with stable New York Heart Association class II-IV CHF receiving ACE inhibitor therapy were r and omly assigned in a double-blind manner to receive either eprosartan , a specific competitive AT1 receptor antagonist ( 400 to 800 mg daily , n = 18 ) or placebo ( n = 18 ) for 8 weeks . The primary outcome measure was left ventricular ejection fraction ( LVEF ) as measured by radionuclide ventriculography , and secondary measures were central hemodynamics assessed by Swan-Ganz catheterization and neurohormonal effects . RESULTS There was no change in LVEF with eprosartan therapy ( mean relative LVEF percentage change [ SEM ] + 10.5 % [ 9.3 ] vs + 10.1 % [ 5.0 ] , respectively ; difference , 0.4 ; 95 % confidence interval [ CI ] , -20.8 to 21.7 ; P = .97 ) . Eprosartan was associated with a significant reduction in diastolic blood pressure and a trend toward a reduction in systolic blood pressure compared with placebo ( -7.3 mm Hg [ 95 % CI , -14.2 to -0.4 ] diastolic ; -8.9 mm Hg [ 95 % CI , -18.6 to 0.8 ] systolic ) . No significant change in heart rate or central hemodynamics occurred during treatment with eprosartan compared with placebo . A trend toward an increase in plasma renin activity was noted with eprosartan therapy . Eprosartan was well tolerated , with an adverse event profile similar to placebo , whereas kidney function remained unchanged . CONCLUSIONS When added to an ACE inhibitor , eprosartan reduced arterial pressure without increasing heart rate . There was no change in LVEF after 2 months of therapy with eprosartan BACKGROUND Albuminuria and hypertension are predictors of poor renal and cardiovascular outcome in diabetic patients . We tested whether dual blockade of the renin-angiotensin system ( RAS ) with both an angiotensin-converting enzyme ( ACE ) inhibitor and an angiotensin II receptor blocker ( ARB ) is superior to maximal recommended dose of ACE inhibitor in type 1 diabetic patients with diabetic nephropathy ( DN ) . METHODS We performed a r and omized , double-blind , crossover trial with 8 weeks treatment with placebo and irbesartan 300 mg ( once daily ) , added on top of enalapril 40 mg ( once daily ) . We included 24 type 1 patients with DN . At the end of each treatment period , albuminuria , 24-hour blood pressure , and glomerular filtration rate ( GFR ) were measured . RESULTS Values on ACE inhibitors + placebo were : albuminuria [ mean ( 95 % CI ) ] , 519 ( 342 to 789 ) mg/24 hours ; blood pressure [ mean ( SEM ) ] , 131 (3)/74 ( 1 ) mm Hg , and GFR [ mean ( SEM ) ] , 65 ( 5 ) mL/min/1.73 m2 . Dual blockade of the RAS induced a reduction in albuminuria [ mean ( 95 % CI ) ] of 25 % ( 15 , 34 ) ( P < 0.001 ) , a reduction in systolic blood pressure of 8 mm Hg ( 4 , 12 ) ( P = 0.002 ) , and a reduction of 4 mm Hg ( 2 , 7 ) ( P = 0.003 ) in diastolic blood pressure . GFR and plasma potassium remained unchanged during both treatment regimes . Dual blockade was safe and well tolerated . CONCLUSION Dual blockade of the RAS is superior to maximal recommended dose of ACE inhibitors with regard to lowering of albuminuria and blood pressure in type 1 patients with DN . Long-term trials are needed to further establish the role of dual blockade of the RAS in renal and cardiovascular protection BACKGROUND The efficacy of ACE-inhibitor therapy is well documented in the treatment of chronic heart failure . As pharmacological mechanisms of ACE-inhibition and angiotensin II AT1-receptor-antagonists differ , an additional positive effect concerning left ventricular function can be expected in combining both classes of drugs . METHODS Twenty patients ( 64.9+/-8.5 years ) with advanced chronic heart failure ( NYHA class III ) receiving long-term medication with digitalis , diuretics and ACE-inhibitors were r and omized to either eprosartan ( 540+/-96 mg/day ) or placebo , according to a blinded protocol . Hemodynamic measurements by impedance cardiography were performed at baseline and after 8.85+/-1 . 5 days of study medication treatment . RESULTS Additional treatment with eprosartan result ed in a higher cardiac output than in the control group ( P<0.05 ) . While in the active treatment group cardiac output increased significantly from baseline ( 2.27 - 3.24 l/min , P=0 . 039 ) , there was no change in the control group . CONCLUSIONS The additional treatment with the AT1-receptor antagonist eprosartan , given to severe heart failure patients , who received digitalis , diuretics and ACE-inhibitors , result ed in a beneficial effect by increasing cardiac output . This effect may be due to eprosartan 's additional property of blocking the autocrine interaction of locally and not ACE-generated angiotensin II with their respective vascular and myocardial AT1-receptors as well as the influence on prejunctional AT1-receptors located on sympathetic nerve terminals OBJECTIVES We sought to evaluate the effects of spironolactone on neurohormonal factors in patients with severe congestive heart failure ( CHF ) . BACKGROUND In the R and omized ALdactone Evaluation Study ( RALES ) , spironolactone , an aldosterone receptor antagonist , significantly reduced mortality in patients with severe CHF . However , the mechanism of action and neurohormonal impact of this therapy remain to be clarified . METHODS The effects of spironolactone ( 25 mg/day ; n = 54 ) or placebo ( n = 53 ) on plasma concentrations of the N-terminal portion of atrial natriuretic factor ( N-proANF ) , brain natriuretic peptide ( BNP ) , endothelin-1 ( ET-1 ) , norepinephrine ( NE ) , angiotensin II ( AII ) , and aldosterone were assessed in a subgroup of 107 patients ( New York Heart Association functional class III to IV ; mean ejection fraction 25 % ) at study entry and at three and six months . RESULTS Compared with the placebo group , plasma levels of BNP ( -23 % at 3 and 6 months ; p = 0.004 and p = 0.05 , respectively ) and N-proANF ( -19 % at 3 months , p = 0.03 ; -16 % at 6 months , p = 0.11 ) were decreased after spironolactone treatment . Over time , spironolactone did not modify the plasma levels of NE and ET-1 . Angiotensin II increased significantly in the spironolactone group at three and six months ( p = 0.003 and p = 0.001 , respectively ) . As expected , a significant increase in aldosterone levels was observed over time in the spironolactone group ( p = 0.001 ) . CONCLUSIONS Spironolactone administration in patients with CHF has opposite effects on circulating levels of natriuretic peptides ( which decrease ) and aldosterone and AII ( which increase ) . The reduction in natriuretic peptides might be related to changes in left ventricular diastolic filling pressure and /or compliance , whereas the increase in AII and aldosterone probably reflects activated feedback mechanisms . Further studies are needed to link these changes to the beneficial effects on survival and to determine whether the addition of an AII antagonist could be useful in this setting BACKGROUND Although the beneficial effects of angiotensin-converting enzyme ( ACE ) inhibitors in patients with heart failure are well recognized , there are theoretical advantages in combining ACE inhibition with angiotensin (AT)1 receptor antagonism . METHODS Twenty patients with mild to moderate heart failure and maximally treated with an ACE inhibitor were r and omly assigned to losartan or placebo . Patients underwent repeated assessment of exercise tolerance , quality of life , central and regional hemodynamics , and neurohumoral and biochemical parameters over a period of 12 weeks . RESULTS Losartan treatment was well tolerated in terms of adverse events , heart rate , and blood pressure response , and there were no significant changes in serum creatinine or potassium . After 12 weeks of treatment , no significant differences were observed between the losartan and placebo groups in exercise tolerance , quality of life , central and regional hemodynamics , or neurohumoral parameters . CONCLUSIONS In patients with mild to moderate heart failure already maximally treated with an ACE inhibitor , additional treatment with losartan is well tolerated , but we have not observed any significant improvement in exercise capacity , quality of life , central and regional hemodynamics , or neurohormones . Our data suggest that the combination of losartan with an ACE inhibitor does not offer any substantial advantages over treatment with an ACE inhibitor alone in these patients In previous studies , the synergistic antiproteinuric effect of the combination therapy of ACE inhibitors and angiotensin II receptor antagonists ( ATRAs ) has been inconsistent in relation to underlying renal diseases . The influence from the blood pressure ( BP ) - reducing effect in some studies might also contribute to this inconclusiveness . To examine the possibility of the benefit being different according to underlying renal diseases , we undertook a crossover therapeutic trial of the combination therapy in two selected homogenous groups of patients with diabetic and non-diabetic renal diseases . The BP-reducing effect was excluded during the study . Nineteen biopsy-proven IgA nephropathy , as examples of non-diabetic renal diseases , and 24 type 2 diabetic nephropathy patients were selected as the study subjects . The subjects had to meet the follow criteria : a creatinine clearance ( Ccr ) between 25 - 90 ml/min/1.73 m2 , 24-hr urinary protein excretion rate over 1.0 g/day and a BP maintained at less than 130/80 mmHg , with more than six-month therapy of ramipril , ( 5.7 + /- 0.4 mg/day , 13 + /- 2 month ) . The baseline data between the two groups showed no significantly differences . After a 12-week stabilization period ( control period ) , 4 mg , once daily , dose of c and esartan ( combination period ) followed by a placebo ( placebo period ) , or vice versa , were administered in addition to the ramipril , for 12 weeks . The combination , with c and esartan , did not change the Ccr , BP , serum and urinary electrolytes or the urea . The 24 hour urinary protein excretion rate was significantly reduced by the combination therapy in the patients with IgA nephropathy ( 3.1 + /- 0.3 g/day in combination , 4.2 + /- 0.3 in control , and 4.3 + /- 0.2 in placebo ; p < 0.05 ) . However , the patients with diabetic nephropathy showed no reduction in their proteinuria with the combination therapy ( 3.8 + /- 0.2 g/day in combination , 3.9 + /- 0.3 in control , and 4.1 + /- 0.3 in placebo ; p = NS ) . The changes in proteinuria showed no relationship with the changes in the BP in IgA nephropathy . In conclusions , the benefit of combination therapy of its antiproteinuric effect was different between IgA and diabetic nephropathy over the 12-week trial . The difference in the pathophysiological role , and the importance of the renin- angiotensin system , between the two diseases might contribute to the discrepancy in the result . We suggest the discrimination of the underlying renal diseases in the study subjects is an important prerequisite for future studies on this issue Recently published studies have shown than angiotensin converting enzyme inhibitors can be combined with angiotensin II antagonists and are highly effective in reducing mortality and improving the quality of life of patients with heart failure.1–3 There is little information about the effects of this combination on the myocardial function of patients with severe myocardial dysfunction . Thus , in 21 patients with stable heart failure of ischaemic aetiology , with New York Heart Association functional class III – IV and a resting left ventricular ejection fraction ( EF ) of ≤ 40 % , who were treated with diuretics , β blockers , and /or digoxin ( given at unchanged dosage ) , we studied the effects on myocardial dysfunction induced by adding either enalapril as a monotherapy , or the combination of enalapril and losartan . Patients were aged 50–75 years and gave their consent . The ethical committee approved the protocol . All patients underwent clinical routine examinations encompassing routine laboratory tests , ECGs , and colour Doppler transthoracic echocardiograms . The study was double blind , and double dummy and r and omised ( three parallel groups ) . Seven patients were treated with placebo ( placebo + Dual blockade of the renin-angiotensin-aldosterone system ( RAAS ) with both ACE inhibitors and angiotensin II receptor-blockers has been shown to reduce both albuminuria and blood pressure compared to either monotherapy . The mechanisms behind these beneficial effects are not known , and we hypothesized that the effect of dual RAAS blockade may be due to a more complete suppression of circulating aldosterone . We performed a combined analysis on three r and omized , double-masked , cross-over trials where 51 type 1 diabetic patients suffering from diabetic nephropathy received 8 weeks of dual RAAS blockade using an angiotensin II receptor blocker in combination with an ACE inhibitor and 8 weeks of monotherapy with the same ACE inhibitor . Albuminuria , 24 h blood pressure , GFR , and plasma aldosterone were determined at the end of each treatment period . Compared to ACE inhibition alone , dual RAAS blockade lowered blood pressure by 7/5 mm Hg from 137/76 mm Hg , decreased albuminuria by 37 % from 558 mg/24 hour , and reduced plasma aldosterone by 28 % from 59 pg/ml and caused a reversible decline in GFR of 4 ml/min/1.73 m2 ( p < or = 0.01 for all comparisons ) . There was and a significant correlation between changes in 24-hour diastolic blood pressure and changes in albuminuria . Furthermore , the antialbuminuric response to dual blockade was influenced by the ACE/ID polymorphism , that is , patients carrying the D-allele had a significantly lower reduction of 31 % compared to the 55 % in patients with the II genotype ( p = 0.021 ) . Multiple linear regression analysis revealed that ACE/ID genotypes and reduction in plasma aldosterone , diastolic blood pressure and GFR is associated with changes in albuminuria on dual blockade treatment ( R2 ( adjusted ) = 0.57 , p < 0.001 ) . Dual RAAS blockade is a new treatment concept that may offer additional cardiovascular and renal protection in type 1 diabetic patients with diabetic nephropathy . The beneficial response may be influenced by genetic factors and reductions in blood pressure and plasma aldosterone concentrations Background Limitation of systemic and glomerular hypertension reduces urinary protein excretion and prevents renal function deterioration . Objective To investigate whether , in hypertensive patients with glomerulonephritis , a combination of an angiotensin converting enzyme inhibitor ( ACEI , fosinopril 20 mg/day ) with an angiotensin receptor blocker ( ARB , irbesartan 150 mg/day ) produces a more profound antiproteinuric effect than either drug alone . Methods Ten non-diabetic patients with glomerulonephritis , normal or slightly reduced but stable renal function ( creatinine clearance 40–106 ml/min ) without immunosuppression were studied . Clinical evaluations , 24 h blood pressure measurements and laboratory tests were performed as follows : ( 1 ) without medication ( baseline ) and in r and om sequence ; ( 2 ) ACEI alone ; ( 3 ) ARB alone ; and ( 4 ) combination of ACEI + ARB . Each period lasted for 6 weeks , separated by three washout periods of 4 weeks each without therapy . Results ACEI and ARB alone reduced proteinuria from 7.9 ± 7.1 to 5.3 ± 5.2 and 5.0 ± 4.9 g/24 h ( mean ± SD ) , respectively . The combination of ACEI + ARB induced a more remarkable reduction of proteinuria in every patient ( to 3.3 ± 3.7 g/24 h ) than either drug alone ( P = 0.039 by ANOVA ) . The enhanced antiproteinuric effect of the combined therapy could not be attributed to a more pronounced reduction of 24 h mean arterial pressure ( basal , 106 ± 8 ; ACEI , 97 ± 5 ; ARB , 98 ± 5 ; ACEI + ARB , 95 ± 5 mmHg ) or creatinine clearance ( basal , 77 ± 27 ; ACEI , 73 ± 31 ; ARB 80 ± 30 ; ACEI + ARB , 73 ± 32 ml/min ) . Conclusions A combination of ACEI and ARB in patients with glomerulonephritis produces a more profound decrease in proteinuria than either drug alone . This additive antiproteinuric effect is not dependent on changes in blood pressure or creatinine clearance . A long-term controlled study is required to confirm the positive effect of this treatment on the progression of renal function loss Background Angiotensin-converting enzyme ( ACE ) inhibitors and angiotensin receptor blocking drugs ( ARB ) block the effect of angiotensin II by different mechanisms . It has been suggested that combined therapy may be more effective at reducing blood pressure ( BP ) than higher doses of either drug . Methods Twenty-three elderly patients with systolic hypertension completed a double-blind crossover study comparing placebo , c and esartan ( C ) 16 mg , C32 mg , lisinopril ( L ) 20 mg , L40 mg and C16 mg + L20 mg . Treatment periods were one month and ambulatory BP measurements were performed at the end of each period . The effects on albumin excretion in eight patients with microalbuminuria were determined . Results All treatments lowered BP . The falls in systolic and diastolic BP with C16 , C32 , L20 and L40 were similar . Plasma renin rose to a similar extent . A plateau effect was reached with C16 and L20 . Systolic BP on the combination of C16 + L20 was lower than on each monotherapy ( C16 , 3.8 mmHg [ p=0.002 ] ; C32 , 6.4 [ 0.0003 ] ; L20 , 2.9 [ 0.05 ] ; L40 , 3.3 [ 0.003 ] ) . The additional fall in BP with the combination appeared to be due to recruitment of non-responders , rather than to an additive effect in most patients . All treatments reduced microalbuminuria to a similar extent . The combination was well tolerated and there was no deterioration in renal function . Conclusion When patients are on a plateau dose of an ACE inhibitor or an ARB , addition of the other drug class has a small but significant incremental effect on BP in the overall group . However , some patients respond better to one drug class than to the other and this may explain the results . This study lends no support to the use of these two drugs in combination to treat hypertension AIMS To investigate the effect of valsartan in the Valsartan-Heart Failure Trial ( Val-HeFT ) when added to angiotensin-converting enzyme inhibitor ( ACEi ) alone in patients with heart failure ( HF ) . METHODS Subjects in Val-HeFT receiving ACEi but not beta-blocker at baseline were analysed ; 1532 were assigned to valsartan and 1502 assigned to placebo . Primary outcome events ( all-cause mortality , hospitalisation for adjudicated heart failure , sudden death with resuscitation and need for > 4 h of parenteral therapy for worsening heart failure ) were monitored . RESULTS Mortality was not affected by valsartan but morbidity endpoints were significantly reduced ( 36.3 % in placebo , 31.0 % in valsartan , p=0.002 ) in patients receiving an ACEi but no beta-blocker . Quality of life ( QOL ) was significantly improved , ejection fraction ( EF ) significantly increased , left ventricular ( LV ) diameter significantly reduced and plasma B-type natriuretic peptide , norepinephrine and aldosterone levels significantly reduced with valsartan compared to placebo . The morbidity benefit was significant in patients on ACEi doses below the median ( 22 % reduction , p=0.003 ) and not statistically significant in those receiving ACEi doses above the median ( 14 % reduction , p=0.143 ) . CONCLUSION Valsartan reduces heart failure hospitalisations and slows LV remodelling in patients treated with an ACEi in the absence of beta-blockade , particularly in those on lower doses of ACEi BACKGROUND To investigate the renoprotective effect of combination therapy with an angiotensin I converting enzyme inhibitor and an angiotensin type I receptor blocker ( ARB ) on diabetic kidney disease , half doses of each monotherapy were given to type 2 diabetic patients with albuminuria . METHODS Urinary albumin index ( UAI ) and blood pressure ( BP ) were measured in a total of 27 out patients with type 2 diabetes mellitus receiving 10 mg imidapril or 8 mg c and esartan per day . Either agent was then substituted with a combination of 5 mg imidapril and 4 mg c and esartan . After 3 months of combination therapy , UAI and BP were measured . Changes in the parameters were assessed by paired t test . RESULTS Although BP was not significantly different prior to and at the end of combination therapy , log-transformed UAI was significantly reduced ( P = 0.003 ) from an initial UAI ( mean log-transformed UAI + /- SD ) of 79.4 (27.4 - 231)mg/g Cre to 52.5 (17.1 - 161)mg/g Cre at the end of combination therapy . The reduction was not associated with the initial UAI , initial BP , decrease in BP , pretreatment medication or other concomitant antihypertensive agents . CONCLUSIONS In patients with type 2 diabetes and nephropathy , dual blockade of the renin system with an angiotensin-converting enzyme inhibitor and angiotensin receptor blocker significantly reduces albuminuria and , thus , may be renoprotective even when the doses of the agents are reduced by one half Angiotensin-converting enzyme ( ACE ) inhibitors and AT1-receptor antagonists ( ARAs ) are widely administered to reduce urinary protein loss and slow the progression of proteinuric nephropathy to end-stage renal failure . Our group recently observed that the combination of ACE inhibitors and ARAs may have an additive antiproteinuric effect , which may occur because ACE inhibitors do not completely reduce angiotensin II ( Ang II ) production . Ang II is also produced by chymase . Thus , combination therapy better antagonizes the effects of Ang II . The purpose of this study is to ascertain whether the additive antiproteinuric effect of ACE inhibitors plus ARAs is dose dependent and related to the drug-induced reduction in systemic blood pressure . Therefore , enalapril ( E ; 10 mg/d ) and losartan ( LOS ; 50 mg/d ) were r and omly administered alone and then in association ; initial dosages were doubled when drugs were administered alone and in association . To determine the influence of the drug-dependent effect on reducing blood pressure and the reduction in urinary proteinuria , both ambulatory and office blood pressures were recorded . E and LOS administered alone reduced proteinuria by the same extent ; no further reduction was observed when E and LOS alone were administered at a doubled dose . When E and LOS were coadministered , proteinuria decreased by a greater extent compared with E and LOS alone ; an additional reduction in proteinuria was observed when combined therapy doses were doubled . The reduction in proteinuria was not correlated with clinical through blood pressure ; however , reductions in diastolic and mean ambulatory blood pressures significantly correlated with the decrease in proteinuria , as well as with creatinine clearance . In conclusion , this study shows that combination therapy with E and LOS has an additive dose-dependent antiproteinuric effect that is likely induced by the drug-related reduction in systemic blood pressure . In normotensive proteinuric patients , it is likely that even a small reduction in systemic blood pressure may affect intraglomerular hemodynamics by a great extent because efferent arteriole regulation is hampered more completely by the coadministration of ACE inhibitors and ARAs Given the increasing incidence and dismal prognosis in congestive heart failure , it is not surprising that strenuous efforts have been made to limit the morbidity and mortality that result from this syndrome . The National Institutes of Health design ed and implemented the Studies of Left Ventricular Dysfunction ( SOLVD ) to assess the effect of therapy with enalapril , an angiotensin-converting enzyme inhibitor , on all cause mortality in a population with left ventricular dysfunction ( i.e. , ejection fraction at or below 35 % ) . Important secondary objectives included the effects of this therapy on cause-specific mortality , development of heart failure , and hospitalization for congestive heart failure . Patients within each of two arms of the trial were r and omized on the basis of the administration ( treatment arm ) or lack ( prevention arm ) of concomitant therapy for congestive heart failure . The trial was double blind and placebo controlled . The mean follow-up period for the combined arms was 39.2 months , during which time there was a 16 % risk reduction in all-cause mortality in the treatment arm of the trial ( P equals 0.008 ) and an 8 % risk reduction in the prevention arm ( P equals NS ) . In the prevention arm , however , there was a 12 % reduction risk for cardiovascular mortality ( P equals 0.12 ) and a 37 % reduction in risk of progression to heart failure ( P is less than 0.001 ) . Thus , the results of SOLVD indicate that therapy with an angiotensin-converting enzyme inhibitor has beneficial effects on morbidity and mortality that are apparent in a broad spectrum of patients with left ventricular dysfunction BACKGROUND The aim of this study was to assess dual renin system intervention with the maximum recommended doses of aliskiren and valsartan , compared with each drug alone in patients with hypertension . METHODS In this double-blind study , 1797 patients with hypertension ( mean sitting diastolic blood pressure 95 - 109 mm Hg and 8-h daytime ambulatory diastolic blood pressure > or = 90 mm Hg ) were r and omly assigned to receive once-daily aliskiren 150 mg ( n=437 ) , valsartan 160 mg ( 455 ) , a combination of aliskiren 150 mg and valsartan 160 mg ( 446 ) , or placebo ( 459 ) for 4 weeks , followed by forced titration to double the dose to the maximum recommended dose for another 4 weeks . The primary endpoint was change in mean sitting diastolic blood pressure from baseline to week 8 endpoint . Analyses were done by intention to treat . This trial is registered at Clinical Trials.gov with the number NCT00219180 . FINDINGS 196 ( 11 % ) patients discontinued study treatment before the end of the trial ( 63 in the placebo group , 53 in the aliskiren group , 43 in the valsartan group , and 37 in the aliskiren/valsartan group ) , mainly due to lack of therapeutic effect . At week 8 endpoint , the combination of aliskiren 300 mg and valsartan 320 mg lowered mean sitting diastolic blood pressure from baseline by 12.2 mm Hg , significantly more than either monotherapy ( aliskiren 300 mg 9.0 mm Hg decrease , p<0.0001 ; valsartan 320 mg , 9.7 mm Hg decrease , p<0.0001 ) , or with placebo ( 4.1 mm Hg decrease , p<0.0001 ) . Rates of adverse events and laboratory abnormalities were similar in all groups . INTERPRETATION The combination of aliskiren and valsartan at maximum recommended doses provides significantly greater reductions in blood pressure than does monotherapy with either agent in patients with hypertension , with a tolerability profile similar to that with aliskiren and valsartan alone The benefits of angiotensin-converting enzyme inhibitors and angiotensin II ( ATII ) receptor antagonist therapy of diabetic nephropathy ( DNP ) are thought to be largely the result of attenuation of ATII effects on proteinuria . The aim of the study was to ascertain whether there is the additive anti-proteinuric effect of enalapril plus losartan in DNP . Twenty-two patients with DNP were studied . Patients were r and omly assigned to enalapril 10 mg/day ( 11 patients ) or losartan 50 mg/day ( 11 patients ) administered in a single oral dose in the morning for 12 weeks . and then , in 10 patients ( five patients from enalapril group and five patients from losartan group ) , combination therapy ( 10 mg/day enalapril and 50 mg/day losartan ) was started and continued for 12 weeks . In 12 patients , initial drugs dosages were doubled ( six patients 20 mg/day enalapril and six patients 100 mg/day losartan ) , and monotherapy was continued for 12 weeks . Blood pressure and proteinuria were measured before and after therapy . Adverse effects were recorded at every visit . Proteinuria decreased by 33 % with enalapril and losartan administered alone ( p < 0.05 ) . Co-administration of enalapril and losartan decreased proteinuria by a greater extent compared with enalapril and losartan administered alone ( 51 % , p<0.05 ) . This proteinuria level was significantly lower than the proteinuria level of 12 weeks therapy with enalapril and losartan alone . The decrease of proteinuria was 37 % in double-dose monotherapy group ( p < 0.05 ) . Reduction of mean arterial blood pressure ( MAP ) in co-administration of enalapril and losartan was higher than enalapril and losartan administered alone ( p < 0.05 ) . Combination of enalapril and losartan decreased proteinuria and MAP by a greater extent compared with enalapril and losartan administered alone . We have found that proteinuria reduction induced by combined therapy is maintained throughout short-term follow-up ; a greater anti-proteinuric response was observed in the patients with DNP BACKGROUND Actions of angiotensin II may contribute to the progression of heart failure despite treatment with currently recommended drugs . We therefore evaluated the long-term effects of the addition of the angiotensin-receptor blocker valsartan to st and ard therapy for heart failure . METHODS A total of 5010 patients with heart failure of New York Heart Association ( NYHA ) class II , III , or IV were r and omly assigned to receive 160 mg of valsartan or placebo twice daily . The primary outcomes were mortality and the combined end point of mortality and morbidity , defined as the incidence of cardiac arrest with resuscitation , hospitalization for heart failure , or receipt of intravenous inotropic or vasodilator therapy for at least four hours . RESULTS Overall mortality was similar in the two groups . The incidence of the combined end point , however , was 13.2 percent lower with valsartan than with placebo ( relative risk , 0.87 ; 97.5 percent confidence interval , 0.77 to 0.97 ; P=0.009 ) , predominantly because of a lower number of patients hospitalized for heart failure ; 455 ( 18.2 percent ) in the placebo group and 346 ( 13.8 percent ) in the valsartan group ( P<0.001 ) . Treatment with valsartan also result ed in significant improvements in NYHA class , ejection fraction , signs and symptoms of heart failure , and quality of life as compared with placebo ( P<0.01 ) . In a post hoc analysis of the combined end point and mortality in subgroups defined according to base-line treatment with angiotensin-converting-enzyme ( ACE ) inhibitors or beta-blockers , valsartan had a favorable effect in patients receiving neither or one of these types of drugs but an adverse effect in patients receiving both types of drugs . CONCLUSIONS Valsartan significantly reduces the combined end point of mortality and morbidity and improves clinical signs and symptoms in patients with heart failure , when added to prescribed therapy . However , the post hoc observation of an adverse effect on mortality and morbidity in the subgroup receiving valsartan , an ACE inhibitor , and a beta-blocker raises concern about the potential safety of this specific combination BACKGROUND The present multicenter study investigated whether the combination of angiotensin-converting enzyme inhibitor ( ACEI ) and angiotensin II receptor blocker ( ARB ) is more beneficial for preventing left ventricular remodeling and suppressing neurohumoral factors than either ACEI or ARB alone . METHODS AND RESULTS One hundred and six patients with mild-to-moderate congestive heart failure treated in 26 Japanese institutes were r and omly assigned to the combination therapy or monotherapy . Changes in physical activity ( New York Heart Association functional classes , Specific Activity Scale ( SAS ) ) , concentrations of neurohumoral factors ( plasma renin activity , angiotensin II , aldosterone , and brain natriuretic peptide ( BNP ) ) , and cardiac function for 6 months were compared between the 2 groups . It was found that the combination therapy , which was administered at doses st and ard in Japan , increased the SAS score ( 4.5 + /- 1.5 to 4.9 + /- 1.5 , p<0.05 ) and decreased the plasma BNP concentration ( 183 + /- 163 to 135 + /- 118 pg/ml , p<0.05 ) . In contrast , there were no changes in SAS score ( 4.5 + /- 1.4 to 4.6 + /- 1.4 , NS ) or BNP concentration ( 156 + /- 157 to 151 + /- 185 pg/ml , NS ) in the patients receiving monotherapy . CONCLUSIONS The results of the study demonstrate that the combination therapy , even at the st and ard doses for Japan , improves physical activity and plasma BNP concentration more than the monotherapy . A larger study is required to assess the effects of the combination therapy on major clinical outcomes We tested the hypothesis that the combination of converting enzyme inhibitor ( CEI ) with losartan ( LOS ) produces a more profound antiproteinuric effect than either drug alone in normotensive patients with immunoglobulin A ( IgA ) nephropathy . Eight normotensive ( mean blood pressure , 88.9 + /- 2.1 mm Hg ) patients with biopsy-proven IgA nephropathy , nonnephrotic proteinuria ( protein , 1 to 3 g/d ) , and normal or slightly reduced creatinine clearance ( range , 69 to 119 mL/min ) were studied . Clinical evaluations and laboratory tests were performed ( 1 ) before CEI treatment ( basal ) and after ( 2 ) CEI alone ( CEI , 12 weeks ) ; ( 3 ) the combination of CEI and LOS , the latter at a dosage of 50 mg/d ( CEI + LOS , 4 weeks ) ; ( 4 ) LOS alone ( LOS ; 50 mg/d ; 12 weeks ) ; ( 5 ) the combination of LOS and CEI ( LOS + CEI , 4 weeks , at the same dosage as CEI + LOS ) ; and ( 6 ) a doubled dose of either CEI alone or LOS alone for 4 weeks . CEI and LOS as monotherapy significantly reduced proteinuria by 38 % and 30 % , respectively . No further reduction of proteinuria was achieved by doubling the dose of CEI or LOS . Both combinations induced a more remarkable reduction of proteinuria ( 73 % ; P < 0.05 v other periods ) than either drug administered alone . The antiproteinuric effect of CEI or LOS and the more remarkable effect achieved with both combinations was not dependent on the reduction of blood pressure and /or creatinine clearance . In conclusion , this study provides first-time evidence that the combination of CEI and LOS in normotensive patients with IgA nephropathy produces a more profound decrease in proteinuria than either drug . This additive antiproteinuric effect is not dependent on changes in systemic blood pressure and creatinine clearance . Nevertheless , a larger controlled study is required to confirm this novel observation |
13,609 | 30,421,580 | There is still insufficient evidence to support the use of endometrial injury in women with implantation failure . | AIM Recent studies have revealed positive effects of endometrial injury on clinical pregnancy rates , but with inconsistent results .
The aim of this meta- analysis was to assess the efficacy of endometrial injury ( biopsy and /or hysteroscopy ) as a potential treatment measure for implantation failure in the in vitro fertilization population . | Background : Implantation failure is one of the most important factors limiting success in IVF treatment . The majority of trials have demonstrated favorable effect of endometrial injury on implantation success rate especially in women with recurrent implantation failure , while some studies failed to detect any benefit . Objective : The purpose of our trial was to explore whether endometrial injury in luteal phase prior to frozen-thawed embryo transfer cycles would improve pregnancy outcomes ? Material s and Methods : We conducted a prospect i ve controlled trial of 93 consecutive subjects at a research and clinical center for infertility . All women were undergone frozen-thawed embryo transfer ( FTE ) cycles . Women in the experimental group underwent endometrial biopsy with a Pipelle catheter in luteal phase proceeding FET cycle . Primary outcomes were implantation and clinical pregnancy rates and secondary outcomes were chemical , ongoing and multiple pregnancy and miscarriage rates . Results : 45 subjects who underwent endometrial injury ( EI ) were compared with 48 control group which did not include any uterine manipulation . There were no significant differences in baseline and cycle characteristics between two groups . The difference in implantation rate was trend to statistically significance , 11.8 % in EI group vs. 20.5 % in control group ( p=0.091 ) . The chemical , clinical and ongoing pregnancy rates were lower in EI group compared with control group but not statistically significant . The multiple pregnancy rate and miscarriage rate also were lower in EI group compared with control group . Conclusion : Based on results of this study , local injury to endometrium in luteal phase prior to FET cycle had a negative impact on implantation and clinical pregnancy rates Purpose Endometrial biopsy preceding implantation in in vitro fertilization ( IVF ) treatment causes a type of injury which facilitates implantation . Pre-treatment hysteroscopic evaluation of uterine cavity also raises the success in IVF . This study investigates whether office hysteroscopy and concurrent endometrial biopsy performed in the luteal phase , on the day of GnRH agonist initiation for long protocol , improves subsequent IVF outcome . Methods A prospect i ve , nonr and omized , controlled study of 128 normoresponder women was performed : In 70 women ( study group ) , office hysteroscopy and concurrent endometrial biopsy were performed on the day of GnRH agonist initiation preceding ET cycle and in 58 women ( control group ) , GnRH agonist was initiated without any intervention . However , uterine cavity was shown to be normal with hysteroscopy within the previous 6 months in those women . Implantation and pregnancy rates were compared between the groups . Results Intrauterine pathologies were observed in 28 % of women in the study group . Implantation rate ( 38 vs. 25 % ; p = 0.04 ) and pregnancy rate per ET ( 67 vs. 45 % ; p = 0.01 ) were found to be significantly higher in the study group compared to the control group . Conclusion Office hysteroscopy and concurrent endometrial biopsy performed in the luteal phase , on the day of GnRH agonist initiation for long protocol , provide direct evaluation of the uterine cavity immediately before ET cycle and also significantly improve the implantation and IVF outcome OBJECTIVE To explore the possibility that endometrial injury modulates the expression of specific genes that may increase uterine receptivity . DESIGN Controlled clinical study . SETTING Clinical IVF unit and academic research center . PATIENT(S ) IVF patients with 28- to 30-day menstrual cycles . INTERVENTION(S ) Endometrial biopsies from two groups of patients were collected on days 20 - 21 of their spontaneous menstrual cycle . The experimental , but not the control , group underwent biopsies on days 11 - 13 and 21 - 24 of their preceding cycle . MAIN OUTCOME MEASURE(S ) Global endometrial gene expression and specific analysis of uroplakin Ib ( UPIb ) mRNA level throughout the menstrual cycle . RESULT ( S ) Local injury modulated the expression of a wide variety of genes . One of the prominently up-regulated genes was the bladder transmembranal protein , UPIb , whose expression by the endometrium is shown here for the first time . Endometrial UPIb mRNA increases after biopsy in the same cycle wct 2with an additional elevation in the following cycle . Immunohistochemical analysis localized the UPIb protein to the gl and ular-epithelial cells . Genes encoding other membrane proteins such as adipose differentiation-related protein and mucin 1 , transmembrane , were also up-regulated . CONCLUSION ( S ) The biopsy-induced increase in the expression of UPIb and other genes encoding membrane proteins supports the possible importance of the membrane structure and stability during implantation . The specific role of UPIb in uterine receptivity should be eluci date Background Mechanical endometrial injury prior to IVF has been suggested as a means to increase implantation rates by improving endometrial receptivity . However , the effects of endometrial injury in proliferative vs. luteal phase have not been studied before . This study aim ed to explore whether endometrial injury in the proliferative phase of the preceding cycle before in vitro fertilization/embryo transfer ( IVF-ET ) improves the clinical outcomes in unselected subfertile women compared with injury in luteal phase . Methods A group of 142 patients who were good responders to hormonal stimulation were r and omized into four groups : injury group ( group A : endometrial injury in proliferative phase , n = 38 ; group B : endometrium injury in luteal phase , n = 32 ) , and non-injury group as control ( group C : non-injury in proliferative phase , n = 36 ; group D : non-injury in luteal phase , n = 36 ) . Patients in injury groups underwent endometrial injury in either proliferative phase or luteal phase in the preceding cycle before IVF treatment . Clinical outcomes including implantation , pregnancy , and live birth rates were analyzed among the four groups . Results The baseline characteristics of the four groups including age , body mass index , duration , type and causes of infertility were similar . There were no significant differences in implantation , clinical pregnancy or live birth rates between injury group and non-injury group . Moreover , there were also no significant differences in implantation , clinical pregnancy , or live birth rates in injury in proliferative phase compared with luteal phase . Conclusions Endometrial injury in the cycle preceding IVF of unselected subfertile women does not increase implantation , clinical pregnancy , or live birth rates . Furthermore , there is no significant difference in clinical outcomes between endometrial injury in the proliferative phase and injury in the luteal phase . Trial registration This study was retrospectively registered on May 26th , 2017 ( ChiCTR-IOR-17011506 ) OBJECTIVE To evaluate the effectiveness of local endometrial injury in women undergoing in vitro fertilization ( IVF ) with at least one previous unsuccessful attempt . STUDY DESIGN R and omized controlled trial . Recruited women were r and omized into two groups . In group A ( pipelle group ) , women underwent pipelle biopsy twice in the luteal phase in the cycle prior to IVF . In group B ( control ) , women did not undergo any intervention prior to IVF . The primary outcome was clinical pregnancy rate . The secondary outcomes included live birth , miscarriage , multiple pregnancy and preterm delivery rates . RESULTS One hundred and eleven women were included in the study with 55 in the pipelle group and 56 in the control arm . The baseline clinical characteristics were similar in both groups . The clinical pregnancy rates were not significantly different between pipelle and control group ( 34.09 % vs. 27.65 % ; Odds ratio , OR 1.35 , 95 % confidence interval , CI 0.55 - 3.30 ) . The live birth ( 31.81 % vs. 25.53 % ; OR 1.36 , 95 % CI 0.55 - 3.39 ) , multiple pregnancy ( 33.33 % vs. 61.54 % ; OR 0.31 , 95 % CI 0.07 - 1.47 ) , miscarriage ( 6.66 % vs. 7.69 % ; OR 0.86 , 95 % CI 0.05 - 15.23 ) and preterm delivery rates ( 35.71 % vs. 66.66 % ; OR 0.28 , 95 % CI 0.05 - 1.4 ) were also not significantly different between the two groups . CONCLUSION Current study did not find any improvement in IVF success rates following endometrial injury in woman undergoing IVF after previous failed attempt STUDY QUESTION Is recurrent implantation failure ( RIF ) associated with decreased expression of platelet and endothelial cell adhesion molecule 1 ( PECAM1 ) and transforming growth factor β1 ( TGF-β1 ) in the endometrium during the implantation window ? SUMMARY ANSWER The present study demonstrates that the expression of PECAM1 and TGF-β1 is significantly decreased in the mid-secretory endometrium in women with RIF , which may account for embryo implantation failure . WHAT IS KNOWN ALREADY RIF has become a bottleneck issue that hampers the improvement of pregnancy rates in IVF-embryo transfer ( IVF-ET ) . The causes of RIF are complex and may involve the dysregulation of various growth factors , metabolites , and inflammatory cytokines . At present , the precise pathogenesis of RIF has not been eluci date d. STUDY DESIGN , SIZE , DURATION This was a prospect i ve case-control study . Endometrial tissue sample s were obtained from January 2014 to December 2016 from two groups of women who had undergone IVF ( RIF group , 22 women who underwent ≥3 ETs including a total of ≥4 good- quality embryos without pregnancy , control group , 18 women who conceived in their first treatment cycle ) . At the same time , sample s were obtained from 18 women with infertility secondary to tubal factor in the early proliferative , late proliferative and mid-secretory phases of the menstrual cycle ( n = 6 per group ) . Sample s used for isolation of primary human endometrial epithelial cells and stromal cells ( HEECs and HESCs ) were collected in December 2017 from six women with infertility secondary to tubal factor . PARTICIPANTS / MATERIAL S , SETTING , METHODS We investigated gene expression using integrative whole genome expression microarray analysis , including differentially expressed gene screening , principal component analysis , and functional enrichment analysis . RT-qPCR , western blotting , immunohistochemistry , immunofluorescence co-localization analysis and short hairpin RNA ( shRNA ) plasmid transfection in Ishikawa cell line , HEECs and HESCs were used to investigate the expression of PECAM1 and TGF-β1 . MAIN RESULTS AND THE ROLE OF CHANCE Integrative data mining of whole-genome expression profiles identified cell adhesion as a key regulator in RIF . Data base retrieval and literature review screened several novel cell adhesion-related genes that might participate in embryo implantation , which include PECAM1 , intercellular adhesion molecule 2 ( ICAM2 ) , integrin subunit β2 ( ITGB2 ) , selectin P ( SELP ) and TEK receptor tyrosine kinase ( TEK ) . Among these targets , the mRNA and protein levels of PECAM1 were significantly lower in the RIF group than those in the control group . During the menstrual cycles of women with secondary infertility , the protein expression level of PECAM1 was the lowest in early proliferative phase , slightly increased in late proliferative phase and was the highest in mid-secretory phase . While the expression level of HOXA10 , an endometrial receptivity marker , kept at a low level in early proliferative phase and increased in late proliferative phase , then maintained at a high level in the mid-secretory phase . Furthermore , TGF-β1 , mediated by PECAM1 , was also decreased significantly in the RIF group . Using shRNA-based approach , we demonstrated that the depletion of PECAM1 significantly decreased the expression of TGF-β1 in Ishikawa cells , as well as in primary HEECs and HESCs . These results indicated that PECAM1 and TGF-β1 might play a pivotal role in modulating endometrial receptivity . LIMITATIONS REASONS FOR CAUTION Although we have shown that PECAM1 and TGF-β1 were down-regulated in the women with RIF , the molecular mechanism of the effect of the factors on the endometrial receptivity remain unclear . WIDER IMPLICATION S OF THE FINDINGS Our findings provide insight into the contribution of PECAM1 and TGF-β1 in regulating implantation , which could be used to develop potential therapeutic methods for RIF . STUDY FUNDING /COMPETING INTEREST(S ) This work was supported by grants from the National Natural Science Foundation of China ( Nos. 81771656 and 81370763 ) , Special fund for clinical research of the Chinese Medical Association ( No. 16020480664 ) , and the Merck Serono China Research Fund for Fertility Agreement . The authors have no competing interests BACKGROUND The success rate of in-vitro fertilisation ( IVF ) remains low and many women undergo multiple treatment cycles . A previous meta- analysis suggested hysteroscopy could improve outcomes in women who have had recurrent implantation failure ; however , studies were of poor quality and a definitive r and omised trial was needed . In the TROPHY trial we aim ed to assess whether hysteroscopy improves the livebirth rate following IVF treatment in women with recurrent failure of implantation . METHODS We did a multicentre , r and omised controlled trial in eight hospitals in the UK , Belgium , Italy , and the Czech Republic . We recruited women younger than 38 years who had normal ultrasound of the uterine cavity and history of two to four unsuccessful IVF cycles . We used an independent web-based trial management system to r and omly assign ( 1:1 ) women to receive outpatient hysteroscopy ( hysteroscopy group ) or no hysteroscopy ( control group ) in the month before starting a treatment cycle of IVF ( with or without intracytoplasmic sperm injection ) . A computer-based algorithm minimised for key prognostic variables : age , body-mass index , basal follicle-stimulating hormone concentration , and the number of previous failed IVF cycles . The order of group assignment was masked to the research ers at the time of recruitment and r and omisation . Embryologists involved in the embryo transfer were masked to group allocation , but physicians doing the procedure knew of group assignment and had hysteroscopy findings accessible . Participants were not masked to their group assignment . The primary outcome was the livebirth rate ( proportion of women who had a live baby beyond 24 weeks of gestation ) in the intention-to-treat population . The trial was registered with the IS RCT N Registry , IS RCT N35859078 . FINDINGS Between Jan 1 , 2010 , and Dec 31 , 2013 , we r and omly assigned 350 women to the hysteroscopy group and 352 women to the control group . 102 ( 29 % ) of women in the hysteroscopy group had a livebirth after IVF compared with 102 ( 29 % ) women in the control group ( risk ratio 1·0 , 95 % CI 0·79 - 1·25 ; p=0·96 ) . No hysteroscopy-related adverse events were reported . INTERPRETATION Outpatient hysteroscopy before IVF in women with a normal ultrasound of the uterine cavity and a history of unsuccessful IVF treatment cycles does not improve the livebirth rate . Further research into the effectiveness of surgical correction of specific uterine cavity abnormalities before IVF is warranted . FUNDING European Society of Human Reproduction and Embryology , European Society for Gynaecological Endoscopy OBJECTIVE To evaluate hysteroscopic findings and estimate the effect of hysteroscopy on achieving a pregnancy in women with a history of 2 implantation failures after in vitro fertilization ( IVF ) . DESIGN Prospect i ve observational and matched case control study . DESIGN CLASSIFICATION II-2 . SETTING Private assisted reproduction units . PATIENTS A total of 1475 patients with a history of 2 consecutive implantation failures after IVF who had a hysteroscopy were studied ; there were 414 matched pairs of women with a similar history who either had or did not have a hysteroscopy . INTERVENTIONS Hysteroscopy ( diagnostic or operative ) , IVF/intracytoplasmic sperm injection cycle . MEASUREMENTS AND MAIN RESULTS Hysteroscopic findings , clinical pregnancy rate ( CPR ) , and ongoing pregnancy rate ( OPR ) were measured . In all , 36.6 % of the study population had abnormal hysteroscopic findings and 22.2 % had unsuspected findings ; women with abnormal hysteroscopic findings showed significantly increased CPR and increased OPR in a new IVF cycle compared with those with a normal hysteroscopy result . Women who had a hysteroscopy showed significantly increased CPR and OPR compared with matched control subjects who did not have the procedure . Hysteroscopy and appropriate therapy significantly increased the chances of achieving a subsequent clinical and ongoing pregnancy . CONCLUSION Women with 2 implantation failures after IVF had a remarkably high possibility for unsuspected abnormalities seen at hysteroscopy . Hysteroscopy could serve as a positive prognostic factor for achieving a subsequent pregnancy BACKGROUND : Management of repeated implantation failure despite transfer of good- quality embryos still remains a dilemma for ART specialists . Scrapping of endometrium in the nontransfer cycle has been shown to improve the pregnancy rate in the subsequent IVF/ET cycle in recent studies . AIM : The objective of this r and omized controlled trial ( RCT ) was to determine whether endometrial injury caused by Pipelle sampling in the nontransfer cycle could improve the probability of pregnancy in the subsequent IVF cycle in patients who had previous failed IVF outcome . SETTING : Tertiary assisted conception center . DESIGN : R and omized controlled study . MATERIAL S AND METHODS : 100 eligible patients with previous failed IVF despite transfer of good- quality embryos were r and omly allocated to the intervention group and control groups . In the intervention group , Pipelle endometrial sampling was done twice : One in the follicular phase and again in the luteal phase in the cycle preceding the embryo transfer cycle . OUTCOME MEASURE : The primary outcome measure was live birth rate . The secondary outcome measures were implantation and clinical pregnancy rates . RESULTS : The live birth rate was significantly higher in the intervention group compared to control group ( 22.4 % and 9.8 % P = 0.04 ) . The clinical pregnancy rate in the intervention group was 32.7 % , while that in the control group was 13.7 % , which was also statistically significant ( P = 0.01 ) . The implantation rate was significantly higher in the intervention group as compared to controls ( 13.07 % vs 7.1 % P = 0.04 ) . CONCLUSIONS : Endometrial injury in nontransfer cycle improves the live birth rate , clinical pregnancy and implantation rates in the subsequent IVF-ET cycle in patients with previous unsuccessful IVF cycles Aim : To evaluate the effect of local injury to the endometrium during spontaneous menstrual cycles before in vitro fertilization ( IVF ) treatment on implantation and pregnancy rates in women with recurrent implantation failure ( RIF ) . Methods : In a prospect i ve r and omized controlled trial ( RCT ) , a total of 36 patients , with RIF undergoing IVF , were r and omized to two groups . In 18 patients , endometrial biopsies were performed using a pipelle curette on days 9–12 and 21–24 of the menstrual cycle preceding IVF treatment . In 18 control patients , a cervical pipelle was performed . Results : The implantation rate ( 2.08 % versus 11.11 % ; p = 0.1 ) , clinical ( 0 % versus 31.25 % ; p < 0.05 ) and live births rates ( 0 % versus 25 % ; p = 0.1 ) were lower in the experimental group compared with controls . Conclusion : Our RCT did not find any benefit from local injury to the endometrium in women with a high number of RIFs . Further studies are warranted to better define the target population of patients who may benefit from this procedure Objective : Repeated implantation failure ( RIF ) is a condition in which the embryos implantation decreases in the endometrium . So , our aim was to evaluate the effect of local endometrial injury on embryo transfer results . Material s and methods : In this simple r and omized clinical trial ( RCT ) , a total of 120 patients were selected . The participants were less than 40 years old , and they are in their minimum two cycles of vitro fertilization ( IVF ) . Patients were divided r and omly into two groups of LEI ( Local endometrial injury ) and a control group ( n = 60 in each group ) . The first group had four small endometrial injuries from anterior , posterior , and lateral uterus walls which were obtained from people who were in 21th day of their previous IVF cycle . The second group was the patients who have not received any intervention . Results : The experimental and control patients were matched in the following factors . Regarding the clinical pregnancy rate , there was no significant difference noted between the experimental and the control group . Conclusion : Local endometrial injury in a preceding cycle does not increase the clinical pregnancy rate in the subsequent FET cycle of patients with repeated implantation failure OBJECTIVE To study whether an injury-induced inflammation might be the mechanism underlying the favorable effect of endometrial biopsy on the implantation rate in in vitro fertilization ( IVF ) patients . DESIGN Controlled clinical study . SETTING A medical center IVF unit and a research institute . PATIENT(S ) Women undergoing IVF who had previous failed treatment cycles . INTERVENTION(S ) Endometrial sample s were collected from two groups of patients on day 21 of their spontaneous menstrual cycle . The experimental , but not the control group underwent prior biopsy treatment on days 8 or/ and 11 to 13 of that same cycle . MAIN OUTCOME MEASURE(S ) Abundance of immune cells , cytokines/chemokines level , correlation between these parameters and pregnancy outcome . RESULT ( S ) A statistically significantly higher amount of macrophages/dendritic cells ( HLA-DR+ CD11c+ cells ) and elevated proinflammatory cytokines , tumor necrosis factor-α ( TNF-α ) , growth-regulated oncogene-α ( GRO-α ) , interleukin-15 ( IL-15 ) , and macrophage inflammatory protein 1B ( MIP-1B ) , were detected in day-21 endometrial sample s of the experimental group . A direct stimulatory effect of TNF-α on MIP-1B , GRO-α , and IL-15 messenger RNA ( mRNA ) expression was demonstrated . A positive correlation was found between the levels of macrophages/dendritic cells , MIP-1B expression , and TNF-α expression and the pregnancy outcome . CONCLUSION ( S ) A biopsy-induced inflammatory response may facilitate the preparation of the endometrium for implantation . Increased MIP-1B expression could possibly serve for prediction of implantation competence Abstract To evaluate the effect of endometrial injury on clinical outcomes in subfertile women with repeated implantation failures ( RIF ) undergoing assisted reproduction . In this prospect i ve nonr and omized controlled trial , 103 subfertile women with RIF were included . Fifty-one underwent endometrial injury through hysteroscopy in the early follicular phase of the previous cycle and 52 underwent the st and ard protocol without any intervention . Live birth and miscarriage were the primary outcomes . Clinical and in vitro fertilization ( IVF ) cycle characteristics , were also compared between groups . Both groups were comparable in terms of baseline and cycle characteristics . Live birth rates were significantly higher in the study , compared with the control group ( 18/51 vs. 8/52 , odds ratio ( OR ) = 0.25 ; 95 % confidence interval ( CI ) = 0.10–0.64 ; p = 0.020 ) , although miscarriage rates were similar ( 7/51 vs. 10/52 , OR= 0.25 ; 95%CI= 0.12–0.66 ; p = 0.452 ) . The rest of the outcomes parameters were comparable between groups . Logistic regression analysis revealed that endometrial injury and duration of subfertility were independent predictors of live birth after control of other variables ( OR = 2.818 ; 95%CI = 1.044–7.605 ; p = 0.041 and OR = 0.674 ; 95%CI = 0.461–0.985 , p = 0.042 , respectively ) . Endometrial injury induced through office hysteroscopy in the preceding cycle in subfertile women with RIF improves live birth rates Background : Though Assisted Reproductive Techniques have overcome many fertility disorders , implantation is still considered , the rate-limiting step for the success of IVF . Aim 0 : The aim of this study was to evaluate the role of endometrial scratching in improving the implantation rate in patients undergoing IVF-ET cycles . Design : Prospect i ve r and omized control trial . Methods and Material : Sixty infertile women with a history of > 1 previous failed IVF-ET cycles were r and omizedinto two groups of 30 each . The patients in group 1 underwent endometrial scratching once between days 14 - 21 of menstrual cycle in the cycle prior to embryo transfer ( ET ) , while in group 2scratching were not done . Implantation rate , ongoing pregnancy rate , abortion rate and live birth rate were comparedbetween both groups . Statistical Analysis : Mean values were compared between two groups using Student′s′t′ independent test . Frequency distributions of categorical variables were compared using Chi-Square/ Fisher′s exact test as appropriate . Results : Implantation rate in group 1 was 19.4 % whereas in group 2 it was 8.1 % . Difference between two groups was statistically significant ( P = 0.028 ) . The live birth rate was higher in the group 2 compared to group 1 , however this difference was not statistically significant ( 3.3 % vs 10 % , P = 0.612 ) . No significant difference was observed between the two groups regarding the ongoing pregnancy rate ( 16.7 % vs 0.0 % ; P = 0.052 ) , abortion rate ( 10.0 % vs 3.3 % , P = 0.612 ) and miscarriage rate ( 6.7 % vs 3.3 % , P = 0.99 ) . Conclusions : Implantation rate increases significantly after endometrial scratching in patients with previous failed IVF-ET The study was conducted to evaluate if the diagnosis and treatment of intrauterine lesions with office hysteroscopy is of value in improving the pregnancy outcome in patients with recurrent in-vitro fertilization and embryo transfer failure . Four hundred and twenty-one patients who had undergone two or more failed IVF-embryo transfer cycles were prospect ively r and omized into two groups . Group I ( n = 211 ) did not have office hysteroscopic evaluation , Group II ( n = 210 ) had office hysteroscopy . The patients who had normal hysteroscopic findings were included in Group IIa ( n = 154 ) and patients who had abnormal hysteroscopic findings were included in Group IIb ( n = 56 ) . Intrauterine lesions diagnosed were operated during the office procedure . Fifty-six ( 26 % ) patients in Group II had intrauterine pathologies and the treatment was performed at the same time . No difference existed in the mean number of oocyte retrieved , fertilization rate , number of embryos transferred or first trimester abortion rates among the patients in groups . Clinical pregnancy rates in Group I , Group IIa and Group IIb were 21.6 % , 32.5 % and 30.4 % respectively . There was a significant difference in the clinical pregnancy rates between patients in Group I and Group IIa ( 21.6 % and 32.5 % , P = 0.044 , respectively ) and Group I and Group IIb ( 21.6 % and 30.4 % , P = 0.044 , respectively ) . There was no significant difference in the clinical pregnancy rate of patients in Groups IIa and IIb . Patients with normal hysterosalpingography but recurrent IVF-embryo transfer failure should be evaluated prior to commencing IVF-embryo transfer cycle to improve the clinical pregnancy rate Abstract The purpose of this study was to find out whether endometrial scratching could improve live birth rate in women with previous IVF failure undergoing fresh IVF cycle . In a r and omized controlled trial , 387women with previous IVF failure were divided into two groups . Group A ( 193 women ) was subjected to endometrial biopsy procedure twice . Group B ( 194 women ) was subjected to a placebo procedure . Our results showed no difference in live birth rate between the two groups of women ( 47.2 % versus 38.1 % , p = 0.08 ) . However , regression analysis revealed that endometrial scratching was an independent predictor of live birth in the subgroup of women with two or more previous failure after control of other independent predictors ( odds ratio ( OR ) 3.4 , p = 0.005 ) . We conclude that endometrial scratching does not improve live birth rate in women undergoing IVF treatment with previous one IVF failure . Nevertheless , it may improve live birth in women with two or more previous IVF failures Objective : The aim of the study was to evaluate if the diagnosis and treatment of uterine cavity abnormalities by hysteroscopy in patients undergoing IVF programme is of any value in improving clinical pregnancy outcome . Methods : 520 patients participated in this prospect i ve r and omized study and were classified into two groups . Group I ( n = 265 ) without office hysteroscopy . Group II ( n = 255 ) had office hysteroscopy and was sub classified into Group II a and Group II b. Group II a ( n = 160 ) had normal hysteroscopic findings whereas Group II b ( n = 95 ) had abnormal office hysteroscopy findings , which were corrected at the same time . Result : There was no difference in the mean number of oocytes retrieved , fertilization rate , and number of embryos transferred among the patients in different groups . Statistically significant difference was observed in terms of clinical pregnancy rates between Group I and Group II a ( 26.2 and 44.44 % , P < 0.05 ) , and Group I and Group II b ( 26.2 and 39.55 % , P < 0.05 ) , respectively . Conclusion : Patients with recurrent IVF embryo transfer failures after normal hysterosalpingography findings should also be reevaluated using hysteroscopy prior to further commencing IVF-embryo transfer cycles in order to enhance the clinical pregnancy rates AIM The aim of this study was to examine the effect of endometrial scratching in women with unexplained infertility . MATERIAL AND METHODS A r and omized controlled trial was conducted in Mansoura University Teaching Hospital and a private practice setting . A total of 105 couples with unexplained infertility were r and omly allocated into two groups : group A comprised 54 women who underwent endometrial scratching in the luteal phase of a spontaneous menstrual cycle ; and group B included 51 women who underwent a placebo procedure . The main outcome measured was cumulative clinical pregnancy rate after 6 months and miscarriage rate . RESULTS Clinical pregnancy rate was significantly higher in the women experiencing endometrial biopsy than in the control group ( 25.9 % and 9.8 % , respectively , P = 0.04 ) . There was no significant difference in miscarriage rate between pregnant women in the endometrial injury group and pregnant women in the control group ( 12.5 % and 16.5 % , respectively , P = 0.79 ) . CONCLUSIONS Endometrial scratching may improve clinical pregnancy rates in couples with unexplained infertility . Adequately powered studies are m and ated to confirm or refute the findings Local injury to the endometrium prior to controlled ovarian stimulation may considerably improve implantation rates and pregnancy outcomes in intracytoplasmic sperm injection patients with high-order implantation failure ( > or = 4 IVF trials and > or = 12 transferred embryos ) OBJECTIVE Exploration of the possibility that local injury of the endometrium increases the incidence of implantation . DESIGN Prospect i ve study . SETTING Clinical IVF unit . PATIENT(S ) A group of 134 patients , defined as good responders to hormonal stimulation , who failed to conceive during one or more cycles of IVF and embryo transfer ( ET ) . INTERVENTION(S ) The IVF treatment and ET were preceded by repeated endometrial biopsies , in a r and omly selected 45 of a total of 134 patients . MAIN OUTCOME MEASURES Outcome of IVF-ET treatments . RESULT ( S ) Transfer of a similar number of embryos ( 3.4 + /- 1.0 and 3.1 + /- 0.9 in the experimental and control patients , respectively ) result ed in rates of implantation ( 27.7 % vs. 14.2 % , P = .00011 ) , clinical pregnancy ( 66.7 % vs. 30.3 % , P = .00009 ) , and live births per ET ( 48.9 % vs. 22.5 % , P = .016 ) that were more than twofold higher in the experimental group as compared to controls . CONCLUSION ( S ) These results suggest that IVF treatment that is preceded by endometrial biopsy doubles the chance for a take-home baby |
13,610 | 30,972,001 | Most addressed topics were risk factors and secondary clinical conditions . | Background : White matter hyperintensities of presumed vascular origin ( WMH ) are a common finding in elderly people and a growing social malady in the aging western societies .
As a manifestation of cerebral small vessel disease , WMH are considered to be a vascular contributor to various sequelae such as cognitive decline , dementia , depression , stroke as well as gait and balance problems .
While pathophysiology and therapeutical options remain unclear , large-scale studies have improved the underst and ing of WMH , particularly by quantitative assessment of WMH .
In this review , we aim ed to provide an overview of the characteristics , research subjects and segmentation techniques of these studies . | Background and Purpose — White matter hyperintensity ( WMH ) , or leukoaraiosis , is a radiologic finding generally assumed to reflect diseased small cerebral vasculature . WMH has significant functional impact through its relation to cognitive decline and risk of ischemic and hemorrhagic stroke . Accumulating evidence suggests that some manifestations of small-vessel disease such as intracerebral hemorrhage are associated with low levels of cholesterol . We sought to determine the relation between hyperlipidemia and WMH severity in patients with acute ischemic stroke ( AIS ) . Methods — We analyzed 2 independent , hospital-based AIS cohorts . Demographic and clinical data were collected prospect ively . WMH was measured using semiautomated volumetric image analysis and a semiquantitative visual grading scale . Univariate and multivariable regression analyses were used to assess the relation between WMH severity and study variables . Results — A total of 631 and 504 subjects in the first and second cohorts , respectively , were included . In univariate analyses , advancing age and hypertension were associated with severity of WMH ( P<0.001 ) in both cohorts . In the multivariable analysis , after controlling for age , sex , and significant risk factors in the univariate and age-adjusted analyses , patients with a history of hyperlipidemia had less severe WMH in both cohorts ( P<0.01 ) . Conclusions — Results from 2 independent cohorts demonstrate that AIS patients with a history of hyperlipidemia have less severe WMH at the time of stroke . These data support the hypothesis that hyperlipidemia may play a relatively protective role in cerebral small-vessel disease Objectives Extracellular vesicles ( EVs ) and their protein levels have been identified as a potential risk marker for the development of vascular disease . In the present study , we assessed whether levels of four previously identified EV proteins ( cystatin C , serpin G1 , serpin F2 and CD14 ) are associated with cerebral white matter lesions ( WMLs ) and brain atrophy . Design Cohort study ; cross-sectional and prospect i ve . Setting Single centre , secondary and tertiary setting . Participants 1309 patients with manifest vascular disease from the Second Manifestations of ARTerial disease-MR ( SMART-MR ) study , of which 994 had successful brain MRI and EV protein level measurements . Outcomes WML and brain parenchymal fraction ( BPF ) , as parameter for brain atrophy , at baseline and follow-up . Statistical methods The relationship between EV protein levels and WML volume ( expressed as log transformed percentage of intracranial volume ) and BPF ( expressed percentage of intracranial volume ) on 1.5 T brain MRI was assessed with multivariable linear regression modelling . Subsequently , the relationship between baseline EV protein levels and progression of atrophy and WML was analysed in 534 patients , in whom a follow-up MRI was obtained after 4 years . Results Higher EV-cystatin C and EV-CD14 were significantly associated with larger WML volume ( linear regression coefficient ( 95 % CI ) 0.10 log % /SD ( 0.04 to 0.17 ) and 0.14 log % /SD ( 0.07 to 0.20 ) , respectively . Higher EV-CD14 was associated with more brain atrophy ( –0.14%/SD ; –0.27 to –0.01 ) . Baseline EV-CD14 was significantly associated with increase of WMLs ( 0.11 log % /SD ( 0.04 to 0.18 ) ) . No relationship with EV-serpins was observed at baseline or at follow-up . Conclusions EV proteins cystatin C and CD14 are related to cerebral WMLs and the progression of brain atrophy in patients with manifest vascular disease , potentially identifying EVs in the aetiology of structural brain changes Background and Purpose — Growth differentiation factor-15 ( GDF-15 ) and soluble (s)ST2 are markers of cardiac and vascular stress . We investigated the associations between circulating concentrations of these biomarkers and incident stroke and sub clinical vascular brain injury in a sample from the Framingham Offspring cohort . Methods — We followed 3374 stroke- and dementia-free individuals ( mean age , 59.0±9.7 years ; 53 % women ) attending the Framingham Offspring sixth examination cycle 11.8±3.0 years for incident stroke . A sub sample of 2463 individuals underwent brain magnetic resonance imaging and neuropsychological testing ≈4.0±1.7 years after the sixth examination . Results — After adjustment for traditional cardiovascular risk factors , B-type natriuretic peptide , high-sensitivity C-reactive protein , and urine albumin levels , higher stress biomarker levels were associated cross-sectionally with lower brain volumes ( & bgr ; coefficients for intracranial volume comparing fourth [ Q4 ] versus first biomarker [ Q1 ] quartiles : −0.71 % for GDF-15 ; P=0.002 and 0.47 % for sST2 ; P=0.02 ) and worse performance on the visual reproduction test ( & bgr ; coefficients for Q4 versus Q1 : −0.62 for GDF-15 ; P=0.009 and −0.40 for sST2 ; P=0.04 ) . Higher GDF-15 concentrations were also associated with greater log-transformed white-matter hyperintensity volumes ( & bgr ; for Q4 versus Q1=0.19 ; P=0.01 ) . Prospect ively , a total of 203 ( 6 % ) individuals developed incident stroke/transient ischemic attack during follow-up . After multivariable adjustment , sST2 remained significantly associated with stroke/transient ischemic attack , hazard ratio for Q4 versus Q1 of 1.76 , 95 % confidence interval of 1.06 to 2.92 , and P=0.03 . Conclusions — Circulating GDF-15 and sST2 are associated with sub clinical brain injury and cognitive impairment . Higher sST2 concentrations are also associated with incident stroke , suggesting potential links between cardiac stress biomarkers and brain injury Accurate automated segmentation of age-related white matter hyperintensity ( WMH ) is desirable for topological studies and those involving large sample s. We assessed the accuracy of a novel automated method for segmentation of WMH on magnetic resonance imaging ( MRI ) in a r and omly selected population -based sample of older people aged > 60 years . The method combined morphological segmentation and statistical classifiers . Validation of this method was performed against expert manual segmentation in a sample of 30 scans , and against semi-automated segmentation in 202 scans . Its performance was also compared with those of other known methods derived from simple thresholding or Gaussian mixture modelling . Automated morphological segmentation combined with an adaptive boosting statistical classifier showed substantial agreement with manual segmentation , with an intraclass correlation coefficient ( ICC ) of 0.90 ( 95 % confidence interval [ CI ] , 0.80 - 0.95 ) for WMH volume and median similarity index ( SI ) of 0.58 ( interquartile range [ IQR ] 0.50 - 0.65 ) . The method also showed similarly high levels of agreement with semi-automated segmentation , with ICC 0.92 ( 95 % CI 0.89 - 0.93 ) and median SI 0.56 ( IQR 0.49 - 0.66 ) . Its best performance was observed for the highest tertile of WMH volume . Threshold-based and Gaussian mixture model-driven automated segmentation generally did not perform well in this study Objective : Our aim was to test the association of vascular risk factor exposure in midlife with progression of MRI markers of brain aging and measures of cognitive decline . Methods : A total of 1,352 participants without dementia from the prospect i ve Framingham Offspring Cohort Study were examined . Multivariable linear and logistic regressions were implemented to study the association of midlife vascular risk factor exposure with longitudinal change in white matter hyperintensity volume ( WMHV ) , total brain volume ( TBV ) , temporal horn volume , logical memory delayed recall , visual reproductions delayed-recall ( VR-d ) , and Trail-Making Test B-A ( TrB-A ) performance a decade later . Results : Hypertension in midlife was associated with accelerated WMHV progression ( p < 0.001 ) and worsening executive function ( TrB-A score ; p = 0.012 ) . Midlife diabetes and smoking were associated with a more rapid increase in temporal horn volume , a surrogate marker of accelerated hippocampal atrophy ( p = 0.017 and p = 0.008 , respectively ) . Midlife smoking also predicted a more marked decrease in total brain volume ( p = 0.025 ) and increased risk of extensive change in WMHV ( odds ratio = 1.58 [ 95%confidence interval 1.07–2.33 ] , p = 0.021 ) . Obesity in midlife was associated with an increased risk of being in the top quartile of change in executive function ( 1.39 [ 1.02–1.88 ] , p = 0.035 ) and increasing waist-to-hip ratio was associated with marked decline in TBV ( 10.81 [ 1.44–81.01 ] , p = 0.021 ) . Longitudinal changes in brain structure were significantly correlated with decline in memory and executive function . Conclusions : Midlife hypertension , diabetes , smoking , and obesity were associated with an increased rate of progression of vascular brain injury , global and hippocampal atrophy , and decline in executive function a decade later Objective Brain tissue segmentation by conventional threshold-based techniques may have limited accuracy and repeatability in older subjects . We present a new multispectral magnetic resonance ( MR ) image analysis approach for segmenting normal and abnormal brain tissue , including white matter lesions ( WMLs ) . Methods We modulated two 1.5 T MR sequences in the red/green colour space and calculated the tissue volumes using minimum variance quantisation . We tested it on 14 subjects , mean age 73.3 ± 10 years , representing the full range of WMLs and atrophy . We compared the results of WML segmentation with those using FLAIR-derived thresholds , examined the effect of sampling location , WML amount and field inhomogeneities , and tested observer reliability and accuracy . Results FLAIR-derived thresholds were significantly affected by the location used to derive the threshold ( P = 0.0004 ) and by WML volume ( P = 0.0003 ) , and had higher intra-rater variability than the multispectral technique ( mean difference ± SD : 759 ± 733 versus 69 ± 326 voxels respectively ) . The multispectral technique misclassified 16 times fewer WMLs . Conclusion Initial testing suggests that the multispectral technique is highly reproducible and accurate with the potential to be applied to routinely collected clinical MRI data Objective To examine the relationship between white matter hyperintensities and headache . Methods White matter hyperintensities burden was assessed semi-quantitatively using Fazekas and Scheltens scales , and by manual and automated volumetry of MRI in a sub- study of the general population -based Nord-Trøndelag Health Study ( HUNT MRI ) . Using vali date d question naires , participants were categorized into four cross-sectional headache groups : Headache-free ( n = 551 ) , tension-type headache ( n = 94 ) , migraine ( n = 91 ) , and unclassified headache ( n = 126 ) . Prospect i ve question naire data was used to further categorize participants into groups according to the evolution of headache during the last 12 years : Stable headache-free , past headache , new onset headache , and persistent headache . White matter hyperintensities burden was compared across headache groups using adjusted multivariate regression models . Results Individuals with tension-type headache were more likely to have extensive white matter hyperintensities than headache-free subjects , with this being the case across all methods of white matter hyperintensities assessment ( Scheltens scale : Odds ratio , 2.46 ; 95 % CI , 1.44–4.20 ) . Migraine or unclassified headache did not influence the odds of having extensive white matter hyperintensities . Those with new onset headache were more likely to have extensive white matter hyperintensities than those who were stable headache-free ( Scheltens scale : Odds ratio , 2.24 ; 95 % CI , 1.13–4.44 ) . Conclusions Having tension-type headache or developing headache in middle age was linked to extensive white matter hyperintensities . These results were similar across all methods of assessing white matter hyperintensities . If white matter hyperintensities treatment strategies emerge in the future , this association should be taken into consideration BACKGROUND AND AIMS Aortic atherosclerosis is an aggregate marker of vascular risk factor exposure and has been associated with intracranial atherosclerosis and stroke . We hypothesized that atherosclerosis of the descending aorta ( DAo ) could be a risk marker for brain aging and injury . METHODS We evaluated 1527 participants ( mean age 59.9 years , 53.5 % women ) in the Framingham Offspring cohort who underwent both aortic and brain MRI . Participants were free of clinical stroke , dementia , or other neurological illness at the time of axial MRI of the thoracic and abdominal DAo and subsequent brain MRI . We related the prevalence and burden of aortic plaque to total cerebral brain volume ( TCBV ) and white matter hyperintensity volume ( WMHV ) . An additional analysis compared incidence of stroke or TIA in participants with and without DAo plaques . RESULTS Presence of thoracic DAo plaque ( 8 % ) was associated with decreased TCBV in sex-pooled analysis ( -0.77 , SE 0.25 , p = 0.002 , equivalent to 4.5 years of aging ) and with increased WMHV only in men ( 0.26 , SE 0.12 , p = 0.032 , equivalent to 6.5 years aging ) . We observed similar associations of DAo plaque burden with TCBV and WMHV . There were 43 strokes and 11 TIAs in prospect i ve follow-up ( median 7 years ) . Presence of DAo plaque was not associated with subsequent stroke or TIA . CONCLUSIONS In this cross-sectional community-based study , we found DAo plaque is associated with accelerated brain aging . These data underscore the potential implication s of incidentally identified sub clinical aortic atherosclerosis and question whether targeted intervention in these high risk individuals can modulate cognitive decline Background Cerebral white matter hyperintensities ( WMHs ) on MRI are common and associated with vascular and functional outcomes . However , the relationship between WMHs and longitudinal trajectories of functional status is not well characterized . We hypothesized that whole brain WMHs are associated with functional decline independently of intervening clinical vascular events and other vascular risk factors . Methods and findings In the Northern Manhattan Study ( NOMAS ) , a population -based racially/ethnically diverse prospect i ve cohort study , 1,290 stroke-free individuals underwent brain MRI and were followed afterwards for a mean 7.3 years with annual functional assessment s using the Barthel index ( BI ) ( range 0–100 ) and vascular event surveillance . Whole brain white matter hyperintensity volume ( WMHV ) ( as percentage of total cranial volume [ TCV ] ) was st and ardized and treated continuously . Generalized estimating equation ( GEE ) models tested associations between whole brain WMHV and baseline BI and change in BI , adjusting for sociodemographic , vascular , and cognitive risk factors , as well as stroke and myocardial infa rct ion ( MI ) occurring during follow-up . Mean age was 70.6 ( st and ard deviation [ SD ] 9.0 ) years , 40 % of participants were male , 66 % Hispanic ; mean whole brain WMHV was 0.68 % ( SD 0.84 ) . In fully adjusted models , annual functional change was −1.04 BI points ( −1.20 , −0.88 ) , with −0.74 additional points annually per SD whole brain WMHV increase from the mean ( −0.99 , −0.49 ) . Whole brain WMHV was not associated with baseline BI , and results were similar for mobility and non-mobility BI domains and among those with baseline BI 95–100 . A limitation of the study is the possibility of a healthy survivor bias , which would likely have underestimated the associations we found . Conclusions In this large population -based study , greater whole brain WMHV was associated with steeper annual decline in functional status over the long term , independently of risk factors , vascular events , and baseline functional status . Sub clinical brain ischemic changes may be an independent marker of long-term functional decline White matter hyperintensities ( WMH ) are a feature of sporadic small vessel disease also frequently observed in magnetic resonance images ( MRI ) of healthy elderly subjects . The accurate assessment of WMH burden is of crucial importance for epidemiological studies to determine association between WMHs , cognitive and clinical data ; their causes , and the effects of new treatments in r and omized trials . The manual delineation of WMHs is a very tedious , costly and time consuming process , that needs to be carried out by an expert annotator ( e.g. a trained image analyst or radiologist ) . The problem of WMH delineation is further complicated by the fact that other pathological features ( i.e. stroke lesions ) often also appear as hyperintense regions . Recently , several automated methods aim ing to tackle the challenges of WMH segmentation have been proposed . Most of these methods have been specifically developed to segment WMH in MRI but can not differentiate between WMHs and strokes . Other methods , capable of distinguishing between different pathologies in brain MRI , are not design ed with simultaneous WMH and stroke segmentation in mind . Therefore , a task specific , reliable , fully automated method that can segment and differentiate between these two pathological manifestations on MRI has not yet been fully identified . In this work we propose to use a convolutional neural network ( CNN ) that is able to segment hyperintensities and differentiate between WMHs and stroke lesions . Specifically , we aim to distinguish between WMH pathologies from those caused by stroke lesions due to either cortical , large or small subcortical infa rcts . The proposed fully convolutional CNN architecture , called uResNet , that comprised an analysis path , that gradually learns low and high level features , followed by a synthesis path , that gradually combines and up- sample s the low and high level features into a class likelihood semantic segmentation . Quantitatively , the proposed CNN architecture is shown to outperform other well established and state-of-the-art algorithms in terms of overlap with manual expert annotations . Clinical ly , the extracted WMH volumes were found to correlate better with the Fazekas visual rating score than competing methods or the expert-annotated volumes . Additionally , a comparison of the associations found between clinical risk-factors and the WMH volumes generated by the proposed method , was found to be in line with the associations found with the expert-annotated volumes Background White matter hyperintensities increase the risk of multiple falls in older people , but the effect of sub-cortical infa rcts is unknown . Aims By pooling data from two Australian population -based studies , we aim ed to investigate the association between subcortical infa rcts and multiple falls and whether this relationship , and that of white matter hyperintensities , is mediated or modified by cognitive or sensorimotor factors . Methods Participants underwent structural magnetic resonance imaging and cognitive and sensorimotor assessment s. Falls were prospect ively measured over 12 months . Subcortical infa rcts were detected visually . Total white matter hyperintensity volume was quantified using automated segmentation methods . Generalized linear models were used to examine if sub-cortical infa rcts and white matter hyperintensities predicted falls . Results The mean age of the sample ( n = 655 ) was 74·5 ( st and ard deviation 6·7 ) years , 336 ( 51·3 % ) males . Overall , 114 ( 17·4 % ) had multiple falls . The majority had no sub-cortical infa rcts ( n = 491 , 75·0 % ) , while 90 had one ( 13·7 % ) , 41 had two ( 6·3 % ) , and 33 had more than or equal to three sub-cortical infa rcts ( 5·0 % ) . The risk of multiple falls was elevated in people with more than or equal to three sub-cortical infa rcts ( adjusted relative risk 1·89 , 95 % confidence interval 1·03 , 3·46 ) and in the highest quarter of white matter hyperintensity volume ( adjusted relative risk 1·46 , 95 % confidence interval 1·00 , 2·13 ) . The effect of sub-cortical infa rcts on falls was amplified by poorer vision ( P = 0·03 ) . The effect of white matter hyperintensities was amplified by poorer vision ( P = 0·008 ) , proprioception ( P = 0·03 ) , and muscle strength ( P = 0·008 ) . There was no modifying effect of cognitive function . Conclusions Increasing burdens of sub-cortical infa rcts and white matter hyperintensities are associated with a risk of falling . Interventions targeting sensorimotor factors along with strategies to prevent sub-cortical infa rcts and white matter hyperintensities may reduce the risk of falls We estimated the progression of brain atrophy and cerebrovascular lesions on MRI in a prospect i ve cohort of patients with various manifestations of arterial disease . Within the SMART-MR study , using brain MRI data from baseline and after on average 3.9 years of follow-up , intracranial volume ( ICV ) , total brain , cortical gray matter , ventricular , white matter lesion volumes and visually rated infa rcts were obtained from 663 patients ( mean age 57 ± 9 years , 81 % men ) . Global and cortical atrophy increased quadratically with age . Men showed more progression of global and cortical atrophy than women ( mean difference in change ( 95 % CI ) : -0.25 ( -0.44 ; -0.06 ) and -0.94 ( -1.35 ; -0.52)% ICV ) and had an increased risk of new brain infa rcts ( OR = 2.7 , 95 % CI 1.2 - 6.1 ) . Compared with coronary artery disease patients , cerebrovascular disease patients showed more progression of cortical and subcortical atrophy and an increased risk of new brain infa rcts , and peripheral arterial disease patients showed more progression of cortical atrophy . These results were independent of cerebrovascular lesions and cardiovascular risk factors . In patients with manifest arterial disease , brain atrophy tended to accelerate with older age and men had more progression of brain atrophy and cerebrovascular lesions than women . Additionally , patients with cerebrovascular and peripheral arterial disease showed the most prominent progression of atrophy and lesions A new method has been developed for probabilistic segmentation of five different types of brain structures : white matter , gray matter , cerebro-spinal fluid without ventricles , ventricles and white matter lesion in cranial MR imaging . The algorithm is based on information from T1-weighted ( T1-w ) , inversion recovery ( IR ) , proton density-weighted ( PD ) , T2-weighted ( T2-w ) and fluid attenuation inversion recovery ( FLAIR ) scans . It uses the K-Nearest Neighbor classification technique that builds a feature space from spatial information and voxel intensities . The technique generates for each tissue type an image representing the probability per voxel being part of it . By application of thresholds on these probability maps , binary segmentations can be obtained . A similarity index ( SI ) and a probabilistic SI ( PSI ) were calculated for quantitative evaluation of the results . The influence of each image type on the performance was investigated by alternately leaving out one of the five scan types . This procedure showed that the incorporation of the T1-w , PD or T2-w did not significantly improve the segmentation results . Further investigation indicated that the combination of IR and FLAIR was optimal for segmentation of the five brain tissue types . Evaluation with respect to the gold st and ard showed that the SI-values for all tissues exceeded 0.8 and all PSI-values exceeded 0.7 , implying an excellent agreement BACKGROUND Elevated parathyroid hormone ( PTH ) levels have been associated with cardiovascular disease risk factors and events . We hypothesized that elevated PTH levels would also be associated with sub clinical cerebrovascular disease . We examined the relationship between elevated PTH level and white matter hyperintensities ( WMHs ) and sub clinical infa rcts measured on brain magnetic resonance imaging ( MRI ) . METHODS PTH was measured at baseline ( 1993 - 1994 ) among participants free of prior clinical stroke who underwent a brain MRI at baseline ( n = 1703 ) and a second brain MRI 10 years later ( n = 948 ) . PTH levels of 65 pg/mL or higher were considered elevated ( n = 204 ) . Participants who did not return for a follow-up MRI had , at baseline , higher PTH and a greater prevalence of cardiovascular risk factors ( P < .05 for all ) ; therefore , multiple imputation was used . The cross-sectional and prospect i ve associations of PTH levels with WMH and MRI-defined infa rcts ( and their progression ) were investigated using multivariable regression models . RESULTS At baseline , the participants had a mean age of 62 years and were 60 % female and 49 % black . Cross-sectionally , after adjusting for demographic and lifestyle factors , elevated PTH level was associated with higher WMH score ( β = .19 , 95 % confidence interval [ CI ] .04-.35 ) and increased odds of prevalent infa rcts ( odds ratio 1.56 , 95 % CI 1.02 - 2.36 ) . Results were attenuated after adjustment for potential mediators of this association ( i.e. , hypertension ) . No prospect i ve associations were found between PTH and incident infa rcts or change in estimated WMH volume , although estimates were imprecise . CONCLUSIONS Although associated cross-sectionally , we did not confirm any association between elevated PTH level and progression of cerebrovascular changes on brain MRIs obtained 10 years apart . The relationship of PTH with sub clinical brain disease warrants further study Background and Purpose — Exhaled carbon monoxide ( CO ) is associated with cardiometabolic traits , sub clinical atherosclerosis , and cardiovascular disease , but its specific relations with stroke are unexplored . We related exhaled CO to magnetic resonance imaging measures of sub clinical cerebrovascular disease cross-sectionally and to incident stroke/transient ischemic attack prospect ively in the Framingham Offspring study . Methods — We measured exhaled CO in 3313 participants ( age 59±10 years ; 53 % women ) , and brain magnetic resonance imaging was available in 1982 individuals ( age 58±10 years ; 54 % women ) . Participants were analyzed according to tertiles of exhaled CO concentration . Results — In age- and sex-adjusted models , the highest tertile of exhaled CO was associated with lower total cerebral brain volumes , higher white-matter hyperintensity volumes , and greater prevalence of silent cerebral infa rcts ( P<0.05 for all ) . The results for total cerebral brain volume and white-matter hyperintensity volume were consistent after removing smokers from the sample , and the association with white-matter hyperintensity volume persisted after multivariable adjustment ( P=0.04 ) . In prospect i ve analyses ( mean follow-up 12.9 years ) , higher exhaled CO was associated with 67 % ( second tertile ) and 97 % ( top tertile ) increased incidence of stroke/transient ischemic attack relative to the first tertile that served as referent ( P<0.01 for both ) . These results were consistent in nonsmokers and were partially attenuated upon adjustment for vascular risk factors . Conclusions — In this large , community-based sample of individuals without clinical stroke/transient ischemic attack at baseline , higher exhaled CO was associated with a greater burden of sub clinical cerebrovascular disease cross-sectionally and with increased risk of stroke/transient ischemic attack prospect ively . Further investigation is necessary to explore the biological mechanisms linking elevated CO with stroke We report the topography of brain white matter hyperintensities ( WMHs ) on T2-weighted fluid attenuated inversion recovery ( FLAIR ) magnetic resonance imaging in 477 healthy subjects aged 60 - 64 years selected r and omly from the community . WMHs were delineated by using a computer algorithm . We found that all subjects had periventricular WMHs and 96.6 % subjects also had deep WMHs . The mean volume of WMHs was 4.9 ml , comprising 0.83 % of the white matter , of which 1.2 ml was severe in intensity . The deep WMHs were distributed throughout the cerebral hemispheres , with the occipital and frontal white matter bearing the greatest burden . The territory of the lenticulostriate arteries had the greatest WMHs . A white matter region of 4 mm adjacent to the cortex was not affected by hyperintensities . The mean ( SD ) number of discrete WMHs was 19.6 ( 7.1 ) per subject , of which 6.1 ( 4.4 ) were severe in intensity . Nearly half ( 48.6 % ) of the subjects had at least one large WMH ( > 12 mm diameter ) and one eighth ( 12.5 % ) of the subjects had at least one large WMH that appeared to be severe in MRI . The overall load of WMHs was similar in men and women , but the latter had a higher proportion of their white matter so affected . This study provides the first detailed topographic analysis of WMHs in a large representative middle-aged sample , emphasizes their high prevalence in mid-adult life and raises issues about their etiology and significance Objective : White matter hyperintensity ( WMH ) may be a marker of an underlying cerebral microangiopathy . Therefore , we hypothesized that WMH would be most severe in patients with lacunar stroke and intracerebral hemorrhage ( ICH ) , 2 types of stroke in which cerebral small vessel ( SV ) changes are pathophysiologically relevant . Methods : We determined WMH volume ( WMHV ) in cohorts of prospect ively ascertained patients with acute ischemic stroke ( AIS ) ( Massachusetts General Hospital [ MGH ] , n = 628 , and the Ischemic Stroke Genetics Study [ ISGS ] , n = 263 ) and ICH ( MGH , n = 122 ) . Results : Median WMHV was 7.5 cm3 ( interquartile range 3.4–14.7 cm3 ) in the MGH AIS cohort ( mean age 65 ± 15 years ) . MGH patients with larger WMHV were more likely to have lacunar stroke compared with cardioembolic ( odds ratio [ OR ] = 1.87 per SD normally transformed WMHV ) , large artery ( OR = 2.25 ) , undetermined ( OR = 1.87 ) , or other ( OR = 1.85 ) stroke subtypes ( p < 0.03 ) . These associations were replicated in the ISGS cohort ( p = 0.03 ) . In a separate analysis , greater WMHV was seen in ICH compared with lacunar stroke ( OR = 1.2 , p < 0.02 ) and in ICH compared with all ischemic stroke subtypes combined ( OR = 1.34 , p < 0.007 ) . Conclusions : Greater WMH burden was associated with SV stroke compared with other ischemic stroke subtypes and , even more strongly , with ICH . These data , from 2 independent sample s , support the model that increasing WMHV is a marker of more severe cerebral SV disease and provide further evidence for links between the biology of WMH and SV stroke Aortic stiffness is associated with cognitive decline and cerebrovascular disease late in life , although these associations have not been examined in young adults . Underst and ing the effects of aortic stiffness on the brain at a young age is important both from a pathophysiological and public health perspective . The aim of this study was to examine the cross-sectional associations of aortic stiffness with cognitive function and brain aging in the Framingham Heart Study Third Generation cohort ( 47 % men ; mean age , 46 years ) . Participants completed the assessment of aortic stiffness ( carotid – femoral pulse wave velocity ) , a neuropsychological test battery assessing multiple domains of cognitive performance and magnetic resonance imaging to examine sub clinical markers of brain injury . In adjusted regression models , higher aortic stiffness was associated with poorer processing speed and executive function ( Trail Making B – A ; & bgr;±SE , −0.08±0.03 ; P<0.01 ) , larger lateral ventricular volumes ( & bgr;±SE , 0.09±0.03 ; P<0.01 ) and a greater burden of white-matter hyperintensities ( & bgr;±SE , 0.09±0.03 ; P<0.001 ) . When stratifying by age , aortic stiffness was associated with lateral ventricular volume in young adults ( 30–45 years ) , whereas aortic stiffness was associated with white-matter injury and cognition in midlife ( 45–65 years ) . In conclusion , aortic stiffness was associated with cognitive function and markers of sub clinical brain injury in young to middle-aged adults . Prospect i ve studies are needed to examine whether aortic stiffening in young adulthood is associated with vascular cognitive impairment later in life The quantitative analysis of magnetic resonance imaging ( MRI ) data has become increasingly important in both research and clinical studies aim ing at human brain development , function , and pathology . Inevitably , the role of quantitative image analysis in the evaluation of drug therapy will increase , driven in part by requirements imposed by regulatory agencies . However , the prohibitive length of time involved and the significant intra- and inter-rater variability of the measurements obtained from manual analysis of large MRI data bases represent major obstacles to the wider application of quantitative MRI analysis . We have developed a fully automatic " pipeline " image analysis framework and have successfully applied it to a number of large-scale , multi-center studies ( more than 1000 MRI scans ) . This pipeline system is based on robust image processing algorithms , executed in a parallel , distributed fashion . This paper describes the application of this system to the automatic quantification of multiple sclerosis lesion load in MRI , in the context of a phase III clinical trial . The pipeline results were evaluated through an extensive validation study , revealing that the obtained lesion measurements are statistically indistinguishable from those obtained by trained human observers . Given that intra- and inter-rater measurement variability is eliminated by automatic analysis , this system enhances the ability to detect small treatment effects not readily detectable through conventional analysis techniques . While useful for clinical trial analysis in multiple sclerosis , this system holds widespread potential for applications in other neurological disorders , as well as for the study of neurobiology in general BACKGROUND AND PURPOSE Cross-sectional studies show that cerebrovascular risk factors are associated with increased brain atrophy , accumulation of abnormal cerebral white matter signals , and clinical ly silent stroke . We extend these findings by examining the relationship between midlife cerebrovascular risk factors and later-life differences in brain atrophy , amount of abnormal white matter , and stroke on MRI . METHODS Subjects were the 414 surviving members of the prospect i ve National Heart , Lung , and Blood Institute Twin Study , who have been examined on 4 separate occasions , spanning the 25 years between 1969 - 1973 and 1995 - 1997 . Quantitative measures of brain volume , volume of abnormal white matter signal ( WMHI ) , and volume of stroke , when present , were obtained from those participating in the fourth examination . RESULTS The mean+/-SD age of the subjects was 47.2+/-3.0 years at initial examination and 72 . 5+/-2.9 years at final examination . Average blood pressure ( BP ) levels were normal , although 32 % of the subjects had received or were currently taking antihypertensive medications . As a group , 31 % had symptomatic cardiovascular disease , 11 % had symptomatic cerebrovascular disease , and 8 % had symptomatic peripheral vascular disease . Both systolic and diastolic BP levels at initial examination were inversely related to brain volume and positively related to WMHI volume . Multiple regression analysis identified BP-related measures and vascular risk factors as significant predictors of brain and WMHI volumes . In addition , the magnitude of orthostatic BP change was significantly associated with WMHI volume . Subjects with extensive amounts of WMHI had significantly higher systolic BP at the final examination and a higher prevalence of symptomatic cardiovascular and cerebrovascular disease , without significant differences in the prevalence of hypertension treatment . CONCLUSIONS Midlife BP measures are significantly associated with later-life brain and WMHI volumes and the prevalence of symptomatic vascular disease . Since WMHI share cerebrovascular risk factors and extensive WMHI are associated with symptomatic vascular disease , extensive WMHI may be a sub clinical expression of cerebrovascular disease . Careful treatment of midlife BP elevations may diminish these later-life brain changes This paper presents a method for detection of cerebral white matter hyperintensities ( WMH ) based on run-time PD- , T1- , and T2-weighted structural magnetic resonance ( MR ) images of the brain along with labeled training examples . Unlike most prior approaches , the method is able to reliably detect WMHs in elderly brains in the absence of fluid-attenuated ( FLAIR ) images . Its success is due to the learning of probabilistic models of WMH spatial distribution and neighborhood dependencies from ground-truth examples of FLAIR-based WMH detections . These models are combined with a probabilistic model of the PD , T1 , and T2 intensities of WMHs in a Markov R and om Field ( MRF ) framework that provides the machinery for inferring the positions of WMHs in novel test images . The method is shown to accurately detect WMHs in a set of 114 elderly subjects from an academic dementia clinic . Experiments show that st and ard off-the-shelf MRF training and inference methods provide robust results , and that increasing the complexity of neighborhood dependency models does not necessarily help performance . The method is also shown to perform well when training and test data are drawn from distinct scanners and subject pools BACKGROUND There is increasing evidence for a link between cerebrovascular disease and depression in the elderly but the mechanisms are still unknown . This study examines the longitudinal relationship between depression and white matter lesions ( WML ) in a sample of elderly aged 65 years and older . METHODS Three City (3C)-Dijon is a 4-year follow-up population -based prospect i ve study of 1658 subjects . At baseline , lifetime major depressive episode diagnosis was established using the Mini International Neuropsychiatric Interview . At each study wave , severity of depressive symptoms was assessed using Center for Epidemiological Studies -Depression ( CES-D ) , and antidepressants intake was recorded . At baseline , lifetime major depression ( LMD ) was defined as lifetime major depressive episode or antidepressant medication intake . At follow-up , subjects were classified " incident depression " if scoring high at CES-D or antidepressant users . At baseline , cerebral magnetic resonance imaging ( MRI ) was performed to quantify WML volumes using an automated method of detection . At 4-year follow-up , 1214 subjects had a second MRI . RESULTS Cross-sectional analysis showed a significantly higher WML volume in subjects with LMD compared with other subjects . Adjusted longitudinal analysis showed that increase in WML load was significantly higher in subjects with baseline LMD ( 2.1 cm(3 ) vs. 1.5 cm(3 ) , p = .004 ) . Among subjects free of depression up to baseline ( n = 956 ) , the higher the baseline WML volume , the higher the risk of developing depression during follow-up ( odds ratio one quartile increase : 1.3 ; 95 % confidence interval : = 1.1 - 1.7 ) . CONCLUSIONS Our data show that depression and WML volumes are strongly related . These results are consistent with the hypothesis of a vascular depression in the elderly OBJECTIVE To estimate brain volumes , white matter lesion ( WML ) volume and asymptomatic infa rcts on MRI in a large cohort of patients with atherosclerotic disease . METHODS Within the SMART-MR ( Second Manifestations of ARTerial disease-Magnetic Resonance ) study , a prospect i ve cohort study on determinants and course of brain changes on MRI , cross-sectional analyses were performed in 1044 patients ( mean age 58+/-10 years , 80 % male ) with coronary artery disease , cerebrovascular disease , peripheral arterial disease , or abdominal aortic aneurysm . Brain segmentation was used to quantify volumes of cortical gray matter , white matter , sulcal and ventricular cerebrospinal fluid , and WML . All volumes were expressed relative to intracranial volume . Brain infa rcts were rated visually and distinctions were made between cortical infa rcts , large subcortical infa rcts , lacunar infa rcts , and infa rcts in the cerebellum and brainstem . RESULTS With older age a nonlinear ( quadratic ) decrease in total brain volume was observed and a nonlinear increase in ventricular volume and WML . Cortical gray matter volume showed a linear decrease with age and was stronger in men than in women . WML volumes also increased more strongly in men than in women , while ventricular volume decrease showed no sex difference . Silent brain infa rcts were present in 14 % of men and women , and increased to 24 % of subjects aged 65 years or older . CONCLUSION In a population with atherosclerotic diseases , decrease in brain volumes with increasing age is comparable with findings from the general population . However , vascular pathology on MRI , as indicated by white matter lesions and silent brain infa rcts may be more common Several brain magnetic resonance imaging ( MRI ) changes are observed in older individuals including white matter lesions ( WML ) , silent brain infa rcts ( SBI ) , and cerebral atrophy . Few studies , however , have assessed the combined association of these changes on the severity of future cognitive decline . In the prospect i ve population -based 3C-Dijon MRI study , 1701 non-demented participants aged 65 to 80 years at entry had a brain MRI . Information on WML , hippocampal volumes , SBI presence , and brain parenchymal fraction were obtained . At 4-year follow-up , participants were screened for cognitive decline and dementia . Severity of cognitive decline was defined as none , moderate , or severe calculated from neuropsychological test performance change . The relation between brain MRI markers and longitudinal change in cognition was studied using polytomous logistic regression and multiple linear regression models controlling for potential confounders . Two-by-two interactions were tested including with the apolipoprotein E genotype . At follow-up , 46 participants showed severe cognitive deterioration and 224 participants showed moderate cognitive deterioration . In multivariable analyses , risk of severe cognitive deterioration as well as the cognitive decline rate were significantly increased in participants with higher WML volume ( p < 0.01 ) and smaller hippocampal volume ( p < 0.01 ) . The results suggested that WML and hippocampal volumes had a cumulative effect on the future level of cognitive decline . The APOE genotype was found to be an effect modifier of this association . Vascular brain changes and degenerative processes coexist in normal older individuals . The co-occurrence of degenerative and non-degenerative pathologies could strongly affect the course of dementia expression OBJECTIVE Evidence is mixed as to whether periventricular or deep white matter hyperintensities ( WMHs ) increase the risk for depressive symptoms , partly because of heterogeneity in depression measurement , short follow-up , and confounding by prodromal dementia . The study objective was to evaluate WMH volume in relation to discrete depressive symptoms over 10 years , stratifying by incident depression and dementia . METHODS In this prospect i ve longitudinal cohort study of a representative population sample from Dijon , France , 1,440 participants aged 65 - 80 years ( median age : 72 years ; 59.5 % women ) without depression , dementia , or stroke at baseline were studied . Baseline T2-weighted images were obtained in a 1.5-T scanner to quantify WMHs ( log cm3 ) . Clinic visits were performed up to five times in a 10-year period to assess incident neurologic diseases and comorbidities . Depressive symptoms were measured with the Center for Epidemiologic Studies Depression Scale and converted to factor z scores , representing somatic symptoms , depressed affect , low positive affect , and interpersonal problems . RESULTS Periventricular WMH volume was uniquely associated with low positive affect among incident depression cases ( β = 0.15 ; 95 % confidence interval [ CI ] : 0.02 - 0.29 ; p = 0.026 ) . Deep WMH volume was uniquely associated with depressed affect among incident dementia cases ( β = 0.36 ; 95 % CI : 0.05 - 0.68 ; p = 0.025 ) . WMH volume ( periventricular , deep , and total ) was associated with interpersonal problems among persons who developed dementia with depression . CONCLUSION The findings highlight that regional WMH volumes and specific depressive symptoms have clinical and prognostic relevance to help differentiate between persons at risk for depression and dementia Background and Purpose — The relationship between type 2 diabetes mellitus ( T2D ) and cerebral small vessel disease ( CSVD ) is unclear . We aim ed to examine the causal effect of T2D , fasting glucose levels , and higher insulin resistance on CSVD using Mendelian r and omization . Methods — Five CSVD phenotypes were studied ; 2 were clinical outcomes associated with CSVD ( lacunar stroke : n=2191/27 297 and intracerebral hemorrhage [ ICH ] : n=2254/8195 [ deep and lobar ICH ] ) , whereas 3 were radiological markers of CSVD ( white matter hyperintensities : n=8429 ; fractional anisotropy [ FA ] : n=8357 ; and mean diffusivity : n=8357 ) . We applied 2 complementary analyses to evaluate the association of T2D with CSVD . First , we used summarized data from genome-wide association study to calculate the effects of T2D-related variants on CSVD with inverse-variance weighted and weighted median approaches . Second , we performed a genetic risk score approach to test the effects of T2D-associated variants on white matter hyperintensities , FA , and mean diffusivity using individual-level data in UK Biobank . Results — T2D was associated with higher risk of lacunar stroke ( odds ratio [ OR ] , 1.15 ; 95 % confidence interval [ CI ] , 1.04–1.28 ; P=0.007 ) and lower mean FA ( OR , 0.78 ; 95 % CI , 0.66–0.92 ; P=0.004 ) but not white matter hyperintensities volume ( OR , 1.01 ; 95 % CI , 0.97–1.04 ; P=0.626 ) , higher mean diffusivity ( OR , 1.04 ; 95 % CI , 0.89–1.23 ; P=0.612 ) , ICH ( OR , 1.07 ; 95 % CI , 0.95–1.20 ; P=0.269 ) , lobar ICH ( OR , 1.07 ; 95 % CI , 0.89–1.28 ; P=0.466 ) , or deep ICH ( OR , 1.16 ; 95 % CI , 0.99–1.36 ; P=0.074 ) . Weighted median and penalized median weighted analysis showed similar effect estimates of T2D on lacunar stroke and FA , but with wider CIs , meaning they were not significant . The genetic score on individual-level data was significantly associated with FA ( OR , 0.63 ; 95 % CI , 0.45–0.89 ; P=0.008 ) after adjusting for potential confounders . Conclusions — Our Mendelian r and omization study provides evidence to suggest that T2D may be causally associated with CSVD , in particular with lacunar stroke and FA Abstract In this paper the Rotterdam Elderly Study is presented . The aim of the study is to investigate determinants of disease occurrence and progression in the elderly . In addition to contributing to our underst and ing of the etiology of geriatric illnesses , the study is expected to lead to specific recommendations for intervention . The study focusses on causally related determinants of major diseases in the elderly . Fields of interest for the Rotterdam Elderly Study are- conditions which interfere the most with the quality of life for the elderly . The aims of the Rotterdam Elderly Study are:(1)To investigate , by means of epidemiologic , clinical and basic research , the determinants of diseases in order to assess their etiologic significance .(2)To investigate potentially modifiable determinants in order to be able to develop preventive strategies by providing specific recommendations for intervention studies . The Rotterdam Elderly Study focusses on four primary areas of research : neurogeriatric diseases , cardiovascular diseases , locomotor diseases and ophthalmologic diseases . It is a prospect i ve follow-up study , in which determinants of disease and determintants of progression of disease will be investigated in the total population of 55 years or over of the district of Ommoord in Rotterdam . It is anticipated that about 1–0,000 people will participate in the study and they will be examined in the period of 1991 to 1995 Objective : To examine the cross-sectional and prospect i ve associations between arterial stiffness and structural brain changes within the Second Manifestations of Arterial Disease – Magnetic Resonance ( SMART-MR ) study , a prospect i ve cohort study among patients with manifest arterial disease . Methods : Distension measurements of the common carotid arteries and a brain MRI were performed in 526 patients ( mean age 59 ± 10 years ) . After a mean follow-up of 4.1 years ( range 3.6–5.8 ) , brain MRI was repeated in 308 patients . Brain segmentation was used to quantify total brain volume , cortical gray matter volume , ventricular volume , and white matter lesion ( WML ) volume ( relative to intracranial volume ) . Infa rcts were rated visually . Results : Cross-sectional multivariable regression analyses showed that 1 SD decrease in carotid distension , indicating increased arterial stiffness , was associated with smaller relative total brain and cortical gray matter volumes ( B = −0.24 % , 95 % confidence interval [ CI ] −0.44 to −0.04 % , and B = −0.47 % , 95 % CI −0.75 to −0.19 % ) , with larger WML volume ( B = 0.09 % , 95 % CI −0.01 to 0.19 % ) , and with higher risk of having nonlacunar ( cortical or large subcortical ) brain infa rcts ( relative risk = 1.44 , 95 % CI 1.14 to 1.81 ) . However , our prospect i ve findings showed that carotid distension was not significantly associated with progression of brain atrophy , WML volume , or brain infa rcts . Conclusion : In this population of patients with manifest arterial disease , stiffening of the carotid arteries was cross-sectionally associated with more brain atrophy , WML volume , and nonlacunar infa rcts , but did not lead to changes in brain volumes or infa rcts after 4 years Objective : To determine the association of conventional cardiovascular risk factors , markers of platelet activation , and thrombogenic blood-borne microvesicles with white matter hyperintensity ( WMH ) load and progression in recently menopausal women . Methods : Women ( n = 95 ) enrolled in the Mayo Clinic Kronos Early Estrogen Prevention Study underwent MRI at baseline and at 18 , 36 , and 48 months after r and omization to hormone treatments . Conventional cardiovascular risk factors , carotid intima-medial thickness , coronary arterial calcification , plasma lipids , markers of platelet activation , and thrombogenic microvesicles were measured at baseline . WMH volumes were calculated using a semiautomated segmentation algorithm based on fluid-attenuated inversion recovery MRI . Correlations of those parameters with baseline WMH and longitudinal change in WMH were adjusted for age , months past menopause , and APOE ε4 status in linear regression analysis . Results : At baseline , WMH were present in all women . The WMH to white matter volume fraction at baseline was 0.88 % ( 0.69 % , 1.16 % ) . WMH volume increased by 122.1 mm3 ( 95 % confidence interval : −164.3 , 539.5 ) at 36 months ( p = 0.003 ) and 155.4 mm3 ( 95 % confidence interval : −92.13 , 599.4 ) at 48 months ( p < 0.001 ) . These increases correlated with numbers of platelet-derived and total thrombogenic microvesicles at baseline ( p = 0.03 ) . Conclusion : Associations of platelet-derived , thrombogenic microvesicles at baseline and increases in WMH suggest that in vivo platelet activation may contribute to a cascade of events leading to development of WMH in recently menopausal women We investigated whether total cerebral blood flow ( CBF ) was associated with brain atrophy , and whether this relation was modified by white matter lesions ( WML ) . Within the Second Manifestations of ARTerial disease-magnetic resonance ( SMART-MR ) study , a prospect i ve cohort study among patients with arterial disease , cross-sectional analyses were performed in 828 patients ( mean age 58±10 years , 81 % male ) with quantitative flow , atrophy , and WML measurements on magnetic resonance imaging ( MRI ) . Total CBF was measured with MR angiography and was expressed per 100 mL brain volume . Total brain volume and ventricular volume were divided by intracranial volume to obtain brain parenchymal fraction ( BPF ) and ventricular fraction ( VF ) . Lower BPF indicates more global brain atrophy , whereas higher VF indicates more subcortical brain atrophy . Mean CBF was 52.0±10.2 mL/min per 100 mL , mean BPF was 79.2±2.9 % , and mean VF was 2.03±0.96 % . Linear regression analyses showed that lower CBF was associated with more subcortical brain atrophy , after adjusting for age , sex , vascular risk factors , intima-media thickness , and lacunar infa rcts , but only in patients with moderate to severe WML ( upper quartile of WML ) : Change in VF per s.d . decrease in CBF 0.18 % , 95 % CI : 0.02 to 0.34 % . Our findings suggest that cerebral hypoperfusion in the presence of WML may be associated with subcortical brain atrophy The Framingham Heart Study ( FHS ) was started in 1948 as a prospect i ve investigation of cardiovascular disease in a cohort of adult men and women . Continuous surveillance of this sample of 5209 subjects has been maintained through biennial physical examinations . In 1971 examinations were begun on the children of the FHS cohort . This study , called the Framingham Offspring Study ( FOS ) , was undertaken to exp and upon knowledge of cardiovascular disease , particularly in the area of familial clustering of the disease and its risk factors . This report review s the sampling design of the FHS and describes the nature of the FOS sample . The FOS families appear to be of typical size and age structure for families with parents born in the late 19th or early 20th century . In addition , there is little evidence that coronary heart disease ( CHD ) experience and CHD risk factors differ in parents of those who volunteered for this study and the parents of those who did not volunteer BACKGROUND Cerebral white matter hyperintensities on magnetic resonance imaging ( MRI ) scans have been associated with vascular disease and late-life depression , both in the general population and in psychiatric patients . Therefore , a cerebrovascular etiology for late-onset depression has been hypothesized . However , longitudinal studies on the causal role of white matter hyperintensities in the development of depressive symptoms in elderly adults are lacking . OBJECTIVE To investigate the relation between white matter hyperintensities and depressive symptoms in elderly subjects at risk of cardiovascular disease . METHODS In the Dutch sample of the PROSPER ( PROspect i ve Study of Pravastatine in the Elderly at Risk of cardiovascular disease ) cohort , 527 non-demented elderly , all aged 70 years or older , received a cranial MRI scan and the 15-item Geriatric Depression Scale , at baseline and 33 months ( SD 1.6 ) later . RESULTS Presence of white matter hyperintensities at baseline was not related to baseline depressive symptoms nor to the development of depressive symptoms during follow-up . Moreover , no association was found between progression of white matter lesion volume and progression of depressive symptoms . CONCLUSION This longitudinal study does not confirm the involvement of cerebrovascular disease expressed as MRI white matter hyperintensities in the development of depressive symptoms in elderly subjects The relation between progression of cerebral small vessel disease ( SVD ) and gait decline is uncertain , and diffusion tensor imaging ( DTI ) studies on gait decline are lacking . We therefore investigated the longitudinal associations between ( micro ) structural brain changes and gait decline in SVD using DTI . 275 participants were included from the Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort ( RUN DMC ) , a prospect i ve cohort of participants with cerebral small vessel disease aged 50–85 years . Gait ( using GAITRite ) and magnetic resonance imaging measures were assessed during baseline ( 2006–2007 ) and follow-up ( 2011 − 2012 ) . Linear regression analysis was used to investigate the association between changes in conventional magnetic resonance and diffusion tensor imaging measures and gait decline . Tract-based spatial statistics analysis was used to investigate region-specific associations between changes in white matter integrity and gait decline . 56.2 % were male , mean age was 62.9 years ( SD8.2 ) , mean follow-up duration was 5.4 years ( SD0.2 ) and mean gait speed decline was 0.2 m/s ( SD0.2 ) . Stride length decline was associated with white matter atrophy ( β = 0.16 , p = 0.007 ) , and increase in mean white matter radial diffusivity and mean diffusivity , and decrease in mean fractional anisotropy ( respectively , β = − 0.14 , p = 0.009 ; β = − 0.12 , p = 0.018 ; β = 0.10 , p = 0.049 ) , independent of age , sex , height , follow-up duration and baseline stride length . Tract-based spatial statistics analysis showed significant associations between stride length decline and fractional anisotropy decrease and mean diffusivity increase ( primarily explained by radial diffusivity increase ) in multiple white matter tracts , with the strongest associations found in the corpus callosum and corona radiata , independent of traditional small vessel disease markers . White matter atrophy and loss of white matter integrity are associated with gait decline in older adults with small vessel disease after 5 years of follow-up . These findings suggest that progression of SVD might play an important role in gait decline ABSTRACT Objectives : To investigate whether severity and progression of periventricular and deep white matter lesions ( WML ) and lacunar infa rcts were associated with progression of brain atrophy . Methods : Within the SMART-MR study , a prospect i ve cohort on MRI changes in patients with symptomatic atherosclerotic disease , 565 patients ( 57 ± 9 years ) without large infa rcts had vascular screening and 1.5 T MRI at baseline and after a mean follow-up of 3.9 years . With automated brain segmentation , total brain , cortical gray matter , ventricular , and WML volumes were estimated and expressed relative to intracranial volume ( % ) . Lacunar infa rcts were rated manually . Results : Using linear regression analyses adjusted for demographics and vascular risk factors , periventricular WML volume at baseline was associated with greater decrease in cortical gray matter volume ( B = −1.73 % , 95 % confidence interval [ CI ] −3.15 % to −0.30 % , per 1 % WML volume increase ) and greater increase in ventricular volume ( B = 0.12 % , 95 % CI 0.04 % to 0.20 % ) . Progression of periventricular WML volume corresponded with a greater decrease in cortical gray matter volume ( B = −0.45 % , 95 % CI −0.9 % to 0 % ) and greater increase in ventricular volume ( B = 0.15 % , 95 % CI 0.1 % to 0.2 % ) . Presence of lacunar infa rcts was associated with greater decline in total brain volume ( B = −0.25 % , 95 % CI −0.49 % to −0.01 % ) and progression of lacunar infa rcts with a greater decrease of total brain ( B = −0.30 % , 95 % CI −0.59 % to 0.01 % ) and cortical gray matter volume ( B = −0.81 % , 95 % CI −1.43 % to −0.20 % ) . Conclusions : In patients with symptomatic atherosclerotic disease , presence and progression of periventricular WML and lacunar infa rcts is associated with greater progression of brain atrophy independent of vascular risk factors High levels of angiotensin-converting-enzyme ( ACE ) may increase the risk of dementia through blood pressure elevation and subsequent development of cerebral small-vessel disease . However , high ACE levels may also decrease this risk through amyloid degradation which prevents brain atrophy . Within the SMART-MR study , a prospect i ve cohort study among patients with symptomatic atherosclerotic disease , serum ACE levels were measured at baseline and a 1.5 Tesla brain MRI was performed at baseline and after on average ( range ) 3.9 ( 3.0 - 5.8 ) years of follow-up in 682 persons ( mean age 58 ± 10 years ) . Brain segmentation was used to quantify total , deep , and periventricular white matter lesion ( WML ) volume , and total brain , cortical gray matter and ventricular volume ( % ICV ) . Lacunar infa rcts were rated visually . Regression analyses were used to examine the prospect i ve associations between serum ACE and brain measures . Patients with the highest serum ACE levels ( > 43.3 U/L ) had borderline significantly more progression of deep WML volumes than patients with the lowest ACE levels ( < 21.8 U/L ) ; mean difference ( 95 % CI ) in change was 0.20 ( -0.02 ; 0.43 ) % ICV . On the contrary , patients with the highest serum ACE levels had significantly less progression of cortical brain atrophy than patients with the lowest ACE levels ; mean difference ( 95 % CI ) in change was 0.78 ( 0.21 ; 1.36 ) % ICV . Serum ACE was not associated with subcortical atrophy , periventricular WML , or lacunar infa rcts . Our results show that higher ACE activity is associated with somewhat more progression of deep WML volume , but with less progression of cortical brain atrophy . This suggests both detrimental and beneficial effects of high ACE levels on the brain Objectives : Assuming the involvement of homocysteine in a generalized small-vessel disease , we investigated the association of homocysteine levels with progression of white matter lesions , lacunar infa rcts , and kidney disease . Methods : Within the SMART-MR ( Second Manifestations of ARTerial disease – Magnetic Resonance ) Study , a prospect i ve cohort study on brain aging in patients with symptomatic atherosclerotic disease , 663 patients ( aged 57 ± 9 years ) had vascular screening and 1.5-tesla MRI at baseline and after a mean follow-up of 3.9 years . Multiple regression analysis was used to estimate the longitudinal association between total homocysteine level , defined as a continuous variable and as hyperhomocysteinemia ( the highest quintile of homocysteine ) , and progression of white matter lesion volume , lacunar infa rcts , and estimated glomerular filtration rate . Results : After adjusting for age , sex , follow-up time , and vascular risk factors , hyperhomocysteinemia was significantly associated with increased risk of white matter lesion progression ( odds ratio 2.4 , 95 % confidence interval [ CI ] 1.5–4.1 ) and lower estimated glomerular filtration rate at follow-up ( B = −3.4 mL/min , 95 % CI −5.9 to −0.9 ) and borderline significantly associated with new lacunar infa rcts ( odds ratio 1.8 , 95 % CI 0.9–3.4 ) . Conclusions : Our findings implicate a role for homocysteine in the development of a generalized small-vessel disease in which both brain and kidney are affected OBJECTIVE To evaluate relationships between magnetic resonance imaging (MRI)-based measures of white matter hyperintensities ( WMHs ) , measured at baseline and longitudinally , and 1-year cognitive decline using a large convenience sample in a clinical trial design with a relatively mild profile of cardiovascular risk factors . DESIGN Convenience sample in a clinical trial design . SUBJECTS A total of 804 participants in the Alzheimer Disease Neuroimaging Initiative who received MRI scans , cognitive testing , and clinical evaluations at baseline , 6-month follow-up , and 12-month follow-up visits . For each scan , WMHs were detected automatically on coregistered sets of T1 , proton density , and T2 MRI images using a vali date d method . Mixed-effects regression models evaluated relationships between risk factors for WMHs , WMH volume , and change in outcome measures including Mini-Mental State Examination ( MMSE ) , Alzheimer Disease Assessment Scale-Cognitive Subscale ( ADAS-Cog ) , and Clinical Dementia Rating Scale sum of boxes scores . Covariates in these models included race , sex , years of education , age , apolipoprotein E genotype , baseline clinical diagnosis ( cognitively normal , mild cognitive impairment , or Alzheimer disease ) , cardiovascular risk score , and MRI-based hippocampal and brain volumes . RESULTS Higher baseline WMH volume was associated with greater subsequent 1-year increase in ADAS-Cog and decrease in MMSE scores . Greater WMH volume at follow-up was associated with greater ADAS-Cog and lower MMSE scores at follow-up . Higher baseline age and cardiovascular risk score and more impaired baseline clinical diagnosis were associated with higher baseline WMH volume . CONCLUSIONS White matter hyperintensity volume predicts 1-year cognitive decline in a relatively healthy convenience sample that was similar to clinical trial sample s , and therefore should be considered as a covariate of interest at baseline and longitudinally in future AD treatment trials Objective : Longitudinal studies of dementia rely on the assumption that individuals who drop out are comparable to those who remain in the study , adjusting for measured covariates . Existing methods to h and le dropouts account for differences based on past health and cognitive measures . We assess whether such adjustments fully account for differences in future dementia risk . Methods : Among Three-City Study participants in Dijon , France , with 1 ( n = 1,633 ) or 2 ( n = 1,168 ) brain MRI scans , we tested whether white matter lesion volume ( WMLV ) , hippocampal volume , or brain CSF volume predicted dropout ( “ unable to contact ” or “ refused interview ” ) in repeated- measures logistic regression with up to 4 follow-ups ( average 3.5 waves ) . Using linear regression , we also estimated differences in MRI volumes and MRI changes by subsequent dropout status and estimated plausible ranges for selective attrition bias based on these associations . Models were adjusted for demographic , health , and cognitive score covariates . Results : Baseline greater WMLV predicted increased odds of dropping out ( adjusted odds ratio = 1.71 ; 95 % confidence interval [ CI ] 1.20−2.43 ) . Among participants with 2 MRI scans , individuals who subsequently dropped out had significantly worse declines in hippocampal volume ( −0.30 SD difference ; 95 % CI −0.43 to −0.17 ) between the first and second MRI scans . Conclusions : Higher future dementia risk , indicated by worse past brain MRI findings , predicted future study dropout . Adjustment for selective attrition , based on MRI markers when available , may help reduce bias in estimates of dementia incidence and improve research on dementia risk factors . MRI findings may also help prospect ively identify cohort members at elevated risk of attrition OBJECTIVE High homocysteine level is a risk factor for atherosclerosis and has been associated with lacunar infa rcts ( LIs ) , white matter lesions ( WML ) and cognitive dysfunction . It is unclear whether homocysteine is associated with cerebral small vessel disease ( cSVD ) on top of pre-existent atherosclerosis . We evaluated the association between homocysteine and cSVD in a large cohort of patients with symptomatic atherosclerotic disease . METHODS Within the SMART-MR study , a prospect i ve cohort study of patients with symptomatic atherosclerotic disease , we estimated cross-sectional associations of total plasma homocysteine ( THCY ) and hyperhomocysteinemia ( HHCY ) with WML volume and presence of LI , using automated brain segmentation in MRIs of 1232 patients and cognitive function in 763 patients . WML were expressed as a logarithmic transformed percentage of total brain volume . RESULTS Linear regression analyses adjusted for age , sex , vascular risk factors and extent of atherosclerosis showed that THCY and HHCY were significantly associated with larger WML volumes ( B=0.01 % : 95 % CI 0.002 - 0.02 % , and B=0.21 % : 95 % CI 0.04 - 0.39 % ) . Increasing THCY was significantly associated with an increased risk of LIs ( OR 1.04 , 95 % CI 1.01 - 1.07 , per 1 μmol ) . Moreover , HHCY was associated with worse cognitive function ( B=-0.12 : 95 % CI -0.22 to -0.01 ) . CONCLUSION In patients with symptomatic atherosclerotic disease , higher homocysteine levels are associated with higher WML volume , presence of LI and slightly worse cognitive function Objective : In the Leukoaraiosis and Disability ( LADIS ) Study , 11 European centers are evaluating the role of age-related white matter changes ( ARWMC ) as an independent determinant of the transition to disability in the elderly ( 65 to 84 years ) . We aim ed at determining the influence of ARWMC on different objective measures of gait and balance . Methods : Six hundred thirty-nine nondisabled individuals were prospect ively enrolled and are being followed-up for 3 years . Subjects are grade d in three st and ardized categories of ARWMC ( mild , moderate , and severe ) according to central MRI reading . Quantitative tests of gait and balance include the Short Physical Performance Battery ( SPPB ; range : 0 [ poor ] to 12 [ normal ] ) , a timed 8-m walk , and a timed single leg stance test . Results : In cross-sectional analysis , deficiencies in gait and balance performance were correlated with the severity of ARWMC ( SPPB : 10.2 ± 2.1 in the mild , 9.9 ± 2.0 in the moderate , 8.9 ± 2.6 in the severe group ; p < 0.001 ) . Walking speed correlated with the severity of ARWMC ( 1.24 ± 0.28 m/second in the mild , 1.18 ± 0.32 m/second in the moderate , and 1.09 ± 0.31 m/second in the severe group ; p < 0.001 ) . Balance was best in individuals with mild ARWMC ( single leg stance time : 18.9 ± 10.8 seconds ) compared with moderate and severe ARWMC ( 16.4 ± 10.8 and 13.6 ± 11.2 seconds ) ( p < 0.001 ) . Physically inactive individuals had a higher risk of a pathologic SPPB score ( moderate vs mild ARWMC : odds ratio 1.60 , 95 % CI 1.02 to 2.52 ; severe vs mild ARWMC : odds ratio 1.75 , 95 % CI 1.09 to 2.80 ) . Conclusions : Our findings support a strong association between the severity of age-related white matter changes and the severity of gait and motor compromise . Physical activity might have the potential to reduce the risk of limitations in mobility BACKGROUND Accumulating evidence links blood pressure variability ( BPV ) with white matter hyperintensities ( WMH ) and stroke . The longitudinal association between BPV with late onset depression ( LOD ) and cognitive decline remains unexplored . METHODS Prospect i ve cohort study of 2812 participant 's age ⩾65 years ( median age 72 years , 63.6 % female ) without dementia or stroke . Serial clinic visits assessed blood pressure , cognitive function , depression disorder , and depressive symptoms . A brain magnetic resonance imaging ( MRI ) sub study was performed in 1275 persons to examine possible associations with WMH . RESULTS The interaction between symptomatic LOD and systolic BPV was associated with cognitive decline on the Isaac Set Test [ slope -4.45 ; 95 % confidence interval ( CI ) -8.92 to -0.16 , p = 0.04 ] , Benton Visual Retention Test ( slope -0.89 ; 95 % CI -1.77 to -0.01 , p = 0.049 ) , Mini Mental State Examination ( slope -1.08 ; 95 % CI -1.86 to -0.30 , p = 0.007 ) and Finger Tapping Test ( slope -7.53 ; 95 % CI -13.71 to -1.34 , p = 0.017 ) but not Trail Making Test-A or -B/A. The MRI sub study demonstrated that systolic BPV was associated with cognitive decline via interactions with depression and total WMH volume , but this was not dependent on either deep or periventricular WMH volumes . CONCLUSIONS The findings show that the interaction between systolic BPV with symptomatic depression and WMH increases cognitive decline in persons ⩾65 years of age . Future work could extend these findings by examining systolic BPV in relation to cognitive decline and WMH in older population s with depression OBJECTIVES To estimate the incidence and prevalence of dementia , Alzheimer 's disease ( AD ) , and vascular dementia ( VaD ) in the Cardiovascular Health Study ( CHS ) cohort . DESIGN Longitudinal cohort study using prospect ively and retrospectively collected data to evaluate dementia . SETTING Four U.S. communities . PARTICIPANTS There were 3,602 CHS participants , including 2,865 white and 492 African-American participants free of dementia , who completed a cranial magnetic resonance image between 1992 and 1994 and were followed for an average of 5.4 years . MEASUREMENTS Dementia was classified by neurologist/psychiatrist committee review using neuropsychological tests , neurological examinations , medical records , physician question naires , and proxy/informant interviews . Demographics and apolipoprotein E ( APOE ) genotype were collected at baseline . Incidence by type of dementia was determined using National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer 's Disease and Related Disorders Association criteria for AD and Alzheimer 's Disease Diagnostic and Treatment Center 's State of California criteria for VaD. RESULTS Classification result ed in 227 persons with prevalent dementia at entry into the study and 480 incident cases during follow-up . Incidence rates of dementia scaled to age 80 were 34.7 per 1,000 person-years for white women , 35.3 for white men , 58.8 for African-American women , and 53.0 for African-American men . Sex differences were not significant within race . Adjusted for age and education , racial differences were only of borderline significance and may have been influenced by ascertainment methodology . Rates differed substantially by educational attainment but were only significant for whites . Those with the APOE epsilon4 allele had an incidence rate at age 80 of 56.4 , compared with 29.6 for those without this allele ( P<.001 ) . In whites , type-specific incidence at age 80 was 19.2 for AD versus 14.6 for VaD. These rates were 34.7 and 27.2 for African Americans . At termination of observation , women had only a slightly higher prevalence of dementia ( 16.0 % ) than men ( 14.7 % ) . CONCLUSION Sex and racial differences were not found , and VaD was higher than reported in other studies . These data provide new estimates of dementia incidence in a community sample for projection of future burden ABSTRACT Low‐density lipoprotein cholesterol ( LDL‐C ) and hypertension have independent and synergistic effects on atherosclerotic cardiovascular disease . However , the role of circulatory LDL‐C and its possible interactions with hypertension in brain health have been poorly investigated . The study aim ed to investigate the relationship between the circulatory LDL‐C level and ( 1 ) brain structures , grey‐matter volume ( GMV ) and white matter hyperintensity ( WMH ) and ( 2 ) cognitive functions , and whether hypertension plays a role in these relationships . Subjects who were non‐stroke and non‐demented were prospect ively recruited from the community‐based I‐Lan Longitudinal Aging Study . High‐resolution 3 T MRI was performed with GM and WMH segmentation . GMVs , total and regional including Alzheimer 's disease‐susceptible area , and WMH volumes were measured . Neurological tests including verbal memory , visuospatial , and verbal executive functions were assessed . Eight‐hundred‐ and ‐two participants ( 59.2±5.7 years ; 44 % men ) were included . Multivariate linear regression analyses showed that low circulatory LDL‐C levels ( < 98mg/dL ) were significantly associated with reduced GMVs in frontal ( st and ardized & bgr;=−0.130 ; p=0.003 ) and posterior cingulate ( & bgr;=−0.113 ; p=0.032 ) regions in hypertensive but not normotensive subjects . In addition , low circulatory LDL‐C levels , combined with hypertension , had the lowest posterior cingulate GMV ( & bgr;=−0.073 ; p=0.021 ) , highest periventricular WMH ( & bgr;=0.089 ; p=0.011 ) and lowest verbal memory test scores ( & bgr;=−0.088 ; p=0.035 ) compared with neither low circulatory LDL‐C level nor hypertension , and either hypertension or low circulatory LDL‐C level . Age , sex , total intracranial volume , vascular risk factors , level of other circulatory lipids , and the taking of anti‐hypertensive and lipid‐lowering medications were adjusted . In conclusion , the role of circulatory LDL‐C level and its interactive effect with hypertension on brain health are firstly demonstrated . A low circulatory LDL‐C level was associated with reduced regional brain GMVs in hypertensive but not normotensive subjects . In addition , there seems a combined detrimental‐effect of low circulatory LDL‐C levels with hypertension on posterior cingulate GMV , WMH , and verbal memory . HIGHLIGHTSReduced regional grey‐matter volumes in subjects with low level of circulatory LDL cholesterol (LDL‐C).Combined effects of low circulatory LDL‐C with hypertension ( HTN ) on brain structures and functions . Reduced posterior cingulate grey‐matter volume in low circulatory LDL‐C combined with HTN.Combined effects also include higher white matter hyperintensities and poorer memory OBJECTIVE We aim ed to examine the cross-sectional and prospect i ve relationship between leisure time physical activity , brain MRI abnormalities and cognitive performance in patients with vascular disease . METHODS Within the SMART-MR study , 1.5 T MRI of the brain and neuropsychological examinations were performed at baseline ( n = 1232 ) and after 3.9 ± 0.4 years follow-up ( n = 663 ) . Automatic brain segmentation was used to quantify intracranial ( ICV ) , total brain , ventricular , and white matter lesion ( WML ) volumes . Brain infa rcts were rated visually . Level of physical activity was expressed in metabolic equivalents ( MET ) hours p/week . With linear regression analysis we examined associations of level of physical activity with brain MRI measures and with cognitive performance , adjusted for potential confounders . For the association with brain infa rcts relative risks ( RR ) were calculated with Poisson regression . RESULTS At baseline , an increase in physical activity of one SD ( 39.7 METh/w ) was significantly associated with larger total brain volume ( B = 0.20 % of ICV ; 95 % CI 0.06 ; 0.33 % ) . A trend was found for the association of physical activity with smaller ventricular volume ( B = -0.04 % of ICV ; 95 % CI -0.09 ; 0.02 % ) and with a decreased risk for brain infa rcts ( RR = 0.91 , 95 % CI : 0.82 - 1.02 ) . No association was found with smaller WML volume ( B = -0.02 % of ICV ; 95 % CI -0.07 ; 0.04 % ) . No associations with change in brain structures over time were observed . Also , no associations between physical activity and cognitive performance or cognitive decline were found . CONCLUSION These data suggest that leisure time physical activity does not have a significant contribution in preventing or slowing down brain abnormalities and cognitive decline in this cohort of middle-aged individuals already burdened with vascular disease |
13,611 | 31,146,698 | Safety outcomes with DTG were generally similar to other core agents .
Conclusion INSTI core agents had superior efficacy and similar safety to PIs and NNRTIs at Week 48 in treatment-naïve patients with HIV-1 , with DTG being among the most efficacious , including in patients with baseline VL > 100,000copies/mL or ≤ 200 CD4+cells/μL , who can be difficult to treat | Background Network meta-analyses ( NMAs ) provide comparative treatment effects estimates in the absence of head-to-head r and omized controlled trials ( RCTs ) .
This NMA compared the efficacy and safety of dolutegravir ( DTG ) with other recommended or commonly used core antiretroviral agents . | BACKGROUND We report data from NEWART , a r and omised phase 4 clinical trial comparing virologic efficacy and safety of nevirapine ( NVP ) vs. ritonavir-boosted atazanavir ( ATV/r ) on a background of tenofovir/emtricitabine ( TDF/FTC ) in HIV-1-infected treatment-naïve patients . This study enrolled patients according to CD4-based initiation criteria for NVP ( < 250 cells/mm(3 ) for women and < 400 cells/mm(3 ) for men ) , to reduce the likelihood of symptomatic hepatic events . NEWART was design ed to support and confirm results from ARTEN , an international trial with similar design and study endpoints . METHODS A total of 152 patients were r and omised 1 : 1 to open-label NVP 200 mg twice daily or ATV/r ( 300/100 mg ) once daily , plus once daily TDF/FTC ( 300/200 mg ) . All participants met CD4(+ ) guidelines at entry . The primary endpoint for non-inferiority was virologic response prior to and at week 48 ( confirmed HIV plasma viral load < 50 copies/ml , without rebound or change in ARVs ) . Safety data , including plasma lipids , were recorded throughout the study . RESULTS The primary endpoint was achieved in 46/75 ( 61.3 % ) and 50/77 ( 64.9 % ) of patients taking NVP and ATV/r , respectively . Frequency of adverse events ( AEs ) was similar between arms , with 88.0 % of NVP-treated patients and 94.8 % of ATV/r-treated patients experiencing at least one AE . Nine patients ( 12 % ) in each arm experienced an AE that led to discontinuation . At week 48 , a significantly greater increase was seen in mean plasma HDL cholesterol ( HDL-C ) in the NVP arm ( 9.6 mg/dl ) vs. the ATV/r arm ( 3.5 mg/dl ) ; p = 0.016 . Also , total cholesterol (TC):HDL-C ratio on-treatment was -0.38 and -0.02 for the NVP and ATV/r arms , respectively ( p = 0.038 ) . CONCLUSIONS Efficacy results were consistent with the ARTEN study demonstrating that NVP was non-inferior to ATV/r when taken in combination with TDF/FTC . Rates of AEs were similar between the two arms , whereas HDL-C increased and TC : HDL-C decreased significantly more in patients taking NVP than ATV/r Introduction : Direct comparison of the efficacy and safety of different agents is needed to guide selection of optimal treatment regimens for therapy-naive HIV-1-infected patients . Methods : Gemini was a 48-week , multicenter , open-label , noninferiority trial in treatment-naive HIV-1-infected adults r and omized to either saquinavir/ritonavir ( SQV/r ) 1000 mg/100 mg twice a day or lopinavir/ritonavir ( LPV/r ) 400 mg/100 mg twice a day , each with emtricitabine/tenofovir 200 mg/300 mg every day . Results : A similar proportion of participants in the SQV/r ( n = 167 ) and LPV/r ( n = 170 ) arms had HIV-1 RNA levels < 50 copies per milliliter at week 48 : 64.7 % vs 63.5 % and estimated difference in proportion for noninferiority : 1.14 % , 96 % confidence interval : −9.6 to11.9 ( P < 0.012 ) , confirming that SQV/r was noninferior to LPV/r treatment . There were no significant differences in week 48 CD4 counts between arms . The rate and severity of adverse events were similar in both groups . There were no significant differences in the median change from baseline between arms in plasma lipids except for triglyceride levels , which were significantly higher in the LPV/r at week 48 . Conclusions : In treatment-naive , HIV-1-infected patients , SQV/r treatment was noninferior in virologic suppression at 48 weeks to LPV/r treatment and offered a better triglyceride profile In a r and omized control trial , Shahin Lockman and colleagues compare nevirapine-based therapy with lopinavir/ritonavir-based therapy for HIV-infected women without previous exposure to antiretroviral treatment Background Rates of cardiovascular disease are higher among HIV-infected patients as a result of the complex interplay between traditional risk factors , HIV-related inflammatory and immunologic changes , and effects of antiretroviral therapy ( ART ) . This study prospect ively evaluated changes in cardiovascular biomarkers in an underrepresented , racially diverse , HIV-1-infected population receiving abacavir/lamivudine as backbone therapy . Methods This 96-week , open-label , r and omized , multicenter study compared once-daily fosamprenavir/ritonavir 1400/100 mg and efavirenz 600 mg , both with ABC/3TC 600 mg/300 mg , in antiretroviral-naïve , HLA-B*5701-negative adults without major resistance mutations to study drugs . We evaluated changes from baseline to weeks 4 , 12 , 24 , 48 , and 96 in interleukin-6 ( IL-6 ) , high-sensitivity C-reactive protein ( hs-CRP ) , soluble vascular adhesion molecule-1 ( sVCAM-1 ) , d-dimer , plasminogen , and fibrinogen . Biomarker data were log-transformed before analysis , and changes from baseline were described using geometric mean ratios . Results This study enrolled 101 patients ( 51 receiving fosamprenavir/ritonavir ; 50 receiving efavirenz ) : 32 % female , 60 % African American , and 38 % Hispanic/Latino ; 66 % ( 67/101 ) completed 96 weeks on study . At week 96 , levels of IL-6 , sVCAM-1 , d-dimer , fibrinogen , and plasminogen were lower than baseline in both treatment groups , and the decrease was statistically significant for sVCAM-1 ( fosamprenavir/ritonavir and efavirenz ) , d-dimer ( fosamprenavir/ritonavir and efavirenz ) , fibrinogen ( efavirenz ) , and plasminogen ( efavirenz ) . Values of hs-CRP varied over time in both groups , with a significant increase over baseline at Weeks 4 and 24 in the efavirenz group . At week 96 , there was no difference between the groups in the percentage of patients with HIV-1 RNA < 50 copies/mL ( fosamprenavir/ritonavir 63 % ; efavirenz 66 % ) by ITT missing-equals-failure analysis . Treatment-related grade 2–4 adverse events were more common with efavirenz ( 32 % ) compared with fosamprenavir/ritonavir ( 20 % ) , and median lipid concentrations increased in both groups over 96 weeks of treatment . Conclusions In this study of underrepresented patients , treatment with abacavir/lamivudine combined with either fosamprenavir/ritonavir or efavirenz over 96 weeks , produced stable or declining biomarker levels except for hs-CRP , including significant and favorable decreases in thrombotic activity ( reflected by d-dimer ) and endothelial activation ( reflected by sVCAM-1 ) . Our study adds to the emerging data that some cardiovascular biomarkers are decreased with initiation of ART and control of HIV viremia . Trial registration Clinical Trials.gov identifier Thomas Campbell and colleagues report findings of a r and omized trial conducted in multiple countries regarding the efficacy of antiretroviral regimens with simplified dosing Objective : To compare the safety and efficacy of two once-daily antiretroviral regimens containing lamivudine ( 3TC ) or tenofovir disoproxil fumarate ( TDF ) , each administered with didanosine ( ddI ) and efavirenz ( EFV ) as initial therapy to HIV-1-infected subjects . Methods : Single centre , r and omized ( 1 : 1 ) , open-label study in antiretroviral-naive , HIV-infected adults . Subjects commenced either 3TC/ddI/EFV ( 3TC group ) or TDF/ddI/EFV ( TDF group ) . Safety , Medication Event Monitoring System ( MEMScap ) and plasma EFV concentration monitoring was performed over the study period . Comparisons between groups were assessed using χ2 test and linear regression analysis was used to assess the relationship between EFV concentrations and virological response . Results : Seventy-seven subjects were enrolled prior to recruitment being suspended , 36 to the 3TC group and 41 to the TDF group . Intention-to-treat analysis in which last observation carried forward ( LOCF ) found the mean viral log10 load [ 95 % confidence interval ( CI ) ] at weeks 4 and 12 to be 2.67 ( 2.47–2.87 ) and 1.83 ( 1.74–1.92 ) for the 3TC group and 2.75 ( 2.45–3.05 ) and 2.28 ( 1.96–2.6 ) for the TDF group ( P = 0.013 ) . Emergence of resistance occurred in five of 41 ( 12.2 % ) subjects in the TDF group up to week 12 compared with none of 36 in the 3TC group , ( P < 0.05 ) ; these five subjects shared similar baseline characteristics ( CD4 + cell counts < 200 × 106 cells/l and HIV-1 RNA > 100 000 copies/ml ) . Despite MEMScap monitoring showing > 99 % adherence in all subjects , among the five failures , three had low EFV concentrations . Conclusion : TDF/ddI/EFV as initial therapy appears to have diminished efficacy in subjects with CD4 < 200 × 106 cells/l and viral load > 100 000 copies/ml . Treatment failure with resistance was not attributable to baseline resistance , efavirenz exposure or poor adherence OBJECTIVE To compare the efficacy and safety of fixed-dose abacavir/lamivudine ( ABC/3TC ) and tenofovir/emtricitabine ( TDF/FTC ) with ritonavir-boosted atazanavir ( ATV/r ) in treatment-naïve Japanese patients with HIV-1 infection . METHODS A 96-week multicenter , r and omized , open-label , parallel group pilot study was conducted . The endpoints were times to virologic failure , safety event and regimen modification . RESULTS 109 patients were enrolled and r and omly allocated ( 54 patients received ABC/3TC and 55 patients received TDF/FTC ) . All r and omized subjects were analyzed . The time to virologic failure was not significantly different between the two arms by 96 weeks ( HR , 2.09 ; 95 % CI , 0.72 - 6.13 ; p=0.178 ) . Both regimens showed favorable viral efficacy , as in the intention-to-treat population , 72.2 % ( ABC/3TC ) and 78.2 % ( TDF/FTC ) of the patients had an HIV-1 viral load < 50 copies/mL at 96 weeks . The time to the first grade 3 or 4 adverse event and the time to the first regimen modification were not significantly different between the two arms ( adverse event : HR 0.66 ; 95 % CI , 0.25 - 1.75 , p=0.407 ) ( regimen modification : HR 1.03 ; 95 % CI , 0.33 - 3.19 , p=0.964 ) . Both regimens were also well-tolerated , as only 11.1 % ( ABC/3TC ) and 10.9 % ( TDF/FTC ) of the patients discontinued the allocated regimen by 96 weeks . Clinical ly suspected abacavir-associated hypersensitivity reactions occurred in only one ( 1.9 % ) patient in the ABC/3TC arm . CONCLUSION Although insufficiently powered to show non-inferiority of viral efficacy of ABC/3TC relative to TDF/FTC , this pilot trial suggested that ABC/3TC with ATV/r is a safe and efficacious initial regimen for HLA-B*5701-negative patients , such as the Japanese population BACKGROUND Efavirenz with tenofovir-disoproxil-fumarate and emtricitabine is a preferred antiretroviral regimen for treatment-naive patients infected with HIV-1 . Rilpivirine , a new non-nucleoside reverse transcriptase inhibitor , has shown similar antiviral efficacy to efavirenz in a phase 2b trial with two nucleoside/nucleotide reverse transcriptase inhibitors . We aim ed to assess the efficacy , safety , and tolerability of rilpivirine versus efavirenz , each combined with tenofovir-disoproxil-fumarate and emtricitabine . METHODS We did a phase 3 , r and omised , double-blind , double-dummy , active-controlled trial , in patients infected with HIV-1 who were treatment-naive . The patients were aged 18 years or older with a plasma viral load at screening of 5000 copies per mL or greater , and viral sensitivity to all study drugs . Our trial was done at 112 sites across 21 countries . Patients were r and omly assigned by a computer-generated interactive web response system to receive either once-daily 25 mg rilpivirine or once-daily 600 mg efavirenz , each with tenofovir-disoproxil-fumarate and emtricitabine . Our primary objective was to show non-inferiority ( 12 % margin ) of rilpivirine to efavirenz in terms of the percentage of patients with confirmed response ( viral load < 50 copies per mL intention-to-treat time-to-loss-of-virological-response [ ITT-TLOVR ] algorithm ) at week 48 . Our primary analysis was by intention-to-treat . We also used logistic regression to adjust for baseline viral load . This trial is registered with Clinical Trials.gov , number NCT00540449 . FINDINGS 346 patients were r and omly assigned to receive rilpivirine and 344 to receive efavirenz and received at least one dose of study drug , with 287 ( 83 % ) and 285 ( 83 % ) in the respective groups having a confirmed response at week 48 . The point estimate from a logistic regression model for the percentage difference in response was -0.4 ( 95 % CI -5.9 to 5.2 ) , confirming non-inferiority with a 12 % margin ( primary endpoint ) . The incidence of virological failures was 13 % ( rilpivirine ) versus 6 % ( efavirenz ; 11%vs 4 % by ITT-TLOVR ) . Grade 2 - 4 adverse events ( 55 [ 16 % ] on rilpivirine vs 108 [ 31 % ] on efavirenz , p<0.0001 ) , discontinuations due to adverse events ( eight [ 2 % ] on rilpivirine vs 27 [ 8 % ] on efavirenz ) , rash , dizziness , and abnormal dreams or nightmares were more common with efavirenz . Increases in plasma lipids were significantly lower with rilpivirine . INTERPRETATION Rilpivirine showed non-inferior efficacy compared with efavirenz , with a higher virological-failure rate , but a more favourable safety and tolerability profile . FUNDING Tibotec BACKGROUND The primary analysis of the FLAMINGO study at 48 weeks showed that patients taking dolutegravir once daily had a significantly higher virological response rate than did those taking ritonavir-boosted darunavir once daily , with similar tolerability . We present secondary efficacy and safety results analysed at 96 weeks . METHODS FLAMINGO was a multicentre , open-label , phase 3b , non-inferiority study of HIV-1-infected treatment-naive adults . Patients were r and omly assigned ( 1:1 ) to dolutegravir 50 mg or darunavir 800 mg plus ritonavir 100 mg , with investigator-selected combination tenofovir and emtricitabine or combination abacavir and lamivudine background treatment . The main endpoints were plasma HIV-1 RNA less than 50 copies per mL and safety . The non-inferiority margin was -12 % . If the lower end of the 95 % CI was greater than 0 % , then we concluded that dolutegravir was superior to ritonavir-boosted darunavir . This trial is registered with Clinical Trials.gov , number NCT01449929 . FINDINGS Of 595 patients screened , 488 were r and omly assigned and 484 included in the analysis ( 242 assigned to receive dolutegravir and 242 assigned to receive ritonavir-boosted darunavir ) . At 96 weeks , 194 ( 80 % ) of 242 patients in the dolutegravir group and 164 ( 68 % ) of 242 in the ritonavir-boosted darunavir group had HIV-1 RNA less than 50 copies per mL ( adjusted difference 12·4 , 95 % CI 4·7 - 20·2 ; p=0·002 ) , with the greatest difference in patients with high viral load at baseline ( 50/61 [ 82 % ] vs 32/61 [ 52 % ] , homogeneity test p=0·014 ) . Six participants ( three since 48 weeks ) in the dolutegravir group and 13 ( four ) in the darunavir plus ritonavir group discontinued because of adverse events . The most common drug-related adverse events were diarrhoea ( 23/242 [ 10 % ] in the dolutegravir group vs 57/242 [ 24 % ] in the darunavir plus ritonavir group ) , nausea ( 31/242 [ 13 % ] vs 34/242 [ 14 % ] ) , and headache ( 17/242 [ 7 % ] vs 12/242 [ 5 % ] ) . INTERPRETATION Once-daily dolutegravir is associated with a higher virological response rate than is once-daily ritonavir-boosted darunavir . Dolutegravir compares favourably in efficacy and safety to a boosted darunavir regimen with nucleoside reverse transcriptase inhibitor background treatment for HIV-1-infected treatment-naive patients . FUNDING ViiV Healthcare and Shionogi & BACKGROUND The HIV integrase str and transfer inhibitor elvitegravir ( EVG ) has been co-formulated with the CYP3A4 inhibitor cobicistat ( COBI ) , emtricitabine ( FTC ) , and tenofovir disoproxil fumarate ( TDF ) into a once-daily , single tablet . We compared EVG/COBI/FTC/TDF with a ritonavir-boosted ( RTV ) protease inhibitor regimen of atazanavir (ATV)/RTV+FTC/TDF as initial therapy for HIV-1 infection . METHODS This phase 3 , non-inferiority study enrolled treatment-naive patients with an HIV-1 RNA concentration of 5000 copies per mL or more and susceptibility to atazanavir , emtricitabine , and tenofovir . Patients were r and omly assigned ( 1:1 ) to receive EVG/COBI/FTC/TDF or ATV/RTV+FTC/TDF plus matching placebos , administered once daily . R and omisation was by a computer-generated r and om sequence , accessed via an interactive telephone and web response system . Patients , and investigators and study staff who gave treatments , assessed outcomes , or analysed data were masked to the assignment . The primary endpoint was HIV RNA concentration of 50 copies per mL or less after 48 weeks ( according to the US FDA snapshot algorithm ) , with a 12 % non-inferiority margin . This trial is registered with Clinical Trials.gov , number NCT01106586 . FINDINGS 1017 patients were screened , 715 were enrolled , and 708 were treated ( 353 with EVG/COBI/FTC/TDF and 355 with ATV/RTV+FTC/TDF ) . EVG/COBI/FTC/TDF was non-inferior to ATV/RTV+FTC/TDF for the primary outcome ( 316 patients [ 89·5 % ] vs 308 patients [ 86·8 % ] , adjusted difference 3·0 % , 95 % CI -1·9 % to 7·8 % ) . Both regimens had favourable safety and tolerability ; 13 ( 3·7 % ) versus 18 ( 5·1 % ) patients discontinued treatment because of adverse events . Fewer patients receiving EVG/COBI/FTC/TDF had abnormal results in liver function tests than did those receiving ATV/RTV+FTC/TDF and had smaller median increases in fasting triglyceride concentration ( 90 μmol/L vs 260 μmol/L , p=0·006 ) . Small median increases in serum creatinine concentration with accompanying decreases in estimated glomerular filtration rate occurred in both study groups by week 2 ; they generally stabilised by week 8 and did not change up to week 48 ( median change 11 μmol/L vs 7 μmol/L ) . INTERPRETATION If regulatory approval is given , EVG/COBI/FTC/TDF would be the first integrase-inhibitor-based regimen given once daily and the only one formulated as a single tablet for initial HIV treatment . FUNDING Gilead Sciences Objective : To compare WHO first-line antiretroviral therapy ( ART ) with nonnucleoside reverse transcriptase inhibitors (NNRTI)-based regimen with a boosted protease inhibitor ( bPI ) regimen in a re source -limited setting regarding treatment outcome and emergence of drug resistance mutations ( DRMs ) . Methods : Treatment-naive adults were r and omized to nevirapine ( NVP ) or ritonavir-boosted lopinavir ( LPV/r ) regimens each in combination with tenofovir (TDF)/emtricitabine ( FTC ) or zidovudine (ZDV)/lamivudine ( 3TC ) . Primary endpoint was the incidence of therapeutical ( clinical and /or virologic ) failure at week 48 with follow-up till week 96 . Results : Four hundred and twenty-five patients ( 120 men ; 305 women ) received at least one dose of the study drug . mITT analysis showed no difference in proportion of therapeutical failure between treatment arms [ 67/209 ( 32 % ) in NVP vs. 63/216 ( 29 % ) LPV/r at week 48 ( P = 0.53 ) ; 88/209 ( 42 % ) in NVP vs. 83/216 ( 38 % ) in LPV/r at week 96 ( P = 0.49 ) ] . Per- protocol analysis demonstrated significantly more virologic failure with NVP than with LPV/r regimens [ at week 48 : 19/167 ( 11 % ) vs. 7/166 ( 4 % ) , P = 0.014 ; at week 96 : 27/158 ( 17 % ) vs. 13/159 ( 8 % ) , P = 0.019 ) ] . Drug resistance mutations to NNRTI were detected in 19 out of 22 ( 86.3 % ) and dual-class resistance to nucleoside reverse transcriptase inhibitor ( NRTI ) and NNRTI in 15 out of 27 ( 68.2 % ) of NVP failing patients . K65R mutation was present in seven out of 14 patients failing NVP-TDF/FTC regimen . No major protease inhibitor-DRM was detected among LPV/r failing patients . Discontinuation for adverse events was similar between treatment groups . Conclusion : In re source -limited setting s , first-line NNRTI-NRTI regimen as compared with bPI-based regimen provides similar outcome but is associated with a significantly higher number of virologic failure and resistance mutations in both classes that jeopardize future options for second-line therapy Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed OBJECTIVE To study and compare the pattern of lipid profile changes in Thai HIV and tuberculosis ( TB ) co-infected patients after receiving two non-nucleoside reverse transcriptase inhibitors (NNRTIs)-based antiretroviral therapy ( ART ) . MATERIAL AND METHOD From an open label , r and omized , comparative trial comparing treatment outcome between HIV and TB co-infected patients receiving nevirapine ( NVP ) or efavirenz ( EFV ) combined with stavudine and lamivudine , patient 's body mass index ( BMI ) , CD4 cell count , plasma HIV-1 RNA , fasting blood glucose , plasma total cholesterol ( TC ) , low density lipoprotein cholesterol ( LDL-C ) , high density lipoprotein cholesterol ( HDL-C ) , and triglyceride ( TG ) were collected at baseline , 24 , and 48 weeks of ART . RESULTS Of the 121 patients included in the present study , mean ( SD ) age was 36.9 ( 8.4 ) years and 66 % were male . After 48 weeks of ART the median ( IQR ) percentage of TC , LDL-C , HDL-C and TG values were 21.1 % ( 5.4 - 40.7 ) , 23.5 % ( -0.8 - 49.8 ) , 22.7 % ( 0 - 50 ) and -1.0 % ( -34.6 - 32.2 ) respectively . The median ( IQR ) percentage change of the HDL-C value was significantly higher in NVP-based than EFV-based ART ( 31.9 [ 9.6 - 50.0 ] vs. 12.2 [ -8.8 - 51.2 ] ; p = 0.03 ) . The proportions of patients with high TC ( 21.5 % ) and high LDL-C ( 29.2 % ) increased and low HDL-C ( 11.6 % ) decreased significantly at 48 weeks of ART compared to baseline ( all , p < 0.01 ) . The proportions of patients with high TC , high TG and low HDL-C were significantly higher in the EFV group than in the NVP group ( p = 0.03 for high TC , p = .01 for high TG and p < 0.01 for low HDL-C ) . CONCLUSION NNRTI-based ART is associated with increases of TC , LDL-C and HDL-C values in Thai HIV and TB co-infected patients . More favorable lipid profile is observed in NVP-based than EFV-based ART Objectives To describe the patterns and correlates of discontinuation of the initial highly active antiretroviral therapy ( HAART ) regimen in an urban , outpatient cohort of antiretroviral-naive patients . Design Retrospective cohort of 345 r and omly selected antiretroviral-naive patients who initiated HAART on 6 selected regimens between January 1997 and May 2001 in New Orleans , LA . Methods An investigator review ed medical records to collect information on concurrent medications , symptoms/diagnoses , staging indicators , and reasons for HAART discontinuation . Proportional hazards regression methods were used to identify predictors of discontinuation . Results After a median follow-up of 8.1 months , 61 % of patients changed or discontinued their initial HAART regimen ; 24 % did so because of an adverse event . The events most commonly cited as the cause for discontinuation were nausea , vomiting , and diarrhea . A detectable viral load was associated with discontinuation at any time , while reporting nausea/vomiting or dizziness at the previous visit were associated with discontinuation during the first 3 months on HAART . Nausea/vomiting and not having AIDS at the time of HAART initiation were associated with discontinuation due to an adverse event at any time , while a high viral load , and dizziness or anorexia/weight loss at the previous visit were associated with discontinuation due to an adverse event in the first 3 months on HAART . Conclusions Gastrointestinal adverse events of HAART are the most frequently cited reason for discontinuation of HAART . An effort should be made to educate patients about these events and to encourage continued adherence . Additionally , appropriate prophylaxes for these events are warranted Background Once-daily ( QD ) ritonavir 100 mg-boosted fosamprenavir 1400 mg ( FPV/r100 ) or atazanavir 300 mg ( ATV/r100 ) , plus tenofovir/emtricitabine ( TDF/FTC ) 300 mg/200 mg , have not been compared as initial antiretroviral treatment . To address this data gap , we conducted an open-label , multicenter 48-week study ( ALERT ) in 106 antiretroviral-naïve , HIV-infected patients ( median HIV-1 RNA 4.9 log10 copies/mL ; CD4 + count 191 cells/mm3 ) r and omly assigned to the FPV/r100 or ATV/r100 regimens . Results At baseline , the FPV/r100 or ATV/r100 arms were well-matched for HIV-1 RNA ( median , 4.9 log10 copies/mL [ both ] ) , CD4 + count ( mean , 176 vs 205 cells/mm3 ) . At week 48 , intent-to-treat : missing/discontinuation = failure analysis showed similar responses to FPV/r100 and ATV/r100 ( HIV-1 RNA < 50 copies/mL : 75 % ( 40/53 ) vs 83 % ( 44/53 ) , p = 0.34 [ Cochran-Mantel-Haenszel test ] ) ; mean CD4 + count change-from-baseline : + 170 vs + 183 cells/mm3 , p = 0.398 [ Wilcoxon rank sum test ] ) . Fasting total/LDL/HDL-cholesterol changes-from-baseline were also similar , although week 48 median fasting triglycerides were higher with FPV/r100 ( 150 vs 131 mg/dL ) . FPV/r100-treated patients experienced fewer treatment-related grade 2–4 adverse events ( 15 % vs 57 % ) , with differences driven by ATV-related hyperbilirubinemia . Three patients discontinued TDF/FTC because their GFR decreased to < 50 mL/min . Conclusion The all-QD regimens of FPV/r100 and ATV/r100 , plus TDF/FTC , provided similar virologic , CD4 + response , and fasting total/LDL/HDL-cholesterol changes through 48 weeks . Fewer FPV/r100-treated patients experienced treatment-related grade 2–4 adverse events Objective : To compare the efficacy of efavirenz ( EFV ) vs lopinavir/ritonavir ( LPV/r ) in combination with azidothymidine/lamivudine in antiretroviral therapy naive , HIV+ individuals presenting for care with CD4 + counts < 200/mm3 . Methods : Prospect i ve , r and omized , open label , multicenter trial in Mexico . HIV-infected subjects with CD4 < 200/mm3 were r and omized to receive open label EFV or LPV/r plus azidothymidine/lamivudine ( fixed-dose combination ) for 48 weeks . R and omization was stratified by baseline CD4 + cell count ( ≤100 or > 100/mm3 ) . The primary endpoint was the percentage of patients with plasma HIV-1 RNA < 50 copies/mL at 48 weeks by intention-to-treat analysis . Results : A total of 189 patients ( 85 % men ) were r and omized to receive EFV ( 95 ) or LPV/r ( 94 ) . Median baseline CD4 + were 64 and 52/mm3 , respectively ( P = not significant ) . At week 48 , by intention-to-treat analysis , 70 % of EFV and 53 % of LPV/r patients achieved HIV-1 RNA < 50 copies/mL [ estimated difference 17 % ( 95 % confidence interval 3.5 to 31 ) , P = 0.013 ] . The proportion with HIV-1 RNA < 400 copies/mL was 73 % with EFV and 65 % with LPV/r ( P = 0.25 ) . Virologic failure occurred in 7 patients on EFV and 17 on LPV/r . Mean CD4 + count increases ( cells/mm3 ) were 234 for EFV and 239 for LPV/r . Mean change in total cholesterol and triglyceride levels were 50 and 48 mg/dL in EFV and 63 and 116 mg/dL in LPV/r ( P = 0.24 and P < 0.01 ) . Conclusions : In these very advanced HIV-infected ARV-naive subjects , EFV-based highly active antiretroviral therapy had superior virologic efficacy than LPV/r-based highly active antiretroviral therapy , with a more favorable lipid profile BACKGROUND Dolutegravir is a once-daily integrase str and transfer inhibitor with no need for pharmacokinetic boosting that is approved for the treatment of HIV-1 infection . Because women are often under-represented in HIV clinical trials , we addressed the safety and efficacy of dolutegravir in women with HIV-1 . METHODS The ARIA study is a r and omised , open-label , multicentre , active-controlled , parallel-group , non-inferiority phase 3b study done in 86 hospital and university infectious disease clinics , local health clinics , and private infectious disease clinics in 12 countries and one US territory , in North America , South America , Europe , Africa , and Asia . Eligible participants were women aged 18 years or older who had HIV-1 RNA viral loads of 500 copies per mL or greater , had received 10 days or less of previous antiretroviral therapy , and had tested negative for the HLA-B*5701 allele . Pregnant women were excluded . Eligible women were r and omly assigned ( 1:1 ) to receive either a single-tablet regimen of dolutegravir plus abacavir and lamivudine once a day ( dolutegravir group ) or a three-tablet combination of ritonavir-boosted atazanavir plus coformulated tenofovir disoproxil fumarate and emtricitabine once a day ( atazanavir group ) . R and om treatment group assignment was stratified by plasma HIV-1 RNA viral loads and CD4 cell count at baseline . The primary endpoint was the proportion of participants with HIV-1 RNA viral loads of less than 50 copies per mL at week 48 in all participants who received at least one dose of study medication ( intention-to-treat exposed population ) . We used a non-inferiority margin of -12 % . Investigators monitored adverse events to assess safety . This study is registered with Clinical Trials.gov , number NCT01910402 . FINDINGS Between Aug 22 , 2013 , and Sept 22 , 2015 , of 705 women assessed , 499 were r and omly assigned to either the dolutegravir group ( n=250 ) or the atazanavir group ( n=249 ) ; two participants from each group were r and omised to treatment but did not receive study medication . At week 48 , 203 ( 82 % ) of 248 participants in the dolutegravir group compared with 176 ( 71 % ) of 247 in the atazanavir group had HIV-1 RNA viral loads of less than 50 copies per mL ( mean difference 10·5 % , 95 % CI 3·1 - 17·8 , p=0·005 ) . One participant in the atazanavir group had nucleoside reverse transcriptase inhibitor-associated resistance that led to reduced emtricitabine susceptibility . Adverse events were similar between the dolutegravir and atazanavir groups ; the most common were nausea ( 46 [ 19 % ] of 248 in the dolutegravir group vs 49 [ 20 % ] of 247 in the atazanavir group ) and headache ( 28 [ 11 % ] vs 32 [ 13 % ] ) . Fewer participants in the dolutegravir group than the atazanavir group reported drug-related adverse events ( 83 [ 33 % ] vs 121 [ 49 % ] ) or adverse events that led to discontinuation ( ten [ 4 % ] vs 17 [ 7 % ] ) . One death was reported in each treatment group , but neither was considered related to the study medications . INTERPRETATION The non-inferior efficacy and similar safety profile of the dolutegravir combined regimen compared with the atazanavir regimen support the use of dolutegravir for HIV-1 infection in treatment-naive women . FUNDING ViiV Healthcare Background : National initiatives offering non-nucleoside reverse transcriptase inhibitor (NNRTI)-based combination antiretroviral therapy ( cART ) have exp and ed in sub-Saharan Africa . The Tshepo study is the first clinical trial evaluating the long-term efficacy and tolerability of efavirenz versus nevirapine-based cART among adults in Botswana . Methods : A 3-year r and omized study ( n = 650 ) using a 3 × 2 × 2 factorial design comparing efficacy and tolerability among : ( i ) zidovudine/lamivudine versus zidovudine/didanosine versus stavudine/lamivudine ; ( ii ) efavirenz versus nevirapine ; and ( iii ) community-based supervision versus st and ard adherence strategies . This paper focuses on comparison ( ii ) . Results : There was no significant difference by assigned NNRTI in time to virological failure with resistance ( log-rank P = 0.14 ) , nevirapine versus efavirenz [ risk ratio ( RR ) 1.54 , 95 % CI 0.86–2.70 ] . Rates of virological failure with resistance were 9.6 % nevirapine-treated ( 95 % CI 6.8–13.5 ) versus 6.6 % efavirenz-treated ( 95 % CI 4.2–10.0 ) at 3 years . Women receiving nevirapine-based cART trended towards higher virological failure rates when compared with efavirenz-treated women , Holm-corrected ( log-rank P = 0.072 ) , nevirapine versus efavirenz ( RR 2.22 , 95 % CI 0.94–5.00 ) . A total of 139 patients had 176 treatment-modifying toxicities , with a shorter time to event in nevirapine-treated versus efavirenz-treated patients ( RR 1.85 , 1.20–2.86 ; log-rank P = 0.0002 ) . Conclusion : Tshepo-treated patients had excellent overall immunological and virological outcomes , and no significant differences were observed by r and omized NNRTI comparison . Nevirapine-treated women trended towards higher virological failure with resistance compared with efavirenz-treated women . Nevirapine-treated adults had higher treatment modifying toxicity rates when compared with those receiving efavirenz . Nevirapine-based cART can continue to be offered to women in sub-Saharan Africa if patient education concerning toxicity is emphasized , routine safety monitoring chemistries are performed and the potential risk of efavirenz-related teratogenicity is considered BACKGROUND In countries with a high incidence of HIV and tuberculosis co-infection , nevirapine and efavirenz are widely used as antiretroviral therapy but both interact with antituberculosis drugs . We aim ed to compare efficacy and safety of a nevirapine-based antiretroviral therapy ( started at full dose ) with an efavirenz-based regimen in co-infected patients . METHODS We did a multicentre , open-label , r and omised , non-inferiority trial at three health centres in Maputo , Mozambique . We enrolled adults ( ≥18 years ) with tuberculosis and previously untreated HIV infection ( CD4 cell counts < 250 cells per μL ) and alanine aminotransferase and total bilirubin concentrations of less than five times the upper limit of normal . 4 - 6 weeks after the start of tuberculosis treatment , we r and omly allocated patients ( 1:1 ) with central r and omisation , block sizes of two to six , and stratified by site and CD4 cell count to nevirapine ( 200 mg twice daily ) or efavirenz ( 600 mg once daily ) , plus lamivudine and stavudine . The primary endpoint was virological suppression at 48 weeks ( HIV-1 RNA < 50 copies per mL ) in all patients who received at least one dose of study drug ( intention-to-treat population ) ; death and loss to follow-up were recorded as treatment failure . The non-inferiority margin for the difference of efficacy was 10 % . We assessed efficacy in intention-to-treat and per- protocol population s and safety in all patients who received study drug . This study is registered with Clinical Trials.gov , number NCT00495326 . FINDINGS Between October , 2007 , and March , 2010 , we enrolled 285 patients into each group . 242 ( 85 % ) patients in the nevirapine group and 233 ( 82 % ) patients in the efavirenz group completed follow-up . In the intention-to-treat population , 184 patients ( 64·6 % , 95 % CI 58·7 - 70·1 ) allocated nevirapine achieved virological suppression at week 48 , as did 199 patients ( 69·8 % , 64·1 - 75·1 ) allocated efavirenz ( one-sided 95 % CI of the difference of efficacy 11·7 % ) . In the per- protocol population , 170 ( 70·0 % , 63·8 - 75·7 ) of 243 patients allocated nevirapine achieved virological suppression at week 48 , as did 194 ( 78·9 % , 73·2 - 83·8 ) of 246 patients allocated efavirenz ( one-sided 95 % CI 15·4 % ) . The median CD4 cell count at r and omisation was 89 cells per μL. 15 patients substituted nevirapine with efavirenz and six patients substituted efavirenz with nevirapine . 20 patients allocated nevirapine ( 7 % ) had grade 3 - 4 increase of alanine aminotransferase compared with 17 patients allocated efavirenz ( 6 % ) . Three patients had severe rash after receipt of nevirapine ( 1 % ) but no patients did after receipt of efavirenz . 18 patients in the nevirapine group died , as did 17 patients in the efavirenz group . INTERPRETATION Although non-inferiority of the nevirapine-regimen was not shown , nevirapine at full dose could be a safe , acceptable alternative for patients unable to tolerate efavirenz . FUNDING French Research Agency for HIV/AIDS and hepatitis ( ANRS ) BACKGROUND The use of either efavirenz or lopinavir-ritonavir plus two nucleoside reverse-transcriptase inhibitors ( NRTIs ) is recommended for initial therapy for patients with human immunodeficiency virus type 1 ( HIV-1 ) infection , but which of the two regimens has greater efficacy is not known . The alternative regimen of lopinavir-ritonavir plus efavirenz may prevent toxic effects associated with NRTIs . METHODS In an open-label study , we compared three regimens for initial therapy : efavirenz plus two NRTIs ( efavirenz group ) , lopinavir-ritonavir plus two NRTIs ( lopinavir-ritonavir group ) , and lopinavir-ritonavir plus efavirenz ( NRTI-sparing group ) . We r and omly assigned 757 patients with a median CD4 count of 191 cells per cubic millimeter and a median HIV-1 RNA level of 4.8 log10 copies per milliliter to the three groups . RESULTS At a median follow-up of 112 weeks , the time to virologic failure was longer in the efavirenz group than in the lopinavir-ritonavir group ( P=0.006 ) but was not significantly different in the NRTI-sparing group from the time in either of the other two groups . At week 96 , the proportion of patients with fewer than 50 copies of plasma HIV-1 RNA per milliliter was 89 % in the efavirenz group , 77 % in the lopinavir-ritonavir group , and 83 % in the NRTI-sparing group ( P=0.003 for the comparison between the efavirenz group and the lopinavir-ritonavir group ) . The groups did not differ significantly in the time to discontinuation because of toxic effects . At virologic failure , antiretroviral resistance mutations were more frequent in the NRTI-sparing group than in the other two groups . CONCLUSIONS Virologic failure was less likely in the efavirenz group than in the lopinavir-ritonavir group . The virologic efficacy of the NRTI-sparing regimen was similar to that of the efavirenz regimen but was more likely to be associated with drug resistance . ( Clinical Trials.gov number , NCT00050895 [ Clinical Trials.gov ] . ) Background The grading of recommendation , assessment , development and evaluation ( GRADE ) approach is widely implemented in health technology assessment and guideline development organisations throughout the world . GRADE provides a transparent approach to reaching judgements about the quality of evidence on the effects of a health care intervention , but is complex and therefore challenging to apply in a consistent manner . Methods We developed a checklist to guide the research er to extract the data required to make a GRADE assessment . We applied the checklist to 29 meta-analyses of r and omised controlled trials on the effectiveness of health care interventions . Two review ers used the checklist for each paper and used these data to rate the quality of evidence for a particular outcome . Results For most ( 70 % ) checklist items , there was good agreement between review ers . The main problems were for items relating to indirectness where considerable judgement is required . Conclusions There was consistent agreement between review ers on most items in the checklist . The use of this checklist may be an aid to improving the consistency and reproducibility of GRADE assessment s , particularly for inexperienced users or in rapid review s without the re sources to conduct assessment s by two research ers independently BACKGROUND Coinfection with human immunodeficiency virus type 1 ( HIV-1 ) increases the risk of hepatitis B virus (HBV)-associated progressive liver disease . Lamivudine has potent activity against both HIV-1 and HBV ; however , lamivudine-resistance mutations in HBV frequently develop . METHODS Sub studies of the safety and efficacy of tenofovir disoproxil fumarate ( tenofovir DF ) for patients coinfected with HIV and HBV were undertaken within 2 phase 3 r and omized controlled trials involving antiretroviral therapy-experienced ( study 907 ) and -naive ( study 903 ) HIV-infected population s. Inclusion criteria were detection of hepatitis B surface antigen , an HBV DNA level > 106 copies/mL at baseline , and HBV DNA specimens available at week 24 ( study 907 ) and week 48 ( study 903 ) . RESULTS In study 907 , the mean decrease in HBV DNA was 4.9 log(10 ) , after 24 weeks , for 10 patients r and omized to receive tenofovir DF , compared with a mean increase of 1.2 log(10 ) for 2 patients r and omized to receive placebo ( P=.041 ) . The mean decrease in HBV DNA during tenofovir DF treatment was similar for patients with wild-type ( 5.3 log(10 ) ) and lamivudine-resistant ( 4.6 log(10 ) ) HBV strains . In study 903 , the mean decrease in HBV DNA was 3.0 log(10 ) , after 48 weeks , for 6 patients r and omized to receive lamivudine , compared with 4.7 log(10 ) for 5 patients r and omized to receive lamivudine and tenofovir DF ( P=.055 ) . Four patients developed tyrosine-methionine-aspartate-aspartate mutations , all in the lamivudine-only treatment arm . CONCLUSION Tenofovir DF has potent anti-HBV efficacy in antiretroviral therapy-experienced and -naive individuals coinfected with HIV and HBV CONTEXT Three-drug antiretroviral regimens are st and ard of care for initial treatment of human immunodeficiency virus 1 ( HIV-1 ) infection , but a 4-drug regimen could improve antiretroviral activity and be more effective than a 3-drug regimen . OBJECTIVE To compare the safety/efficacy of 3-drug vs 4-drug regimens for initial treatment of HIV-1 infection . DESIGN The AIDS Clinical Trials Group ( ACTG ) A5095 study , a r and omized , double-blind , placebo-controlled study with enrollment and follow-up conducted from March 22 , 2001 , to March 1 , 2005 , and enrolling treatment-naive , HIV-1-infected patients with HIV-1 RNA levels of 400 copies/mL or greater from US clinical trials units of the ACTG . INTERVENTIONS Zidovudine/lamivudine plus efavirenz ( 3-drug regimen ) vs zidovudine/lamivudine/abacavir plus efavirenz ( 4-drug regimen ) . MAIN OUTCOME MEASURES Time to virologic failure ( defined as time to first of 2 successive HIV-1 RNA levels > or = 200 copies/mL at or after week 16 ) , CD4 cell count changes , and grade 3 or 4 adverse events . HIV-1 RNA data were intent-to-treat , regardless of treatment changes . RESULTS Seven hundred sixty-five patients with a baseline mean HIV-1 RNA level of 4.86 log10 ( 72,444 ) copies/mL and CD4 cell count of 240 cells/mm3 were r and omized . After a median 3-year follow-up , 99 ( 26 % ) of 382 and 94 ( 25 % ) of 383 patients receiving the 3-drug and 4-drug regimens , respectively , reached protocol -defined virologic failure ; time to virologic failure was not significantly different ( hazard ratio , 0.95 ; 97.5 % confidence interval , 0.69 - 1.33 ; P = .73 ) . In planned subgroup analyses , increased risk for virologic failure was seen in non-Hispanic black patients ( adjusted hazard ratio , 1.66 ; 95 % confidence interval , 1.18 - 2.34 ; P = .003 ) . At 3 years , the HIV-1 RNA level was less than 200 copies/mL in 152 ( 90 % ) of 169 and 143 ( 92 % ) of 156 patients receiving the 3-drug and 4-drug regimens , respectively ( P = .59 ) , and less than 50 copies/mL in 144 ( 85 % ) of 169 and 137 ( 88 % ) of 156 patients ( P = .39 ) . CD4 cell count increases and grade 3 or 4 adverse events were not significantly different . CONCLUSIONS In treatment-naive patients , there were no significant differences between the 3-drug and 4-drug antiretroviral regimens ; overall , at least approximately 80 % of patients had HIV-1 RNA levels less than 50 copies/mL through 3 years . These results support current guidelines recommending 2 nucleosides plus efavirenz for initial treatment of HIV-1 infection ; adding abacavir as a fourth drug provided no additional benefit . CLINICAL TRIALS REGISTRATION clinical trials.gov Identifier : NCT00013520 Background : The present primary analysis of AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects ( ARTEMIS ) compares the efficacy and safety of once-daily darunavir/ritonavir ( DRV/r ) with that of lopinavir/ritonavir ( LPV/r ) in treatment-naive patients . Methods : Patients with HIV-1 RNA at least 5000 copies/ml were stratified by HIV-1 RNA and CD4 cell count in a phase III , open-label trial , and r and omized to receive DRV/r 800/100 mg qd or LPV/r 800/200 mg total daily dose ( bid or qd ) plus fixed-dose tenofovir and emtricitabine for 192 weeks . The primary objective was to demonstrate non-inferiority of DRV/r as compared with LPV/r in HIV-1 RNA less than 50 copies/ml per- protocol time-to-loss of virologic response at 48 weeks . Results : Six hundred and eighty-nine patients were r and omized and treated ; mean baseline HIV-1 RNA : 4.85 log10 copies/ml and median CD4 count : 225 cells/μl . At 48 weeks , 84 % of DRV/r and 78 % of LPV/r patients achieved HIV-1 RNA less than 50 copies/ml ( estimated difference = 5.6 [ 95 % confidence interval −0.1–11]% ) , demonstrating non-inferiority of DRV/r as compared with LPV/r ( P < 0.001 ; per- protocol time-to-loss of virologic response ) . Patients with HIV-1 RNA at least 100 000 copies/ml had a significantly higher response rate with DRV/r ( 79 % ) versus LPV/r ( 67 % ; P < 0.05 ) . Median CD4 cell count increases ( non-completer = failure ; cells/μl ) were 137 for DRV/r and 141 for LPV/r . DRV/r had a lower incidence of possibly treatment-related grade 2–4 gastrointestinal-related adverse events ( 7 versus 14 % ) and treatment-related moderate-to-severe diarrhea ( 4 versus 10 % ) than LPV/r . Adverse events leading to discontinuation were DRV/r : 3 % and LPV/r : 7 % . Conclusion : DRV/r 800/100 mg qd was non-inferior to LPV/r 800/200 mg at 48 weeks , with a more favorable safety profile . Significantly higher response rates were observed with DRV/r in patients with HIV-1 RNA at least 100 000 copies/ml . DRV/r 800/100 mg offers a new effective and well tolerated once-daily , first-line treatment option for treatment-naive patients Background : Atazanavir ( ATV ) , the first once-daily protease inhibitor approved for the treatment of HIV-1 infection , is recommended for use in antiretroviral ( ARV ) treatment-naive and -experienced patients . Study AI424 - 089 was a prospect i ve , r and omized , open-label , 96-week study comparing 2 ATV-based treatment regimens in ARV-naive HIV-infected patients . Methods : Adults with HIV RNA levels ≥2000 copies/mL were r and omized ( 1:1 ) to once-daily ATV at a dose of 300 mg with ritonavir at a dose of 100 mg ( ATV300/RTV ) or ATV at a dose of 400 mg ( ATV400 ) ; both regimens included lamivudine and an investigational extended-release formulation of stavudine . The primary endpoint for this noninferiority study was the proportion of patients ( response rate ) with an HIV RNA load < 400 copies/mL at week 48 . Results : Response rates at week 48 were 86 % and 85 % on the ATV300/RTV and ATV400 regimens , respectively ( difference estimate [ 95 % confidence interval ] = 1.5 [ −8.2 to 11.1 ] ) . There were 3 and 10 patients with virologic failure in the ATV300/RTV and ATV400 groups , respectively . One patient ( ATV400 ) developed phenotypic resistance to ATV associated with an I50L substitution . Adverse event-related discontinuations were 8 % among ATV300/RTV-treated patients and < 1 % among ATV400-treated patients . Plasma lipid elevations were low with both regimens . Both regimens were well tolerated . Conclusions : These findings demonstrate the safety and efficacy of the ATV300/RTV regimen and confirm the safety and efficacy of ATV400 in an ARV-naive patient population BACKGROUND Atazanavir/ritonavir is as effective as lopinavir/ritonavir , with a more favourable lipid profile and less gastrointestinal toxicity , in treatment-experienced HIV-1-infected patients . We compared these two combinations directly in treatment-naive patients . METHODS In this open-label , international non-inferiority study , 883 antiretroviral-naive , HIV-1-infected patients were r and omly assigned to receive atazanavir/ritonavir 300/100 mg once daily ( n=440 ) or lopinavir/ritonavir 400/100 mg twice daily ( n=443 ) , in combination with fixed-dose tenofovir/emtricitabine 300/200 mg once daily . R and omisation was done with a computer-generated central ised r and omisation schedule and was stratified by baseline levels of HIV RNA ( viral load ) and geographic region . The primary endpoint was the proportion of patients with viral load less than 50 copies per mL at week 48 . The main efficacy analysis was done by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00272779 . FINDINGS At week 48 , 343 ( 78 % ) of 440 patients receiving atazanavir/ritonavir and 338 ( 76 % ) of 443 patients receiving lopinavir/ritonavir had achieved a viral load of less than 50 copies per mL ( difference 1.7 % , 95 % CI -3.8 to 7.1 ) . Mean increases from baseline in CD4 cell count were similar ( 203 cells per muL in the atazanavir/ritonavir group vs 219 cells per muL in the lopinavir/ritonavir group ) . 25 ( 6 % ) patients in the atazanavir/ritonavir group and 26 ( 6 % ) in the lopinavir/ritonavir group were virological failures by week 48 . Only two patients , both in the atazanavir/ritonavir group , had non-polymorphic protease inhibitor resistance mutations emerge on treatment , which conferred phenotypic resistance to atazanavir in one patient . Serious adverse events were noted in 51 ( 12 % ) of 441 patients in the atazanavir/ritonavir group and in 42 ( 10 % ) of 437 patients in the lopinavir/ritonavir group . Fewer patients in the atazanavir/ritonavir group than in the lopinavir/ritonavir group experienced grade 2 - 4 treatment-related diarrhoea ( 10 [ 2 % ] vs 50 [ 11 % ] ) and nausea ( 17 [ 4 % ] vs 33 [ 8 % ] ) . Grade 2 - 4 jaundice was seen in 16 ( 4 % ) of 441 patients in the atazanavir/ritonavir group versus none of 437 patients in the lopinavir/ritonavir group ; grade 3 - 4 increases in total bilirubin were seen in 146 ( 34 % ) of 435 patients on atazanavir/ritonavir and in one ( < 1 % ) of 431 patients on lopinavir/ritonavir . INTERPRETATION In treatment-naive patients , atazanavir/ritonavir once-daily demonstrated similar antiviral efficacy to lopinavir/ritonavir twice-daily , with less gastrointestinal toxicity but with a higher rate of hyperbilirubinaemia BACKGROUND Few r and omized trials comparing antiretroviral therapy ( ART ) regimens have been conducted in re source -limited setting s. METHODS In the Republic of South Africa , antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals > 14 years old with a CD4 cell count < 200 cells/μL or a prior AIDS diagnosis were r and omized to receive efavirenz ( EFV ) or lopinavir/ritonavir ( LPV/r ) with either zidovudine ( ZDV ) plus didanosine ( ddI ) or stavudine ( d4 T ) plus lamivudine ( 3TC ) in an open-label , 2-by-2 factorial study and followed up for the primary outcome of AIDS or death and prespecified secondary outcomes , including CD4 cell count and viral load changes , treatment discontinuation , and grade 4 events . RESULTS In total , 1771 persons were r and omized and followed up for a median of 24.7 months . AIDS or death occurred in ( 1 ) 163 participants assigned EFV and 157 assigned LPV/r ( hazard ratio [ HR ] , 1.04 [ 95 % confidence interval { CI } , 0.84 - 1.30 ] ) and in ( 2 ) 170 participants assigned ZDV+ddI and 150 assigned d4T+3TC ( HR , 1.15 [ 95 % CI , 0.93 - 1.44 ] ) . HIV RNA levels were lower ( P < .001 ) and CD4 cell counts were greater ( P < .01 ) over follow-up for d4T+3TC versus ZDV+ddI. Rates of potentially life-threatening adverse events and overall treatment discontinuation were similar for d4T+3TC and ZDV+ddI ; however , more participants discontinued d4 T because of toxicity ( 12.6 % ) than other treatments ( < 5 % ) . CONCLUSION EFV and LPV/r are effective components of first-line ART . The poorer viral and immune responses with ZDV+ddI and the greater toxicity-associated discontinuation rate with d4T+3TC suggest that these treatments be used cautiously as initial therapy . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00342355 In a prospect i ve , open-label , 104-week study , patients who were infected with human immunodeficiency virus type 1 ( virus load , < 50 copies/mL ) and who were receiving protease inhibitor-based therapy were r and omly assigned to continue treatment with a protease inhibitor or to replace it with abacavir or efavirenz . Treatment failure , defined as virological failure ( virus load , > 500 copies/microL ) or any clinical or biochemical adverse event with a grade of > or=3 ( on the basis of the World Health Organization [ WHO ] or American Heart Association [ AHA ] scales ) , was the primary outcome measurement . Failure rates were more frequent in the group treated with protease inhibitors ( P<.01 ) , and there were no significant differences in the rate of treatment failure between the group treated with efavirenz and the group treated with abacavir . Tolerability was better in the groups treated with abacavir or with efavirenz versus those treated with protease inhibitors . Fewer patients who received efavirenz experienced viral rebound . Among all groups , the mean increase in the CD4 cell count was 131 cells/microL ( P<.001 ) , with no significant difference between groups . This switching strategy maintains optimal levels of virological suppression and may improve lipid profiles in most patients BACKGROUND Zidovudine , lamivudine , and efavirenz comprise a highly effective and well-tolerated triple regimen for antiretroviral-naive patients . Evaluating other unique nucleoside reverse-transcriptase inhibitor ( NRTI ) combinations for long-term viral suppression is desirable . METHODS This multicenter , r and omized , double-blind noninferiority clinical trial compared the efficacy and safety of abacavir with that of zidovudine plus lamivudine and efavirenz in 649 antiretroviral-naive HIV-infected patients . The primary objective was a comparison of proportions of patients achieving plasma HIV-1 RNA levels < or=50 copies/mL through week 48 of the study . RESULTS At study week 48 , 70 % of patients in the abacavir group , compared with 69 % in the zidovudine group , maintained confirmed plasma HIV-1 RNA levels of < or=50 copies/mL ( in the intent-to-treat exposed population ) . Virologic failure was infrequent ( 6 % in the abacavir group and 4 % in the zidovudine group ) . There was a significant CD4(+ ) cell response ( 209 cells/mm(3 ) in the abacavir group and 155 cells/mm(3 ) in the zidovudine group ) . Safety profiles were as expected . CONCLUSION Abacavir provided an effective and durable antiretroviral response that was noninferior to zidovudine , when combined with lamivudine and efavirenz BACKGROUND Durable suppression of replication of the human immunodeficiency virus ( HIV ) depends on the use of potent , well-tolerated antiretroviral regimens to which patients can easily adhere . METHODS We conducted an open-label , noninferiority study involving 517 patients with HIV infection who had not previously received antiretroviral therapy and who were r and omly assigned to receive either a regimen of tenofovir disoproxil fumarate ( DF ) , emtricitabine , and efavirenz once daily ( tenofovir-emtricitabine group ) or a regimen of fixed-dose zidovudine and lamivudine twice daily plus efavirenz once daily ( zidovudine-lamivudine group ) . The primary end point was the proportion of patients without baseline resistance to efavirenz in whom the HIV RNA level was less than 400 copies per milliliter at week 48 of the study . RESULTS Through week 48 , significantly more patients in the tenofovir-emtricitabine group reached and maintained the primary end point of less than 400 copies of HIV RNA per milliliter than did those in the zidovudine-lamivudine group ( 84 percent vs. 73 percent , respectively ; 95 percent confidence interval for the difference , 4 to 19 percent ; P=0.002 ) . This difference excludes the inferiority of the tenofovir DF , emtricitabine , and efavirenz regimen , indicating a significantly greater response with this regimen . Significant differences were also seen in the proportion of patients with HIV RNA levels of less than 50 copies per milliliter ( 80 percent in the tenofovir-emtricitabine group vs. 70 percent in the zidovudine-lamivudine group ; 95 percent confidence interval for the difference , 2 to 17 percent ; P=0.02 ) and in increases in CD4 cell counts ( 190 vs. 158 cells per cubic millimeter , respectively ; 95 percent confidence interval for the difference , 9 to 55 ; P=0.002 ) . More patients in the zidovudine-lamivudine group than in the tenofovir-emtricitabine group had adverse events result ing in discontinuation of the study drugs ( 9 percent vs. 4 percent , respectively ; P=0.02 ) . In none of the patients did the K65R mutation develop . CONCLUSIONS Through week 48 , the combination of tenofovir DF and emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efavirenz and proved superior in terms of virologic suppression , CD4 response , and adverse events result ing in discontinuation of the study drugs . ( Clinical Trials.gov number , NCT00112047 . BACKGROUND The integrase inhibitor elvitegravir ( EVG ) has been co-formulated with the CYP3A4 inhibitor cobicistat ( COBI ) , emtricitabine ( FTC ) , and tenofovir disoproxil fumarate ( TDF ) in a single tablet given once daily . We compared the efficacy and safety of EVG/COBI/FTC/TDF with st and ard of care-co-formulated efavirenz (EFV)/FTC/TDF-as initial treatment for HIV infection . METHODS In this phase 3 trial , treatment-naive patients from outpatient clinics in North America were r and omly assigned by computer-generated allocation sequence with a block size of four in a 1:1 ratio to receive EVG/COBI/FTC/TDF or EFV/FTC/TDF , once daily , plus matching placebo . Patients and study staff involved in giving study treatment , assessing outcomes , and collecting and analysing data were masked to treatment allocation . Eligibility criteria included screening HIV RNA concentration of 5000 copies per mL or more , and susceptibility to efavirenz , emtricitabine , and tenofovir . The primary endpoint was HIV RNA concentration of fewer than 50 copies per mL at week 48 . The study is registered with Clinical Trials.gov , number NCT01095796 . FINDINGS 700 patients were r and omly assigned and treated ( 348 with EVG/COBI/FTC/TDF , 352 with EFV/FTC/TDF ) . EVG/COBI/FTC/TDF was non-inferior to EFV/FTC/TDF ; 305/348 ( 87·6 % ) versus 296/352 ( 84·1 % ) of patients had HIV RNA concentrations of fewer than 50 copies per mL at week 48 ( difference 3·6 % , 95 % CI -1·6 % to 8·8 % ) . Proportions of patients discontinuing drugs for adverse events did not differ substantially ( 13/348 in the EVG/COBI/FTC/TDF group vs 18/352 in the EFV/FTC/TDF group ) . Nausea was more common with EVG/COBI/FTC/TDF than with EFV/FTC/TDF ( 72/348 vs 48/352 ) and dizziness ( 23/348 vs 86/352 ) , abnormal dreams ( 53/348 vs 95/352 ) , insomnia ( 30/348 vs 49/352 ) , and rash ( 22/348 vs 43/352 ) were less common . Serum creatinine concentration increased more by week 48 in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group ( median 13 μmol/L , IQR 5 to 20 vs 1 μmol/L , -6 to 8 ; p<0·001 ) . INTERPRETATION If regulatory approval is given , EVG/COBI/FTC/TDF would be the only single-tablet , once-daily , integrase-inhibitor-based regimen for initial treatment of HIV infection . FUNDING Gilead Sciences BACKGROUND Antiretroviral therapy is complicated by drug interactions and contraindications . Novel regimens are needed . METHODS This open label study r and omly assigned treatment-naive , human immunodeficiency virus (HIV)-infected subjects to receive tenofovir-emtricitabine with efavirenz ( Arm I ) , with ritonavir-boosted atazanavir ( Arm II ) , or with zidovudine/abacavir ( Arm III ) . Pair-wise comparisons of differences in time-weighted mean change from baseline plasma HIV-RNA to week 48 formed the primary analysis . Treatment arms were noninferior if the upper limit of the 95 % confidence interval ( CI ) was < 0.5 log(10 ) copies/mL. Secondary objectives included virologic , immunologic and safety end points . RESULTS The intention-to-treat population comprised 322 patients ( Arm I , n = 114 ; Arm II , n = 105 ; and Arm III , n = 103 ) . Noninferiority for the primary end point was established . Analysis for superiority showed that Arm III was significantly less potent than Arm I ( -0.20 log(10 ) copies/mL ; 95 % CI , -0.39 to -0.01 log(10 ) copies/mL ; P = .038 ) . The proportions of patients on each of Arm I ( 95 % ) and Arm II ( 96 % ) with < 200 copies/mL were not different ( P = .75 ) , but the percentage of patients in Arm III with < 200 copies/mL ( 82 % ) was significantly lower ( P = .005 ) . CD4 + cell counts did not differ . Serious adverse events were more frequent in Arm III ( n = 30 ) than in Arm I or Arm II ( n = 15 for each ; P = .062 ) . CONCLUSIONS A novel quadruple nucleo(t)side combination demonstrated significantly less suppression of HIV replication , compared with the suppression demonstrated by st and ard antiretroviral therapy regimens , although it did meet the predetermined formal definition of noninferiority . Secondary analyses indicated statistically inferior virologic and safety performance . Efavirenz and ritonavir-boosted atazanavir arms were equivalent in viral suppression and safety BACKGROUND Antiretroviral therapy has greatly reduced HIV mortality and morbidity . However , the best sequence of regimens and implication s of initial regimen for long-term therapeutic success are not well defined . METHODS In INITIO , a large international r and omised trial , we compared antiretroviral therapy with two nucleoside analogue reverse transcriptase inhibitors ( didanosine+stavudine ) plus either a non-nucleoside reverse transcriptase inhibitor ( efavirenz , EFV ) or a protease inhibitor ( nelfinavir , NFV ) , or both ( EFV/NFV ) , in patients with HIV-1 infection who had not previously received antiretroviral drugs . Primary outcomes were proportion with undetectable HIV RNA in plasma , and change in CD4 count from baseline at 3 years . Analyses were by intention-to-treat . This study is registered as an International St and ard R and omised Controlled Trial , number IS RCT N44582462 . FINDINGS We followed up 911 participants ( 297 EFV , 311 NFV , 303 EFV/NFV ) . At 3 years , the proportion with HIV RNA less than 50 copies per mL was highest in the EFV group ( 188 [ 74 % ] EFV , 162 [ 62 % ] NFV , 155 [ 62 % ] EFV/NFV ; p=0.004 ) . Mean ( 95 % CI ) increases in CD4 count were 316x10(6 ) cells per L ( 288 - 343 ) for EFV , 289x10(6 ) cells per L ( 262 - 316 ) for NFV , and 274x10(6 ) cells per L ( 231 - 291 ) for EFV/NFV ( p=0.1 ) . Fewer participants in the EFV group than in the other groups stopped adequate antiretroviral therapy for more than 30 days ( p=0.005 ) . Participants in the EFV/NFV group had shorter time to stopping the initial regimen ( p<0.0001 ) and to a treatment modifying adverse event ( p=0.04 ) than those in the other groups . INTERPRETATION Starting antiretroviral therapy with a three-drug/two-class regimen including efavirenz was better than starting with regimens including nelfinavir or efavirenz plus nelfinavir in terms of virological suppression and durability of the initial regimen . The shorter time on adequate antiretroviral therapy or to a treatment-modifying adverse event might explain the absence of additional benefit for the four-drug regimen BACKGROUND Dolutegravir ( S/GSK1349572 ) , a once-daily , unboosted integrase inhibitor , was recently approved in the United States for the treatment of human immunodeficiency virus type 1 ( HIV-1 ) infection in combination with other antiretroviral agents . Dolutegravir , in combination with abacavir-lamivudine , may provide a simplified regimen . METHODS We conducted a r and omized , double-blind , phase 3 study involving adult participants who had not received previous therapy for HIV-1 infection and who had an HIV-1 RNA level of 1000 copies per milliliter or more . Participants were r and omly assigned to dolutegravir at a dose of 50 mg plus abacavir-lamivudine once daily ( DTG-ABC-3TC group ) or combination therapy with efavirenz-tenofovir disoproxil fumarate (DF)-emtricitabine once daily ( EFV-TDF-FTC group ) . The primary end point was the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter at week 48 . Secondary end points included the time to viral suppression , the change from baseline in CD4 + T-cell count , safety , and viral resistance . RESULTS A total of 833 participants received at least one dose of study drug . At week 48 , the proportion of participants with an HIV-1 RNA level of less than 50 copies per milliliter was significantly higher in the DTG-ABC-3TC group than in the EFV-TDF-FTC group ( 88 % vs. 81 % , P=0.003 ) , thus meeting the criterion for superiority . The DTG-ABC-3TC group had a shorter median time to viral suppression than did the EFV-TDF-FTC group ( 28 vs. 84 days , P<0.001 ) , as well as greater increases in CD4 + T-cell count ( 267 vs. 208 per cubic millimeter , P<0.001 ) . The proportion of participants who discontinued therapy owing to adverse events was lower in the DTG-ABC-3TC group than in the EFV-TDF-FTC group ( 2 % vs. 10 % ) ; rash and neuropsychiatric events ( including abnormal dreams , anxiety , dizziness , and somnolence ) were significantly more common in the EFV-TDF-FTC group , whereas insomnia was reported more frequently in the DTG-ABC-3TC group . No participants in the DTG-ABC-3TC group had detectable antiviral resistance ; one tenofovir DF-associated mutation and four efavirenz-associated mutations were detected in participants with virologic failure in the EFV-TDF-FTC group . CONCLUSIONS Dolutegravir plus abacavir-lamivudine had a better safety profile and was more effective through 48 weeks than the regimen with efavirenz-tenofovir DF-emtricitabine . ( Funded by ViiV Healthcare ; SINGLE Clinical Trials.gov number , NCT01263015 . ) BACKGROUND Dolutegravir has been shown to be non-inferior to an integrase inhibitor and superior to a non-nucleoside reverse transcriptase inhibitor ( NNRTI ) . In FLAMINGO , we compared dolutegravir with darunavir plus ritonavir in individuals naive for antiretroviral therapy . METHODS In this multicentre , open-label , phase 3b , non-inferiority study , HIV-1-infected antiretroviral therapy-naive adults with HIV-1 RNA concentration of 1000 copies per mL or more and no resistance at screening were r and omly assigned ( 1:1 ) to receive either dolutegravir 50 mg once daily or darunavir 800 mg plus ritonavir 100 mg once daily , with investigator-selected tenofovir-emtricitabine or abacavir-lamivudine . R and omisation was stratified by screening HIV-1 RNA ( ≤100,000 or > 100,000 copies per mL ) and nucleoside reverse transcriptase inhibitor ( NRTI ) selection . The primary endpoint was the proportion of patients with HIV-1 RNA concentration lower than 50 copies per mL ( Food and Drug Administration [ FDA ] snapshot algorithm ) at week 48 with a 12 % non-inferiority margin . This trial is registered with Clinical Trials.gov , NCT01449929 . FINDINGS Recruitment began on Oct 31 , 2011 , and was completed on May 24 , 2012 , in 64 research centres in nine countries worldwide . Of 595 patients screened , 484 patients were included in the analysis ( 242 in each group ) . At week 48 , 217 ( 90 % ) patients receiving dolutegravir and 200 ( 83 % ) patients receiving darunavir plus ritonavir had HIV-1 RNA of less than 50 copies per mL ( adjusted difference 7·1 % , 95 % CI 0·9 - 13·2 ) , non-inferiority and on pre-specified secondary analysis dolutegravir was superior ( p=0·025 ) . Confirmed virological failure occurred in two ( < 1 % ) patients in each group ; we recorded no treatment-emergent resistance in either group . Discontinuation due to adverse events or stopping criteria was less frequent for dolutegravir ( four [ 2 % ] patients ) than for darunavir plus ritonavir ( ten [ 4 % ] patients ) and contributed to the difference in response rates . The most commonly reported ( ≥10 % ) adverse events were diarrhoea ( dolutegravir 41 [ 17 % ] patients vs darunavir plus ritonavir 70 [ 29 % ] patients ) , nausea ( 39 [ 16 % ] vs 43 [ 18 % ] ) , and headache ( 37 [ 15 % ] vs 24 [ 10 % ] ) . Patients receiving dolutegravir had significantly fewer low-density lipoprotein values of grade 2 or higher ( 11 [ 2 % ] vs 36 [ 7 % ] ; p=0·0001 ) . INTERPRETATION Once-daily dolutegravir was superior to once-daily darunavir plus ritonavir . Once-daily dolutegravir in combination with fixed-dose NRTIs represents an effective new treatment option for HIV-1-infected , treatment-naive patients . FUNDING ViiV Healthcare and Shionogi & CONTEXT Tenofovir disoproxil fumarate ( DF ) is a once-daily nucleotide analogue reverse transcriptase inhibitor . OBJECTIVE To evaluate the efficacy and safety of tenofovir DF compared with stavudine in antiretroviral-naive patients . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve , r and omized , double-blind study conducted at 81 centers in the United States , South America , and Europe from June 9 , 2000 , to January 30 , 2004 . A total of 753 patients infected with HIV who were antiretroviral naive were screened and 602 patients entered the study . INTERVENTION Patients were r and omized to receive either tenofovir DF ( n = 299 ) or stavudine ( n = 303 ) , with placebo , in combination with lamivudine and efavirenz . MAIN OUTCOME MEASURE Proportion of patients with HIV RNA levels of less than 400 copies/mL at week 48 . RESULTS In the primary intent-to-treat analysis in which patients with missing data or who added or switched antiretroviral medications before week 48 were considered as failures , the proportion of patients with HIV RNA of less than 400 copies/mL at week 48 was 239 ( 80 % ) of 299 in patients receiving tenofovir DF and 253 ( 84 % ) of 301 in patients receiving stavudine ( 95 % confidence interval , -10.4 % to 1.5 % ) , exceeding the predefined -10 % limit for equivalence . However , equivalence was demonstrated in the secondary analyses ( HIV RNA < 50 copies/mL ) at week 48 and through 144 weeks . Virologic failure was associated most frequently with efavirenz and lamivudine resistance . Through 144 weeks , the K65R mutation emerged in 8 and 2 patients in the tenofovir DF and stavudine groups , respectively ( P = .06 ) . A more favorable mean change from baseline in fasting lipid profile was noted in the tenofovir DF group at week 144 : for triglyceride levels ( + 1 mg/dL for tenofovir DF [ n = 170 ] vs + 134 mg/dL for stavudine [ n = 162 ] , P<.001 ) , total cholesterol ( + 30 mg/dL [ n = 170 ] vs + 58 mg/dL [ n = 162 ] , P<.001 ) , direct low-density lipoprotein cholesterol ( + 14 mg/dL [ n = 169 ] vs + 26 mg/dL [ n = 161 ] , P<.001 ) , and high-density lipoprotein cholesterol ( + 9 mg/dL [ n = 168 ] vs + 6 mg/dL [ n = 154 ] , P = .003 ) . Investigator-reported lipodystrophy was less common in the tenofovir DF group compared with the stavudine group ( 9 [ 3 % ] of 299 vs 58 [ 19 % ] of 301 , P<.001 ) . The number of bone fractures and the renal safety profile were similar between the 2 groups . CONCLUSIONS Through 144 weeks , the combination of tenofovir DF , lamivudine , and efavirenz was highly effective and comparable with stavudine , lamivudine , and efavirenz in antiretroviral-naive patients . However , tenofovir DF appeared to be associated with better lipid profiles and less lipodystrophy BACKGROUND To our knowledge , to date , no prospect i ve , r and omized , clinical trial has compared st and ard doses of efavirenz- and nevirapine-based antiretroviral therapy among patients with concurrent human immunodeficiency virus type 1 ( HIV-1 ) infection and tuberculosis ( TB ) who are receiving rifampicin . METHODS Rifampicin recipients with concurrent HIV-1 infection and TB were r and omized to receive antiretroviral therapy that included either efavirenz ( 600 mg per day ) or nevirapine ( 400 mg per day ) . Efavirenz and nevirapine concentrations at 12 h after dosing ( C12 ) were monitored at weeks 6 and 12 . CD4 + cell counts and HIV-1 RNA levels were assessed every 12 weeks . RESULTS One hundred forty-two patients were r and omized into 2 groups equally . The mean body weight of patients was 53 kg , the mean CD4 + cell count was 65 cells/mm3 , and the median HIV-1 RNA level was 5.8 log10 copies/mL. At weeks 6 and 12 , the mean C12 of efavirenz ( + /- st and ard deviation ) were 4.27+/-4.49 and 3.54+/-3.78 mg/L , respectively , and those for nevirapine were 5.59+/-3.48 and 5.6+/-2.65 mg/L , respectively . Interpatient variability in the efavirenz group was 2.3-fold greater than that in the nevirapine group ( coefficient of variation , 107 % vs. 47 % ) . At week 12 , 3.1 % of patients in the efavirenz group and 21.3 % in the nevirapine group had C12 values that were less than the recommended minimum concentrations ( odds ratio , 8.396 ; 95 % confidence interval , 1.808 - 38.993 ; P= .002 ) . Intention-to-treat analysis revealed that 73.2 % and 71.8 % of patients in the efavirenz and nevirapine groups , respectively , achieved HIV-1 RNA levels < 50 copies/mL at week 48 , with respective mean CD4 + cell counts of 274 and 252 cells/mm3 ( P > .05 ) . Multivariate analysis revealed that patients with low C12 values and those with a body weight < 55 kg were 3.6 and 2.4 times more likely , respectively , to develop all-cause treatment failure ( P < .05 ) . CONCLUSIONS Antiretroviral therapy regimens containing efavirenz ( 600 mg per day ) were less compromised by concomitant use of rifampicin than were those that contained nevirapine ( 400 mg per day ) in patients with concurrent HIV-1 infection and TB . Low drug exposure and low body weight are important predictive factors for treatment failure BACKGROUND Use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection . We compared the safety and efficacy of raltegravir with efavirenz as part of combination antiretroviral therapy for treatment-naive patients . METHODS Patients from 67 study centres on five continents were enrolled between Sept 14 , 2006 , and June 5 , 2008 . Eligible patients were infected with HIV-1 , had viral RNA ( vRNA ) concentration of more than 5000 copies per mL , and no baseline resistance to efavirenz , tenofovir , or emtricitabine . Patients were r and omly allocated by interactive voice response system in a 1:1 ratio ( double-blind ) to receive 400 mg oral raltegravir twice daily or 600 mg oral efavirenz once daily , in combination with tenofovir and emtricitabine . The primary efficacy endpoint was achievement of a vRNA concentration of less than 50 copies per mL at week 48 . The primary analysis was per protocol . The margin of non-inferiority was 12 % . This study is registered with Clinical Trials.gov , number NCT00369941 . FINDINGS 566 patients were enrolled and r and omly allocated to treatment , of whom 281 received raltegravir , 282 received efavirenz , and three were never treated . At baseline , 297 ( 53 % ) patients had more than 100 000 vRNA copies per mL and 267 ( 47 % ) had CD4 counts of 200 cells per microL or less . The main analysis ( with non-completion counted as failure ) showed that 86.1 % ( n=241 patients ) of the raltegravir group and 81.9 % ( n=230 ) of the efavirenz group achieved the primary endpoint ( difference 4.2 % , 95 % CI -1.9 to 10.3 ) . The time to achieve such viral suppression was shorter for patients on raltegravir than on efavirenz ( log-rank test p<0.0001 ) . Significantly fewer drug-related clinical adverse events occurred in patients on raltegravir ( n=124 [ 44.1 % ] ) than those on efavirenz ( n=217 [ 77.0 % ] ; difference -32.8 % , 95 % CI -40.2 to -25.0 , p<0.0001 ) . Serious drug-related clinical adverse events occurred in less than 2 % of patients in each drug group . INTERPRETATION Raltegravir-based combination treatment had rapid and potent antiretroviral activity , which was non-inferior to that of efavirenz at week 48 . Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients . FUNDING Merck BACKGROUND The non-nucleoside reverse transcriptase inhibitor ( NNRTI ) , rilpivirine ( TMC278 ; Tibotec Pharmaceuticals , County Cork , Irel and ) , had equivalent sustained efficacy to efavirenz in a phase 2b trial in treatment-naive patients infected with HIV-1 , but fewer adverse events . We aim ed to assess non-inferiority of rilpivirine to efavirenz in a phase 3 trial with common background nucleoside or nucleotide reverse transcriptase inhibitors ( N[t]RTIs ) . METHODS We undertook a 96-week , phase 3 , r and omised , double-blind , double-dummy , non-inferiority trial in 98 hospitals or medical centres in 21 countries . We enrolled adults ( ≥18 years ) not previously given antiretroviral therapy and with a screening plasma viral load of 5000 copies per mL or more and viral sensitivity to background N(t)RTIs . We r and omly allocated patients ( 1:1 ) using a computer-generated interactive web-response system to receive oral rilpivirine 25 mg once daily or efavirenz 600 mg once daily ; all patients received an investigator-selected regimen of background N(t)RTIs ( tenofovir-disoproxil-fumarate plus emtricitabine , zidovudine plus lamivudine , or abacavir plus lamivudine ) . The primary outcome was non-inferiority ( 12 % margin on logistic regression analysis ) at 48 weeks in terms of confirmed response ( viral load < 50 copies per mL , defined by the intent-to-treat time to loss of virologic response [ TLOVR ] algorithm ) in all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT00543725 . FINDINGS From May 22 , 2008 , we screened 947 patients and enrolled 340 to each group . 86 % of patients ( 291 of 340 ) who received at least one dose of rilpivirine responded , compared with 82 % of patients ( 276 of 338 ) who received at least one dose of efavirenz ( difference 3.5 % [ 95 % CI -1.7 to 8.8 ] ; p(non-inferiority)<0.0001 ) . Increases in CD4 cell counts were much the same between groups . 7 % of patients ( 24 of 340 ) receiving rilpivirine had a virological failure compared with 5 % of patients ( 18 of 338 ) receiving efavirenz . 4 % of patients ( 15 ) in the rilpivirine group and 7 % ( 25 ) in the efavirenz group discontinued treatment due to adverse events . Grade 2 - 4 treatment-related adverse events were less common with rilpivirine ( 16 % [ 54 patients ] ) than they were with efavirenz ( 31 % [ 104 ] ; p<0.0001 ) , as were rash and dizziness ( p<0.0001 for both ) and increases in lipid levels were significantly lower with rilpivirine than they were with efavirenz ( p<0.0001 ) . INTERPRETATION Despite a slightly increased incidence of virological failures , a favourable safety profile and non-inferior efficacy compared with efavirenz means that rilpivirine could be a new treatment option for treatment-naive patients infected with HIV-1 . FUNDING Tibotec BACKGROUND Selection of first-line antiretroviral therapy requires consideration of efficacy as well as effects on lipids given the increased concern about cardiovascular risk in HIV-1 patients . METHODS ARTEN is a r and omized , open-label , non-inferiority trial that compares nevirapine ( NVP ) 200 mg twice daily or 400 mg once daily to atazanavir/ritonavir ( ATZ/r ) 300 mg/100 mg once daily , each combined with fixed-dose tenofovir disoproxil fumarate ( TDF ) 300 mg/emtricitabine ( FTC ) 200 mg once daily , in antiretroviral-naive HIV-1 patients with CD4(+ ) T-cell counts < 400 ( men ) and < 250 cells/mm(3 ) ( women ) . The primary end point was plasma HIV RNA<50 copies/ml at two consecutive visits prior to week 48 . RESULTS A total of 569 patients were r and omized and treated . Overall , 66.8 % of NVP and 65.3 % of ATZ/r patients achieved the primary end point ( difference 1.9 % , 95 % CI -5.9 - 9.8 % ) . Similar rates of serious adverse events were observed ( 9.6 % on NVP versus 8.8 % on ATZ/r ) , although discontinuations due to adverse events were more frequent with NVP than ATZ/r ( 13.6 % versus 3.6 % , respectively ) . None of the 28 patients virologically failing ATZ/r selected resistance mutations , while they were selected in 29/44 patients virologically failing NVP . NVP induced a significantly greater increase in high-density lipoprotein cholesterol ( HDL-c ) and apolipoprotein A1 from baseline than ATZ/r , whereas triglycerides increased significantly more with ATZ/r than NVP . Mean change from baseline in TC : HDL-c ratio was -0.24 for NVP and 0.13 for ATZ/r ( P=0.0001 ) . CONCLUSIONS NVP demonstrated at week 48 non-inferior antiviral efficacy compared with ATZ/r when given along with TDF/FTC , despite more drug-related discontinuations with NVP than ATZ/r . NVP was associated with a lower atherogenic lipid profile than ATZ/r although resistance mutations were more frequently selected with NVP than ATZ/r Objectives : To compare the safety and efficacy of the two single-tablet regimens ( STRs ) , rilpivirine/emtricitabine/tenofovir disoproxil fumarate ( RPV/FTC/TDF ) and efavirenz/emtricitabine/tenofovir DF ( EFV/FTC/TDF ) , in HIV-1-infected , treatment-naive adults . Design : This is a phase 3b , r and omized , open-label , multicenter , international , 96-week study . Methods : Participants were r and omized 1 : 1 to receive either RPV/FTC/TDF or EFV/FTC/TDF . The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies/ml at week 48 by the Snapshot algorithm . Results : A total of 786 participants were r and omized . RPV/FTC/TDF was noninferior to EFV/FTC/TDF ( 85.8 vs. 81.6 % ) at week 48 for HIV-1 RNA less than 50 copies/ml [ difference 4.1 % , 95 % confidence interval ( CI ) −1.1 to 9.2 % ] . A statistically significant difference in efficacy favoring RPV/FTC/TDF was demonstrated for participants with baseline HIV-1 RNA 100 000 copies/ml or less [ ( n = 510 ) 88.8 % RPV/FTC/TDF vs. 81.6 % EFV/FTC/TDF ( difference 7.2 % , 95 % CI 1.1–13.4 % ) ] . In participants with baseline HIV-1 RNA more than 100 000 copies/ml ( n = 276 ) , RPV/FTC/TDF demonstrated noninferior efficacy compared with EFV/FTC/TDF ( 79.9 vs. 81.7 % , respectively , difference −1.8 % , 95 % CI −11.1 to 7.5 % ) . In the RPV/FTC/TDF arm , more virologic failure was observed as baseline HIV-1 RNA levels increased . There were more participants with emergent resistance in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm ( 4 vs. 1 % , respectively ) . There were fewer discontinuations because of adverse events with RPV/FTC/TDF ( 2.5 % ) than with EFV/FTC/TDF ( 8.7 % ) . Conclusion : In treatment-naive participants , RPV/FTC/TDF demonstrated noninferior efficacy and improved tolerability compared with EFV/FTC/TDF , as well as a statistically significant difference in efficacy for participants with baseline HIV-1 RNA 100 000 copies/ml or less at week 48 Background : Abacavir/lamivudine and tenofovir/emtricitabine fixed-dose combinations are commonly used first-line antiretroviral therapies , yet few studies have comprehensively compared their safety profiles . Methods : Forty-eight-week data are presented from this multicenter , r and omized , open-label study comparing the safety profiles of abacavir/lamivudine and tenofovir/emtricitabine , both administered with efavirenz , in HLA-B*5701-negative HIV-1-infected adults . Results : Three hundred eighty-five subjects were enrolled in the study . The overall rate of withdrawal was high ( 28 % ) . Changes in estimated glomerular filtration rate from baseline were similar between arms [ difference 0.953 mL·min−1·1.73 m−2 ( 95 % confidence interval : −1.445 to 3.351 ) , P = 0.435 ] . Urinary excretion of retinol-binding protein and β-2 microglobulin increased significantly more in the tenofovir/emtricitabine arm ( + 50 % ; + 24 % ) compared with the abacavir/lamivudine arm ( no change ; −47 % ) ( P < 0.0001 ) . A lower proportion achieved viral load < 50 copies per milliliter in the abacavir/lamivudine arm ( 114 of 192 , 59 % ) compared with the tenofovir/emtricitabine arm ( 137 of 193 , 71 % ) [ difference 11.6 % ( 95 % confidence interval : 2.2 to 21.1 ) ] . The overall virological failure rate was low . The adverse event rate was similar between arms ( except drug hypersensitivity , reported more in the abacavir/lamivudine arm ) . Conclusions : The study showed no difference in estimated glomerular filtration rate between the arms , however , increases in markers of tubular dysfunction were observed in the tenofovir/emtricitabine arm , the long-term consequence of which is unclear . A significant difference in efficacy favoring tenofovir/emtricitabine was observed BACKGROUND The Cochrane Collaboration is strongly encouraging the use of a newly developed tool , the Cochrane Collaboration Risk of Bias Tool ( CCRBT ) , for all review groups . However , the psychometric properties of this tool to date have yet to be described . Thus , the objective of this study was to add information about psychometric properties of the CCRBT including inter-rater reliability and concurrent validity , in comparison with the Effective Public Health Practice Project Quality Assessment Tool ( EPHPP ) . METHODS Both tools were used to assess the method ological quality of 20 r and omized controlled trials included in our systematic review of the effectiveness of knowledge translation interventions to improve the management of cancer pain . Each study assessment was completed independently by two review ers using each tool . We analysed the inter-rater reliability of each tool 's individual domains , as well as final grade assigned to each study . RESULTS The EPHPP had fair inter-rater agreement for individual domains and excellent agreement for the final grade . In contrast , the CCRBT had slight inter-rater agreement for individual domains and fair inter-rater agreement for final grade . Of interest , no agreement between the two tools was evident in their final grade assigned to each study . Although both tools were developed to assess ' quality of the evidence ' , they appear to measure different constructs . CONCLUSIONS Both tools performed quite differently when evaluating the risk of bias or method ological quality of studies in knowledge translation interventions for cancer pain . The newly introduced CCRBT assigned these studies a higher risk of bias . Its psychometric properties need to be more thoroughly vali date d , in a range of research fields , to underst and fully how to interpret results from its application BACKGROUND The 2NN Study was a r and omised comparison of the non-nucleoside reverse-transcriptase inhibitors ( NNRTI ) nevirapine and efavirenz . METHODS In this multicentre , open-label , r and omised trial , 1216 antiretroviral-therapy-naive patients were assigned nevirapine 400 mg once daily , nevirapine 200 mg twice daily , efavirenz 600 mg once daily , or nevirapine ( 400 mg ) and efavirenz ( 800 mg ) once daily , plus stavudine and lamivudine , for 48 weeks . The primary endpoint was the proportion of patients with treatment failure ( less than 1 log(10 ) decline in plasma HIV-1 RNA in the first 12 weeks or two consecutive measurements of more than 50 copies per mL from week 24 onwards , disease progression [ new Centers for Disease Control and Prevention grade C event or death ] , or change of allocated treatment ) . Analyses were by intention to treat . FINDINGS Treatment failure occurred in 96 ( 43.6 % ) of 220 patients assigned nevirapine once daily , 169 ( 43.7 % ) of 387 assigned nevirapine twice daily , 151 ( 37.8 % ) of 400 assigned efavirenz , and 111 ( 53.1 % ) of 209 assigned nevirapine plus efavirenz . The difference between nevirapine twice daily and efavirenz was 5.9 % ( 95 % CI -0.9 to 12.8 ) . There were no significant differences among the study groups in the proportions with plasma HIV-1 RNA concentrations below 50 copies per mL at week 48 ( p=0.193 ) or the increases in CD4-positive cells ( p=0.800 ) . Nevirapine plus efavirenz was associated with the highest frequency of clinical adverse events , and nevirapine once daily with significantly more hepatobiliary laboratory toxicities than efavirenz . Of 25 observed deaths , two were attributed to nevirapine . INTERPRETATION Antiretroviral therapy with nevirapine or efavirenz showed similar efficacy , so triple-drug regimens with either NNRTI are valid for first-line treatment . There are , however , differences in safety profiles . Combination of nevirapine and efavirenz did not improve efficacy but caused more adverse events BACKGROUND Lopinavir-ritonavir is a preferred protease inhibitor co-formulation for initial HIV-1 treatment . Fosamprenavir-ritonavir has shown similar efficacy and safety to lopinavir-ritonavir when each is combined with two nucleoside reverse transcriptase inhibitors . We compared the two treatments directly in antiretroviral-naive patients . METHODS This open-label , non-inferiority study included 878 antiretroviral-naive , HIV-1-infected patients r and omised to receive either fosamprenavir-ritonavir 700 mg/100 mg twice daily or lopinavir-ritonavir 400 mg/100 mg twice daily , each with the co-formulation of abacavir-lamivudine 600 mg/300 mg once daily . Primary endpoints were proportion of patients achieving HIV-1 RNA less than 400 copies per mL at week 48 and treatment discontinuations because of an adverse event . The intent-to-treat analysis included all patients exposed to at least one dose of r and omised study medication . This study is registered with Clinical Trials.gov , number NCT00085943 . FINDINGS At week 48 , non-inferiority of fosamprenavir-ritonavir to lopinavir-ritonavir ( 95 % CI around the treatment difference -4.84 to 7.05 ) was shown , with 315 of 434 ( 73 % ) patients in the fosamprenavir-ritonavir group and 317 of 444 ( 71 % ) in the lopinavir-ritonavir group achieving HIV-1 RNA less than 400 copies per mL. Treatment discontinuations due to an adverse event were few and occurred with similar frequency in the two treatment groups ( fosamprenavir-ritonavir 53 , 12 % ; lopinavir-ritonavir 43 , 10 % ) . Diarrhoea , nausea , and abacavir hypersensitivity were the most frequent drug-related grade 2 - 4 adverse events . Treatment-emergent drug resistance was rare ; no patient had virus that developed reduced susceptibility to fosamprenavir-ritonavir or lopinavir-ritonavir . INTERPRETATION Fosamprenavir-ritonavir twice daily in treatment-naive patients provides similar antiviral efficacy , safety , tolerability , and emergence of resistance as lopinavir-ritonavir , each in combination with abacavir-lamivudine BACKGROUND In the primary analysis of SPRING-2 at week 48 , dolutegravir showed non-inferior efficacy to and similar tolerability to raltegravir in adults infected with HIV-1 and naive for antiretroviral treatment . We present the 96 week results . METHODS SPRING-2 is an ongoing phase 3 , r and omised , double-blind , active-controlled , non-inferiority study in treatment-naive adults infected with HIV-1 that started in Oct 19 , 2010 . We present results for the safety cutoff date of Jan 30 , 2013 . Patients had to be aged 18 years or older and have HIV-1 RNA concentrations of 1000 copies per mL or more . Patients were r and omly assigned ( 1:1 ) to receive either dolutegravir ( 50 mg once daily ) or raltegravir ( 400 mg twice daily ) , plus investigator-selected tenofovir-emtricitabine or abacavir-lamivudine . Prespecified 96 week secondary endpoints included proportion of patients with HIV-1 RNA less than 50 copies per mL , CD4 cell count changes from baseline , safety , tolerability , and genotypic or phenotypic resistance . We used an intention-to-treat exposed population ( received at least one dose of study drug ) for the analyses . Sponsor staff were masked to treatment assignment until primary analysis at week 48 ; investigators , site staff , and patients were masked until week 96 . FINDINGS Of 1035 patients screened , 827 were r and omly assigned to study group , and 822 received at least one dose of the study drug ( 411 patients in each group ) . At week 96 , 332 ( 81 % ) of 411 patients in the dolutegravir group and 314 ( 76 % ) of 411 patients in the raltegravir group had HIV-1 RNA less than 50 copies per mL ( adjusted difference 4∙5 % , 95 % CI -1∙1 % to 10∙0 % ) confirming non-inferiority . Secondary analyses of efficacy such as per protocol ( HIV RNA < 50 copies per mL : 83 % for dolutegravir and 80 % for raltegravir ) and treatment-related discontinuation equals failure ( 93 % without failure for dolutegravir ; 91 % for raltegravir ) supported non-inferiority . Virological non-response occurred less frequently in the dolutegravir group ( 22 [ 5 % ] patients for dolutegravir vs 43 [ 10 % ] patients for raltegravir ) . Median increases in CD4 cell count from baseline were similar between groups ( 276 cells per μL for dolutegravir and 264 cells per μL for raltegravir ) . Ten patients ( 2 % ) in each group discontinued because of adverse events , with few such events between weeks 48 and 96 ( zero in the dolutegravir group and one in the raltegravir group ) . No study -related serious adverse events occurred between week 48 and week 96 . At virological failure , no additional resistance to integrase inhibitors or nucleotide reverse transcriptase inhibitors was detected since week 48 or in any patient receiving dolutegravir . INTERPRETATION At week 96 , once-daily dolutegravir was non-inferior to twice-daily raltegravir in treatment-naive , patients with HIV-1 . Once-daily dosing without requirement for a pharmacokinetic booster makes dolutegravir-based therapy an attractive treatment option for HIV-1-infected treatment-naive patients Objective : To assess lipoatrophy , other toxicities , and efficacy associated with abacavir as compared with stavudine in HIV-infected antiretroviral-naive patients . Methods : This was a prospect i ve , r and omized , open trial , stratified by viral load and CD4 cell count , conducted January 2001 to July 2004 . Two hundred thirty-seven adult patients with HIV infection initiating antiretroviral therapy were assigned to receive abacavir ( n = 115 ) or stavudine ( n = 122 ) , both combined with lamivudine and efavirenz . The primary endpoint was the proportion of patients with lipoatrophy as assessed by physician and patient observation at 96 weeks . Results : A lower proportion of patients assigned to abacavir developed clinical signs of lipoatrophy ( 4.8 % vs. 38.3 % ; P < 0.001 ) . These observations were confirmed by anthropometric data . Dual energy x-ray absorptiometry ( DEXA ) scans performed in 57 patients showed significantly greater total limb fat loss in the stavudine arm ( −1579 vs. 913 g ; P < 0.001 ) . The lipid profile in abacavir patients presented more favorable changes in the levels of triglycerides ( P = 0.03 ) , high-density lipoprotein cholesterol ( HDLc ; P < 0.001 ) , and apolipoprotein A1 ( P < 0.001 ) as well as in the ratio between total cholesterol and HDLc ( P = 0.005 ) . Throughout the study , a higher proportion of patients in the stavudine group received lipid-lowering agents as compared to the abacavir group ( 17 % vs. 4 % ; P = 0.002 ) . Similar virologic and immunologic responses were observed . Conclusions : Assuming the limitations inherent to clinical assessment , this study shows a notably weaker association of abacavir with lipoatrophy than stavudine . DEXA scans and anthropometric measurements supported the clinical findings . In addition , the lipid changes that occurred were more favorable in patients receiving abacavir BACKGROUND Dolutegravir ( S/GSK1349572 ) is a once-daily HIV integrase inhibitor with potent antiviral activity and a favourable safety profile . We compared dolutegravir with HIV integrase inhibitor raltegravir , as initial treatment for adults with HIV-1 . METHODS SPRING-2 is a 96 week , phase 3 , r and omised , double-blind , active-controlled , non-inferiority study that began on Oct 19 , 2010 , at 100 sites in Canada , USA , Australia , and Europe . Treatment-naive adults ( aged ≥ 18 years ) with HIV-1 infection and HIV-1 RNA concentrations of 1000 copies per mL or greater were r and omly assigned ( 1:1 ) via a computer-generated r and omisation sequence to receive either dolutegravir ( 50 mg once daily ) or raltegravir ( 400 mg twice daily ) . Study drugs were given with coformulated tenofovir/emtricitabine or abacavir/lamivudine . R and omisation was stratified by screening HIV-1 RNA ( ≤ 100,000 copies per mL or > 100,000 copies per mL ) and nucleoside reverse transcriptase inhibitor backbone . Investigators were not masked to HIV-1 RNA results before r and omisation . The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies per mL at 48 weeks , with a 10 % non-inferiority margin . Main secondary endpoints were changes from baseline in CD4 cell counts , incidence and severity of adverse events , changes in laboratory parameters , and genotypic or phenotypic evidence of resistance . Our primary analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT01227824 . FINDINGS 411 patients were r and omly allocated to receive dolutegravir and 411 to receive raltegravir and received at least one dose of study drug . At 48 weeks , 361 ( 88 % ) patients in the dolutegravir group achieved an HIV-1 RNA value of less than 50 copies per mL compared with 351 ( 85 % ) in the raltegravir group ( adjusted difference 2·5 % ; 95 % CI -2·2 to 7·1 ) . Adverse events were similar between treatment groups . The most common events were nausea ( 59 [ 14 % ] patients in the dolutegravir group vs 53 [ 13 % ] in the raltegravir group ) , headache ( 51 [ 12 % ] vs 48 [ 12 % ] ) , nasopharyngitis ( 46 [ 11 % ] vs 48 [ 12 % ] ) , and diarrhoea ( 47 [ 11 % ] in each group ) . Few patients had drug-related serious adverse events ( three [ < 1 % ] vs five [ 1 % ] ) , and few had adverse events leading to discontinuation ( ten [ 2 % ] vs seven [ 2 % ] in each group ) . CD4 cell counts increased from baseline to week 48 in both treatment groups by a median of 230 cells per μL. Rates of grade d laboratory toxic effects were similar . We noted no evidence of treatment-emergent resistance in patients with virological failure on dolutegravir , whereas of the patients with virologic failure who received raltegravir , one ( 6 % ) had integrase treatment-emergent resistance and four ( 21 % ) had nucleoside reverse transcriptase inhibitors treatment-emergent resistance . INTERPRETATION The non-inferior efficacy and similar safety profile of dolutegravir compared with raltegravir means that if approved , combination treatment with once-daily dolutegravir and fixed-dose nucleoside reverse transcriptase inhibitors would be an effective new option for treatment of HIV-1 in treatment-naive patients . FUNDING ViiV Healthcare BACKGROUND Tenofovir disoproxil fumarate can cause renal and bone toxic effects related to high plasma tenofovir concentrations . Tenofovir alafenamide is a novel tenofovir prodrug with a 90 % reduction in plasma tenofovir concentrations . Tenofovir alafenamide-containing regimens can have improved renal and bone safety compared with tenofovir disoproxil fumarate-containing regimens . METHODS In these two controlled , double-blind phase 3 studies , we recruited treatment-naive HIV-infected patients with an estimated creatinine clearance of 50 mL per min or higher from 178 outpatient centres in 16 countries . Patients were r and omly assigned ( 1:1 ) to receive once-daily oral tablets containing 150 mg elvitegravir , 150 mg cobicistat , 200 mg emtricitabine , and 10 mg tenofovir alafenamide ( E/C/F/tenofovir alafenamide ) or 300 mg tenofovir disoproxil fumarate ( E/C/F/tenofovir disoproxil fumarate ) with matching placebo . R and omisation was done by a computer-generated allocation sequence ( block size 4 ) and was stratified by HIV-1 RNA , CD4 count , and region ( USA or ex-USA ) . Investigators , patients , study staff , and those assessing outcomes were masked to treatment group . All participants who received one dose of study drug were included in the primary intention-to-treat efficacy and safety analyses . The main outcomes were the proportion of patients with plasma HIV-1 RNA less than 50 copies per mL at week 48 as defined by the the US Food and Drug Adminstration ( FDA ) snapshot algorithm ( pre-specified non-inferiority margin of 12 % ) and pre-specified renal and bone endpoints at 48 weeks . These studies are registered with Clinical Trials.gov , numbers NCT01780506 and NCT01797445 . FINDINGS We recruited patients from Jan 22 , 2013 , to Nov 4 , 2013 ( 2175 screened and 1744 r and omly assigned ) , and gave treatment to 1733 patients ( 866 given E/C/F/tenofovir alafenamide and 867 given E/C/F/tenofovir disoproxil fumarate ) . E/C/F/tenofovir alafenamide was non-inferior to E/C/F/tenofovir disoproxil fumarate , with 800 ( 92 % ) of 866 patients in the tenofovir alafenamide group and 784 ( 90 % ) of 867 patients in the tenofovir disoproxil fumarate group having plasma HIV-1 RNA less than 50 copies per mL ( adjusted difference 2·0 % , 95 % CI -0·7 to 4·7 ) . Patients given E/C/F/tenofovir alafenamide had significantly smaller mean serum creatinine increases than those given E/C/F/tenofovir disoproxil fumarate ( 0·08 vs 0·12 mg/dL ; p<0·0001 ) , significantly less proteinuria ( median % change -3 vs 20 ; p<0·0001 ) , and a significantly smaller decrease in bone mineral density at spine ( mean % change -1·30 vs -2·86 ; p<0·0001 ) and hip ( -0·66 vs -2·95 ; p<0·0001 ) at 48 weeks . INTERPRETATION Through 48 weeks , more than 90 % of patients given E/C/F/tenofovir alafenamide or E/C/F/tenofovir disoproxil fumarate had virological success . Renal and bone effects were significantly reduced in patients given E/C/F/tenofovir alafenamide . Although these studies do not have the power to assess clinical safety events such as renal failure and fractures , our data suggest that E/C/F/tenofovir alafenamide will have a favourable long-term renal and bone safety profile . FUNDING Gilead Sciences BACKGROUND Nevirapine ( NVP ) can be safely and effectively administered once-daily but has not been assessed in human immunodeficiency virus (HIV)-infected patients with tuberculosis ( TB ) . We studied the safety and efficacy of once-daily NVP , compared with efavirenz ( EFV ; st and ard therapy ) ; both drugs were administered in combination with 2 nucleoside reverse-transcriptase inhibitors . METHODS An open-label , noninferiority , r and omized controlled clinical trial was conducted at 3 sites in southern India . HIV-infected patients with TB were treated with a st and ard short-course anti-TB regimen ( 2EHRZ(3)/4RH(3 ) ; [ 2 months of Ethambutol , Isoniazid , Rifampicin , Pyrazinamide / 4 months of Isoniazid and Rifampicin ] thrice weekly ) and r and omized to receive once-daily EFV at a dose of 600 mg or NVP at a dose of 400 mg ( after 14 days of 200 mg administered once daily ) with didanosine 250/400 mg and lamivudine 300 mg after 2 months . Sputum smears and mycobacterial cultures were performed every month . CD4 + cell count , viral load , and liver function test results were monitored periodically . Primary outcome was a composite of death , virological failure , default , or serious adverse event ( SAE ) at 24 weeks . Both intent-to-treat and per protocol analyses were done , and planned interim analyses were performed . RESULTS A total of 116 patients ( 75 % [ 87 patients ] of whom had pulmonary TB ) , with a mean age of 36 years , a median CD4 + cell count of 84 cells/mm(3 ) , and a median viral load of 310 000 copies/mL , were r and omized . At 24 weeks , 50 of 59 patients in the EFV group and 37 of 57 patients in the NVP group had virological suppression ( P = .024 ) . There were no deaths , 1 SAE , and 5 treatment failures in the EFV arm , compared with 5 deaths , 2 SAEs , and 10 treatment failures in the NVP arm . The trial was halted by the data and safety monitoring board at the second interim analysis . Favorable TB treatment outcomes were observed in 93 % of the patients in the EFV arm and 84 % of the patients in the NVP arm ( P = .058 ) . CONCLUSIONS Compared with a regimen of didanosine , lamivudine , and EFV , a regimen of once-daily didanosine , lamivudine , and NVP was inferior and was associated with more frequent virologic failure and death . Clinical Trials Registration . NCT00332306 Objective : To compare alternative class-sparing antiretroviral regimens in treatment-naive subjects . Design : Open-label , multicenter , r and omized trial of up to 3 consecutive treatment regimens over 96 weeks . Methods : Two hundred ninety-one subjects received abacavir ( ABC ) and lamivudine and efavirenz ( nonnucleoside reverse transcriptase inhibitors [ NNRTIs ] ) , ritonavir-boosted amprenavir ( protease inhibitor [ PI ] ) , or stavudine ( nucleoside reverse transcriptase inhibitor [ NRTI ] ) by r and om assignment . The primary end points were the percentages of subjects with plasma HIV-1 RNA levels < 400 copies/mL and time to treatment failure over 96 weeks . Results : Ninety percent of subjects completed 96 weeks of follow-up , and 79 % remained on study treatment . At week 96 , there were no differences between arms in the percentages of subjects with plasma HIV-1 RNA levels < 400 and < 50 copies/mL , mean changes in plasma HIV-1 RNA levels , time to treatment failure , time to first or second virologic failure , or CD4 + cell counts . The NNRTI arm had a greater percentages of subjects with RNA levels ≤50 copies/mL at weeks 24 and 48 and a greater overall duration of plasma HIV-1 RNA levels < 400 copies/mL. Three subjects in the NNRTI arm had treatment failure on their first regimen and switched therapy compared with 16 in the NRTI arm and 13 in the PI arm . Twenty-one subjects had hypersensitivity reactions attributed to ABC ( 7.3 % ) . Fewer drugs were used by subjects in the NNRTI arm , and fewer subjects in the NNRTI arm used 3 drug classes . Conclusions : All treatment regimens demonstrated excellent 96-week results . Secondary analyses favored the NNRTI regimen over the PI and NRTI regimens BACKGROUND Integrase str and transfer inhibitors ( INSTIs ) are recommended components of initial antiretroviral therapy with two nucleoside reverse transcriptase inhibitors . Bictegravir is a novel , potent INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinical ly relevant drug-drug interactions . We aim ed to assess the efficacy and safety of bictegravir coformulated with emtricitabine and tenofovir alafenamide as a fixed-dose combination versus coformulated dolutegravir , abacavir , and lamivudine . METHODS We did this double-blind , multicentre , active-controlled , r and omised controlled non-inferiority trial at 122 outpatient centres in nine countries in Europe , Latin America , and North America . We enrolled HIV-1 infected adults ( aged ≥18 years ) who were previously untreated ( HIV-1 RNA ≥500 copies per mL ) ; HLA-B*5701-negative ; had no hepatitis B virus infection ; screening genotypes showing sensitivity to emtricitabine , tenofovir , lamivudine , and abacavir ; and an estimated glomerular filtration rate of 50 mL/min or more . Participants were r and omly assigned ( 1:1 ) , via a computer-generated allocation sequence ( block size of four ) , to receive coformulated bictegravir 50 mg , emtricitabine 200 mg , and tenofovir alafenamide 25 mg or coformulated dolutegravir 50 mg , abacavir 600 mg , and lamivudine 300 mg , with matching placebo , once daily for 144 weeks . R and omisation was stratified by HIV-1 RNA ( ≤100 000 copies per mL , > 100 000 to ≤400 000 copies per mL , or > 400 000 copies per mL ) , CD4 count ( < 50 cells per μL , 50 - 199 cells per μL , or ≥200 cells per μL ) , and region ( USA or ex-USA ) . Investigators , participants , and study staff giving treatment , assessing outcomes , and collecting data were masked to group assignment . The primary endpoint was the proportion of participants with plasma HIV-1 RNA less than 50 copies per mL at week 48 , as defined by the US Food and Drug Administration snapshot algorithm , with a prespecified non-inferiority margin of -12 % . All participants who received one dose of study drug were included in primary efficacy and safety analyses . This trial is registered with Clinical Trials.gov , number NCT02607930 . FINDINGS Between Nov 13 , 2015 , and July 14 , 2016 , we r and omly assigned 631 participants to receive coformulated bictegravir , emtricitabine , and tenofovir alafenamide ( n=316 ) or coformulated dolutegravir , abacavir , and lamivudine ( n=315 ) , of whom 314 and 315 patients , respectively , received at least one dose of study drug . At week 48 , HIV-1 RNA less than 50 copies per mL was achieved in 92·4 % of patients ( n=290 of 314 ) in the bictegravir , emtricitabine , and tenofovir alafenamide group and 93·0 % of patients ( n=293 of 315 ) in the dolutegravir , abacavir , and lamivudine group ( difference -0·6 % , 95·002 % CI -4·8 to 3·6 ; p=0·78 ) , demonstrating non-inferiority of bictegravir , emtricitabine , and tenofovir alafenamide to dolutegravir , abacavir , and lamivudine . No individual developed treatment-emergent resistance to any study drug . Incidence and severity of adverse events was mostly similar between groups except for nausea , which occurred less frequently in patients given bictegravir , emtricitabine , and tenofovir alafenamide than in those given dolutegravir , abacavir , and lamivudine ( 10 % [ n=32 ] vs 23 % [ n=72 ] ; p<0·0001 ) . Adverse events related to study drug were less common with bictegravir , emtricitabine , and tenofovir alafenamide than with dolutegravir , abacavir , and lamivudine ( 26 % [ n=82 ] vs 40 % [ n=127 ] ) , the difference being driven by a higher incidence of drug-related nausea in the dolutegravir , abacavir , and lamivudine group ( 5 % [ n=17 ] vs 17 % [ n=55 ] ; p<0·0001 ) . INTERPRETATION At 48 weeks , coformulated bictegravir , emtricitabine , and tenofovir alafenamide achieved virological suppression in 92 % of previously untreated adults and was non-inferior to coformulated dolutegravir , abacavir , and lamivudine , with no treatment-emergent resistance . Bictegravir , emtricitabine , and tenofovir alafenamide was safe and well tolerated with better gastrointestinal tolerability than dolutegravir , abacavir , and lamivudine . Because coformulated bictegravir , emtricitabine , and tenofovir alafenamide does not require HLA B*5701 testing and provides guideline -recommended treatment for individuals co-infected with HIV and hepatitis B , this regimen might lend itself to rapid or same-day initiation of therapy in the clinical setting . FUNDING Gilead Sciences BACKGROUND Integrase str and transfer inhibitors ( INSTIs ) coadministered with two nucleoside or nucleotide reverse transcriptase inhibitors ( NRTIs ) are recommended as first-line treatment for HIV , and coformulated fixed-dose combinations are preferred to facilitate adherence . We report 48-week results from a study comparing initial HIV-1 treatment with bictegravir-a novel INSTI with a high in-vitro barrier to resistance and low potential as a perpetrator or victim of clinical ly relevant drug interactions-coformulated with the NRTI combination emtricitabine and tenofovir alafenamide as a fixed-dose combination to dolutegravir administered with coformulated emtricitabine and tenofovir alafenamide . METHODS In this r and omised , double-blind , multicentre , placebo-controlled , non-inferiority trial , HIV-infected adults were screened and enrolled at 126 outpatient centres in 10 countries in Australia , Europe , Latin America , and North America . Participants were previously untreated adults ( HIV-1 RNA ≥500 copies per mL ) with estimated glomerular filtration rate of at least 30 mL/min . Chronic hepatitis B virus or hepatitis C co-infection was allowed . We r and omly assigned participants ( 1:1 ) to receive oral fixed-dose combination bictegravir 50 mg , emtricitabine 200 mg , and tenofovir alafenamide 25 mg or dolutegravir 50 mg with coformulated emtricitabine 200 mg and tenofovir alafenamide 25 mg , with matching placebo , once a day for 144 weeks . Investigators , participants , study staff , and those assessing outcomes were masked to treatment group . All participants who received at least one dose of study drug were included in primary efficacy and safety analyses . The primary endpoint was the proportion of participants with plasma HIV-1 RNA of less than 50 copies per mL at week 48 ( US Food and Drug Administration snapshot algorithm ) , with a prespecified non-inferiority margin of -12 % . This study is registered with Clinical Trials.gov , number NCT02607956 . FINDINGS Between Nov 11 , 2015 , and July 15 , 2016 , 742 participants were screened for eligibility , of whom 657 were r and omly assigned to treatment ( 327 with bictegravir , emtricitabine , and tenofovir alafenamide fixed-dose combination [ bictegravir group ] and 330 with dolutegravir plus emtricitabine and tenofovir alafenamide [ dolutegravir group ] ) . 320 participants who received the bictegravir regimen and 325 participants who received the dolutegravir regimen were included in the primary efficacy analyses . At week 48 , HIV-1 RNA < 50 copies per mL was achieved in 286 ( 89 % ) of 320 participants in the bictegravir group and 302 ( 93 % ) of 325 in the dolutegravir group ( difference -3·5 % , 95·002 % CI -7·9 to 1·0 , p=0·12 ) , showing non-inferiority of the bictegravir regimen to the dolutegravir regimen . No treatment-emergent resistance to any study drug was observed . Incidence and severity of adverse events were similar between groups , and few participants discontinued treatment due to adverse events ( 5 [ 2 % ] of 320 in the bictegravir group and 1 [ < 1 % ] 325 in the dolutegravir group ) . Study drug-related adverse events were less common in the bictegravir group than in the dolutegravir group ( 57 [ 18 % ] of 320 vs 83 [ 26 % ] of 325 , p=0·022 ) . INTERPRETATION At 48 weeks , virological suppression with the bictegravir regimen was achieved and was non-inferior to the dolutegravir regimen in previously untreated adults . There was no emergent resistance to either regimen . The fixed-dose combination of bictegravir , emtricitabine , and tenofovir alafenamide was safe and well tolerated compared with the dolutegravir regimen . FUNDING Gilead Sciences OBJECTIVES Boosted PIs are commonly prescribed in patients presenting with advanced HIV infection . We assessed the efficacy and tolerability of once-daily ritonavir-boosted atazanavir or darunavir plus two NRTIs in HIV-1-infected ART-naive patients with severe immunosuppression , targeting at least an 85 % success rate at week 48 . METHODS This 48 week , open-label , non-comparative , r and omized , multicentre trial included ART-naive patients with CD4 cell counts < 200 cells/mm(3 ) , with plasma HIV-1 RNA > 1000 copies/mL and without genotypic mutations conferring resistance to the study drugs . Patients were r and omized ( 1:1 ) to receive once-daily atazanavir/ritonavir ( 300/100 mg ) or darunavir/ritonavir ( 800/100 mg ) plus tenofovir disoproxil fumarate/emtricitabine or abacavir/lamivudine . The primary endpoint was treatment success , defined as plasma HIV-1 RNA ≤50 copies/mL at week 48 and no permanent PI/ritonavir discontinuation . The study was registered with Clinical Trials.gov ( NCT01928407 ) . RESULTS One hundred and twenty patients were enrolled : 77 % were men , 30 % were born in Africa and 39 % had AIDS . The median baseline CD4 and plasma HIV-RNA values were 69 cells/mm(3 ) and 5.4 log10 copies/mL. All but four patients received tenofovir disoproxil fumarate/emtricitabine . The week 48 treatment success rate was 66 % ( 95 % CI 54%-78 % ) with atazanavir/ritonavir and 80 % ( 95 % CI 68%-89 % ) with darunavir/ritonavir . The median CD4 cell count increased similarly in the two groups ( Δweek 48 to week 0 : + 194 cells/mm(3 ) ) . Adverse events occurred in 23 and 18 patients , respectively . CONCLUSIONS Despite good adherence , neither study regimen reached the predefined objective , suggesting a need for more potent regimens for patients with advanced HIV infection BACKGROUND Although efavirenz and lopinavir/ritonavir(r ) are both recommended antiretroviral agents in antiretroviral-naïve HIV-infected patients , there are few r and omized comparisons of their efficacy and tolerability . METHODS A multicenter and r and omized study was performed including 126 antiretroviral-naïve patients , r and omly assigned to efavirenz+Kivexa ( n=63 ) or lopinavir/r+Kivexa ( n=63 ) . Efficacy endpoints were the percentage of patients with HIV-RNA < or = 50 copies/mL at week 48 and CD4 recovery . Safety was assessed by comparing toxicity and discontinuations . Statistical analyses were performed on an intention-to-treat ( ITT ) basis ( Missing = Failure ) . RESULTS At week 48 , 56.7 % of patients in the efavirenz and 63.2 % in the lopinavir/r groups showed HIV-1 RNA < 50 copies/mL ( P=0.770 ) ( intention-to-treat analysis ; Missing = Failure ) . Only 1 ( 1.53 % ) patient from each group experienced virological failure . CD4 values increased in both groups ( 298 cells in the efavirenz group , P=0.001 ; 249 cells in the lopinavir/r group , P=0.002 ; P=0.126 between groups ) . HDL-cholesterol only increased in the efavirenz group ( from 39+/-12 mg/dL to 49+/-11 ; P=0.001 ) . Discontinuations were more frequent in the lopinavir/r group ( 36.5 % versus 28.5 % ; P=0.193 ) , but more patients with efavirenz interrupted due to toxicity ( 11.1 % versus 6.3 % ) ; most of them were attributed to hypersensitivity reaction . CONCLUSIONS Similar virological efficacy was observed for efavirenz and lopinavir/r , when administered with Kivexa in antiretroviral-naïve patients , while immunological improvement was slightly superior for efavirenz . The higher rate of discontinuation due to toxicity in the efavirenz group was related to a higher incidence of hypersensitivity reaction . Nowadays , the use of the new formulation of lopinavir/r and the HLA-B*5701 genotype test before starting abacavir should improve the safety profiles of these regimens Background : Abacavir sulfate/lamivudine ( ABC/3TC ) and tenofovir DF/emtricitabine ( TDF/FTC ) are widely used nucleoside reverse transcriptase inhibitors for initial HIV-1 treatment . This is the first completed , r and omized clinical trial to directly compare the efficacy , safety , and tolerability of these agents , each in combination with lopinavir/ritonavir in antiretroviral-naive patients . Methods : Six hundred and eighty-eight antiretroviral-naive , HIV-1-infected patients were r and omized in this double-blind , placebo-matched , multicenter , noninferiority study to receive a once-daily regimen of either ABC/3TC 600 mg/300 mg or TDF/FTC 300 mg/200 mg , both with lopinavir/ritonavir 800 mg/200 mg . Primary endpoints were the proportion of patients with HIV-1 RNA below 50 copies/ml at week 48 ( missing = failure , switch included analysis ) and the proportion of patients experiencing adverse events over 96 weeks . Results : At week 48 , 68 % in the ABC/3TC group vs. 67 % in the TDF/FTC group achieved an HIV-1 RNA below 50 copies/ml ( intent-to-treat exposed missing = failure , 95 % confidence interval on the difference −6.63 to 7.40 , P = 0.913 ) , demonstrating the noninferiority of ABC/3TC to TDF/FTC at week 48 . Noninferiority of the two regimens was sustained at week 96 ( 60 % vs. 58 % , respectively , 95 % confidence interval −5.41 to 9.32 , P = 0.603 ) . In addition , efficacy of both regimens was similar in patients with baseline HIV-1 RNA ≥ 100 000 copies/ml or CD4 + cell counts below 50 cells/μl . Median CD4 + recovery ( ABC/3TC vs. TDF/FTC , cells/μl ) was + 250 vs. + 247 by week 96 . Premature study discontinuation due to adverse events occurred in 6 % of patients in both groups . Protocol -defined virologic failure occurred in 14 % of patients in both groups . Conclusion : Both ABC/3TC and TDF/FTC provided comparable antiviral efficacy , safety , and tolerability when each was combined with lopinavir/ritonavir in treatment-naive patients BACKGROUND The combination of didanosine , lamivudine , and efavirenz ( ddI/3TC/EFV ) for the initial treatment of human immunodeficiency virus type 1 ( HIV-1 ) infection has been insufficiently analyzed in clinical trials . METHODS We conducted an open-label , r and omized study to compare the noninferiority of ddI/3TC/EFV with the lamivudine-zidovudine tablet and EFV ( COM/EFV ) , both administered with food to improve tolerability and convenience . Patients were stratified by HIV-1 RNA level of < 5.0 log(10 ) or > or = 5.0 log(10 ) copies/mL. The primary end point was the percentage of patients with an HIV-1 RNA level of < 50 copies/mL at week 48 , determined by intention-to-treat analysis . RESULTS Three hundred sixty-nine patients were r and omized : 186 for ddI/3TC/EFV treatment and 183 for COM/EFV treatment . Both groups were well matched in terms of baseline characteristics ; 19.3 % of patients received a Centers for Disease Control and Prevention assessment of clinical category C , median HIV RNA level was 5.0 log(10 ) copies/mL , and median CD4(+ ) cell count was 208 cells/microL. At week 48 , by intention-to-treat analysis , 70 % of patients in the ddI/3TC/EFV group and 63 % of patients in the COM/EFV group had an HIV-1 RNA level of < 50 copies/mL ( treatment difference , 7.1 % ; 95 % confidence interval , -2.39 % to 16.59 % ) . Fourteen patients ( 8 % ) in the ddI/3TC/EFV arm ( not the COM/EFV arm ) and 26 patients ( 14 % ) in the COM/EFV arm ( not the ddI/3TC/EFV arm ) [ corrected ] discontinued the study medication because of adverse events ( P = .046 ) . One patient ( 1 % ) in the ddI/3TC/EFV arm and 11 patients ( 6 % ) in the COM/EFV arm discontinued medication because of hematological toxicity ( P = .003 ) . CONCLUSIONS At week 48 , ddI/3TC/EFV administered once per day with food did not have results inferior to those of COM/EFV treatment . A statistically significantly higher proportion of patients in the COM/EFV arm than in the ddI/3TC/EFV arm discontinued therapy because of adverse events , mainly because of hematological toxicity . CLINICAL TRIALS REGISTRATION NCT00256828 Abstract Background : The objective of this study was to compare the efficacy of ritonavir boosted atazanavir versus ritonavir boosted lopinavir or efavirenz , all in combination with 2 nucleoside analogue reverse transcriptase inhibitors ( NRTIs ) , over 144 weeks in antiretroviral-naïve HIV-1-infected individuals . Methods : A prospect i ve open-label r and omized controlled trial was conducted at 29 sites in Sweden and Norway between April 2004 and December 2009 . Patients were r and omized to receive either efavirenz 600 mg once daily ( EFV ) , or atazanavir 300 mg and ritonavir 100 mg once daily ( AZV/r ) , or lopinavir 400 mg and ritonavir 100 mg twice daily ( LPV/r ) . The primary endpoints were the proportion of patients with HIV-1 RNA < 50 copies/ml at 48 and 144 weeks . Results : Of 245 patients enrolled , 243 were r and omized and 239 received the allocated intervention : 77 EFV , 81 AZV/r , and 81 LPV/r . Median ( interquartile range ) CD4 cell counts at baseline were 150 ( 80–200 ) , 170 ( 80–220 ) , and 150 ( 90–216 ) per microlitre , respectively . At week 48 the proportion ( 95 % confidence interval ( CI ) ) of patients achieving HIV-1 RNA < 50 copies/ml was 86 (78–94)% in the EFV arm , 78 (69–87)% in the AZV/r arm and , 69 (59–78)% in the LPV/r arm in the intention-to-treat analysis . There was a significant difference between the EFV and LPV/r arm ( p = 0.014 ) . At week 144 , the proportion ( 95 % CI ) of patients achieving HIV-1 RNA < 50 copies/ml was 61 (50–72)% , 58 (47–69)% , 51 (41–63)% , respectively ( p = 0.8 ) . Patients with CD4 cell counts of ≤ 200/μl or HIV-1 RNA > 100,000 copies/ml at baseline had similar response rates in all arms . Conclusion : EFV was superior to LPV/r at week 48 , but there were no significant differences between the 3 arms in the long-term ( 144 weeks ) follow-up BACKGROUND Nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy is not suitable for all treatment-naive HIV-infected persons . OBJECTIVE To evaluate 3 nonnucleoside reverse transcriptase inhibitor-sparing initial antiretroviral regimens to show equivalence for virologic efficacy and tolerability . DESIGN A phase 3 , open-label study r and omized in a 1:1:1 ratio with follow-up for at least 96 weeks . ( Clinical Trials.gov : NCT00811954 ) . SETTING 57 sites in the United States and Puerto Rico . PATIENTS Treatment-naive persons aged 18 years or older with HIV-1 RNA levels greater than 1000 copies/mL without resistance to nucleoside reverse transcriptase inhibitors or protease inhibitors . INTERVENTION Atazanavir , 300 mg/d , with ritonavir , 100 mg/d ; raltegravir , 400 mg twice daily ; or darunavir , 800 mg/d , with ritonavir , 100 mg/d , plus combination emtricitabine , 200 mg/d , and tenofovir disoproxil fumarate , 300 mg/d . MEASUREMENTS Virologic failure , defined as a confirmed HIV-1 RNA level greater than 1000 copies/mL at or after 16 weeks and before 24 weeks or greater than 200 copies/mL at or after 24 weeks , and tolerability failure , defined as discontinuation of atazanavir , raltegravir , or darunavir for toxicity . A secondary end point was a combination of virologic efficacy and tolerability . RESULTS Among 1809 participants , all pairwise comparisons of incidence of virologic failure over 96 weeks showed equivalence within a margin of equivalence defined as -10 % to 10 % . Raltegravir and ritonavir-boosted darunavir were equivalent for tolerability , whereas ritonavir-boosted atazanavir result ed in a 12.7 % and 9.2 % higher incidence of tolerability discontinuation than raltegravir and ritonavir-boosted darunavir , respectively , primarily because of hyperbilirubinemia . For combined virologic efficacy and tolerability , ritonavir-boosted darunavir was superior to ritonavir-boosted atazanavir , and raltegravir was superior to both protease inhibitors . Antiretroviral resistance at the time of virologic failure was rare but more frequent with raltegravir . LIMITATION The trial was open-label , and ritonavir was not provided . CONCLUSION Over 2 years , all 3 regimens attained high and equivalent rates of virologic control . Tolerability of regimens containing raltegravir or ritonavir-boosted darunavir was superior to that of the ritonavir-boosted atazanavir regimen . PRIMARY FUNDING SOURCE National Institute of Allergy and Infectious Diseases |
13,612 | 31,638,461 | No significant differences were found between MIRC and ORC in two oncologic outcomes : the recurrence rate and mortality .
Additionally , no significant differences were found in three pathologic outcomes : lymph node yield , positive lymph nodes , and positive surgical margins .
With respect to perioperative outcomes , however , MIRC showed a significantly longer operating time , less estimated blood loss , lower blood transfusion rate , shorter time to regular diet , and shorter length of hospital stay than ORC .
The incidence of complications was similar between the two techniques .
We found no statistically significant differences in the above outcomes between robot-assisted radical cystectomy and ORC or between laparoscopic radical cystectomy and ORC with the exception of the complication rate .
Conclusions MIRC is an effective and safe surgical approach in the treatment of bladder cancer . | Background We performed a systematic review and meta- analysis to evaluate the efficacy and safety of minimally invasive radical cystectomy ( MIRC ) versus open radical cystectomy ( ORC ) for bladder cancer . | The aim of this study was to compare the morbidity , mortality , oncological results and quality of life between laparoscopic radical cystectomy ( LRC ) and open radical cystectomy ( ORC ) in the elderly patients over 75 years old . Between January 2012 and January 2015 , 60 patients were recruited into this study , who were r and omly assigned in a 1:1 ratio to either LRC or ORC group . Baseline patient characteristics , pathological factors , operative and postoperative characteristics , postoperative complications and survival data were retrospectively collected , analyzed and compared between the two groups . Patients in LRC group and ORC group had comparable baseline characteristics and pathological factors ( all P > 0.05 ) . LRC group required longer operative time ( 408.2 ± 76.9 vs. 311.7 ± 65.3 min , P = 0.000 ) and had less EBL ( 621.6 ± 100.7 vs. 1088.5 ± 109.4 ml , P = 0.000 ) compared with ORC group . The incidence of infection and ileus within 90 days after surgery in ORC group was significantly higher than LRC group(6.9 % vs. 28.6 % , P = 0.041 ; 3.4 % vs. 25 % , P = 0.025 ) . At a median follow-up of 28 months ( range 12–48 months ) , the survival analysis showed that there were no significant differences between the LRC and ORC groups in overall survival ( log-rank χ2 = 0.122 ; P = 0.726 ) , or progress-free survival ( log-rank χ2 = 0.153 ; P = 0.696 ) . In conclusion , this study confirmed that LRC could achieve similar tumor treatment efficacy compared to ORC , with fewer perioperative complications and less blood loss . We suggest that LRC should be considered as the primary intervention for patients aged over 75 years old with muscle invasive bladder cancer or non-muscle invasive bladder cancer with high risk factors PURPOSE Robotic assisted laparoscopic radical cystectomy for bladder cancer has been reported with potential for improvement in perioperative morbidity compared to the open approach . However , most studies are retrospective with significant selection bias . MATERIAL S AND METHODS A pilot prospect i ve r and omized trial evaluating perioperative outcomes and oncologic efficacy of open vs robotic assisted laparoscopic radical cystectomy for consecutive patients was performed from July 2009 to June 2011 . RESULTS To date 47 patients have been r and omized with data available on 40 patients for analysis . Each group was similar with regard to age , gender , race , body mass index and comorbidities , as well as previous surgeries , operative time , postoperative complications and final pathological stage . We observed no significant differences between oncologic outcomes of positive margins ( 5 % each , p = 0.50 ) or number of lymph nodes removed for open radical cystectomy ( 23 , IQR 15 - 28 ) vs robotic assisted laparoscopic radical cystectomy ( 11 , IQR 8.75 - 21.5 ) groups ( p = 0.135 ) . The robotic assisted laparoscopic radical cystectomy group ( 400 ml , IQR 300 - 762.5 ) was noted to have decreased estimated blood loss compared to the open radical cystectomy group ( 800 ml , IQR 400 - 1,100 ) and trended toward a decreased rate of excessive length of stay ( greater than 5 days ) ( 65 % vs 90 % , p = 0.11 ) compared to the open radical cystectomy group . The robotic group also trended toward fewer transfusions ( 40 % vs 50 % , p = 0.26 ) . CONCLUSIONS Our study vali date s the concept of r and omizing patients with bladder cancer undergoing radical cystectomy to an open or robotic approach . Our results suggest no significant differences in surrogates of oncologic efficacy . Robotic assisted laparoscopic radical cystectomy demonstrates potential benefits of decreased estimated blood loss and decreased hospital stay compared to open radical cystectomy . Our results need to be vali date d in a larger multicenter prospect i ve r and omized clinical trial BACKGROUND Open radical cystectomy ( ORC ) and urinary diversion in patients with bladder cancer ( BCa ) are associated with significant perioperative complication risk . OBJECTIVE To compare perioperative complications between robot-assisted radical cystectomy ( RARC ) and ORC techniques . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve r and omized controlled trial was conducted during 2010 and 2013 in BCa patients scheduled for definitive treatment by radical cystectomy ( RC ) , pelvic lymph node dissection ( PLND ) , and urinary diversion . Patients were r and omized to ORC/PLND or RARC/PLND , both with open urinary diversion . Patients were followed for 90 d postoperatively . INTERVENTION St and ard ORC or RARC with PLND ; all urinary diversions were performed via an open approach . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Primary outcomes were overall 90-d grade 2 - 5 complications defined by a modified Clavien system . Secondary outcomes included comparison of high- grade complications , estimated blood loss , operative time , pathologic outcomes , 3- and 6-mo patient-reported quality -of-life ( QOL ) outcomes , and total operative room and inpatient costs . Differences in binary outcomes were assessed with the chi-square test , with differences in continuous outcomes assessed by analysis of covariance with r and omization group as covariate and , for QOL end points , baseline score . RESULTS AND LIMITATIONS The trial enrolled 124 patients , of whom 118 were r and omized and underwent RC/PLND . Sixty were r and omized to RARC and 58 to ORC . At 90 d , grade 2 - 5 complications were observed in 62 % and 66 % of RARC and ORC patients , respectively ( 95 % confidence interval for difference , -21 % to -13 % ; p=0.7 ) . The similar rates of grade 2 - 5 complications at our m and ated interim analysis met futility criteria ; thus , early closure of the trial occurred . The RARC group had lower mean intraoperative blood loss ( p=0.027 ) but significantly longer operative time than the ORC group ( p<0.001 ) . Pathologic variables including positive surgical margins and lymph node yields were similar . Mean hospital stay was 8 d in both arms ( st and ard deviation , 3 and 5 d , respectively ; p=0.5 ) . Three- and 6-mo QOL outcomes were similar between arms . Cost analysis demonstrated an advantage to ORC compared with RARC . A limitation is the setting at a single high-volume , referral center ; our findings may not be generalizable to all setting s. CONCLUSIONS This trial failed to identify a large advantage for robot-assisted techniques over st and ard open surgery for patients undergoing RC/PLND and urinary diversion . Similar 90-d complication rates , hospital stay , pathologic outcomes , and 3- and 6-mo QOL outcomes were observed regardless of surgical technique . PATIENT SUMMARY Of 118 patients with bladder cancer who underwent radical cystectomy , pelvic lymph node dissection , and urinary diversion , half were r and omized to open surgery and half to robot-assisted laparoscopic surgery . We compared the rate of complications within 90 d after surgery for the open group versus the robotic group and found no significant difference between the two groups . TRIAL REGISTRATION Clinical Trials.gov identifier NCT01076387 , www . clinical trials.gov BACKGROUND In recent years , surgeons have begun to report case series of minimally invasive approaches to radical cystectomy , including robotic-assisted techniques demonstrating the surgical feasibility of this procedure with the potential of lower blood loss and more rapid return of bowel function and hospital discharge . Despite these experiences and observations , at this point high levels of clinical evidence with regard to the benefits of robotic cystectomy are absent , and the current experiences represent case series with limited comparisons to historical controls at best . OBJECTIVE We report our results on a prospect i ve r and omized trial of open versus robotic-assisted laparoscopic radical cystectomy with regard to perioperative outcomes , complications , and short-term narcotic usage . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve r and omized single-center noninferiority study comparing open versus robotic approaches to cystectomy in patients who are c and i date s for radical cystectomy for urothelial carcinoma of the bladder . Of the 41 patients who underwent surgery , 21 were r and omized to the robotic approach and 20 to the open technique . INTERVENTION Radical cystectomy , bilateral pelvic lymphadenectomy , and urinary diversion by either an open approach or by a robotic-assisted laparoscopic technique . MEASUREMENTS The primary end point was lymph node ( LN ) yield with a noninferiority margin of four LNs . Secondary end points included demographic characteristics , perioperative outcomes , pathologic results , and short-term narcotic use . RESULTS AND LIMITATIONS On univariate analysis , no significant differences were found between the two groups with regard to age , sex , body mass index , American Society of Anesthesiologists classification , anticoagulation regimen of aspirin , clinical stage , or diversion type . Significant differences were noted in operating room time , estimated blood loss , time to flatus , time to bowel movement , and use of inpatient morphine sulfate equivalents . There was no significant difference in regard to overall complication rate or hospital stay . On surgical pathology , in the robotic group 14 patients had pT2 disease or higher ; 3 patients had pT3/T4 disease ; and 4 patients had node-positive disease . In the open group , eight patients had pT2 disease or higher ; five patients had pT3/T4 disease ; and seven patients had node-positive disease . The mean number of LNs removed was 19 in the robotic group versus18 in the open group . Potential study limitations include the limited clinical and oncologic follow-up and the relatively small and single-institution nature of the study . CONCLUSIONS We present the results of a prospect i ve r and omized controlled noninferiority study with a primary end point of LN yield , demonstrating the robotic approach to be noninferior to the open approach . The robotic approach also compares favorably with the open approach in several perioperative parameters BACKGROUND Radical cystectomy is the surgical st and ard for invasive bladder cancer . Robot-assisted cystectomy has been proposed to provide similar oncological outcomes with lower morbidity . We aim ed to compare progression-free survival in patients with bladder cancer treated with open cystectomy and robot-assisted cystectomy . METHODS The RAZOR study is a r and omised , open-label , non-inferiority , phase 3 trial done in 15 medical centres in the USA . Eligible participants ( aged ≥18 years ) had biopsy-proven clinical stage T1-T4 , N0-N1 , M0 bladder cancer or refractory carcinoma in situ . Individuals who had previously had open abdominal or pelvic surgery , or who had any pre-existing health conditions that would preclude safe initiation or maintenance of pneumoperitoneum were excluded . Patients were central ly assigned ( 1:1 ) via a web-based system , with block r and omisation by institution , stratified by type of urinary diversion , clinical T stage , and Eastern Cooperative Oncology Group performance status , to receive robot-assisted radical cystectomy or open radical cystectomy with extracorporeal urinary diversion . Treatment allocation was only masked from pathologists . The primary endpoint was 2-year progression-free survival , with non-inferiority established if the lower bound of the one-sided 97·5 % CI for the treatment difference ( robotic cystectomy minus open cystectomy ) was greater than -15 percentage points . The primary analysis was done in the per- protocol population . Safety was assessed in the same population . This trial is registered with Clinical Trials.gov , number NCT01157676 . FINDINGS Between July 1 , 2011 , and Nov 18 , 2014 , 350 participants were r and omly assigned to treatment . The intended treatment was robotic cystectomy in 176 patients and open cystectomy in 174 patients . 17 ( 10 % ) of 176 patients in the robotic cystectomy group did not have surgery and nine ( 5 % ) patients had a different surgery to that they were assigned . 21 ( 12 % ) of 174 patients in the open cystectomy group did not have surgery and one ( 1 % ) patient had robotic cystectomy instead of open cystectomy . Thus , 302 patients ( 150 in the robotic cystectomy group and 152 in the open cystectomy group ) were included in the per- protocol analysis set . 2-year progression-free survival was 72·3 % ( 95 % CI 64·3 to 78·8 ) in the robotic cystectomy group and 71·6 % ( 95 % CI 63·6 to 78·2 ) in the open cystectomy group ( difference 0·7 % , 95 % CI -9·6 % to 10·9 % ; pnon-inferiority=0·001 ) , indicating non-inferiority of robotic cystectomy . Adverse events occurred in 101 ( 67 % ) of 150 patients in the robotic cystectomy group and 105 ( 69 % ) of 152 patients in the open cystectomy group . The most common adverse events were urinary tract infection ( 53 [ 35 % ] in the robotic cystectomy group vs 39 [ 26 % ] in the open cystectomy group ) and postoperative ileus ( 33 [ 22 % ] in the robotic cystectomy group vs 31 [ 20 % ] in the open cystectomy group ) . INTERPRETATION In patients with bladder cancer , robotic cystectomy was non-inferior to open cystectomy for 2-year progression-free survival . Increased adoption of robotic surgery in clinical practice should lead to future r and omised trials to assess the true value of this surgical approach in patients with other cancer types . FUNDING National Institutes of Health National Cancer Institute Introduction Bladder cancer ( BC ) is a common malignancy and one of the most expensive to manage . Radical cystectomy ( RC ) with pelvic lymphadenectomy is a gold st and ard treatment for high-risk BC . Reductions in morbidity and mortality from RC may be achieved through robot-assisted RC ( RARC ) . Prospect i ve comparisons between open RC ( ORC ) and RARC have been limited by sample size , use of extracorporeal reconstruction and use of outcomes important for ORC . Conversely , while RARC is gaining in popularity , there is little evidence to suggest it is superior to ORC . We are undertaking a prospect i ve r and omised controlled trial ( RCT ) to compare RARC with intracorporeal reconstruction ( iRARC ) and ORC using multimodal outcomes to explore qualitative and quantitative recovery after surgery . Methods and analysis iROC is a multicentre prospect i ve RCT in English National Health Service ( NHS ) cancer centres . We will r and omise 320 patients undergoing RC to either iRARC or ORC . Treatment allocation will occur after trial entry and consent . The primary outcome is days alive and out of hospital within the first 90 days from surgery . Secondary outcomes will measure functional recovery ( activity trackers , chair-to-st and tests and health related quality of life ( HRQOL ) question naires ) , morbidity ( complications and readmissions ) , cost-effectiveness ( using EuroQol-5 Domain-5 levels ( EQ-5D-5L ) and unit costs ) and surgeon fatigue . Patients will be analysed according to intention to treat . The primary outcome will be transformed and analysed using regression . All statistical assumptions will be investigated . Secondary outcomes will be analysed using appropriate regression methods . An internal feasibility study of the first 30 patients will evaluate recruitment rates , acceptance of r and omised treatment choice , compliance outcome collection and to revise our sample size . Ethics and dissemination The study has ethical approval ( REC reference 16/NE/0418 ) . Findings will be made available to patients , clinicians , funders and the NHS through peer- review ed publications , social media and patient support groups . Trial registration numbers IS RCT N13680280 and NCT03049410 OBJECTIVE To evaluate the effect of the minimally invasive approach on spending and perioperative outcomes for patients undergoing radical cystectomy for bladder cancer . In a r and omized control trial conducted at high-volume centers , robotic , and open cystectomy were shown to have similar outcomes . However , because the majority of cystectomies are performed in low-volume centers , it is unknown whether these findings are broadly generalizable . MATERIAL S AND METHODS We identified Medicare patients who underwent radical cystectomy for bladder cancer between 2008 and 2015 . We examined the length of stay , readmission rate , and 90-day spending after minimally invasive or open cystectomy . We used multiple regressions to estimate the association between minimally invasive surgery and the outcomes , accounting for patient , hospital , and surgeon factors that may influence these outcomes . RESULTS Of 4760 patients , 693 ( 14.6 % ) underwent minimally invasive cystectomy and 4067 ( 85.4 % ) had an open approach . Minimally invasive cystectomy was associated with shorter length of stay ( 10.1 days vs 11.9 days , P < .001 ) , but no difference in readmission rate ( 27.4 % vs 26.8 % , P = .77 ) . Minimally invasive cystectomy was associated with lower adjusted 90-day episode spending ( $ 34,369 vs $ 38,071 , P < .001 ) . CONCLUSION In patients across diverse institutions in the United States , minimally invasive cystectomy was associated with a shorter length of stay than open cystectomy and reduced 90-day episode spending , but with no significant difference in readmission rate BACKGROUND Open radical cystectomy ( ORC ) has proven to be an important component in the treatment of high-risk bladder cancer ( BCa ) . ORC surgical morbidity remains high ; therefore , minimally invasive surgical techniques have been introduced in an attempt to improve patient outcomes . OBJECTIVE To compare cancer outcomes in BCa patients managed with ORC or robotic-assisted radical cystectomy ( RARC ) . DESIGN , SETTING , AND PARTICIPANTS A prospect i ve , r and omized trial was completed between 2010 and 2013 . Patients were r and omized to ORC/pelvic lymphadenectomy ( PLND ) or RARC/PLND , with all undergoing open/extracorporeal urinary diversion . Median follow-up was 4.9 ( IQR : 3.9 - 5.9 ) yr after surgery among surviving patients . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Secondary outcomes to the trial included recurrence-free , cancer-specific , and overall survival . RESULTS AND LIMITATIONS The trial r and omized 118 patients who underwent RC/PLND and urinary diversion . Sixty were r and omized to RARC and 58 to ORC . Four RARC-assigned patients refused r and omization and received ORC ; however , an intention to treat analysis was performed . No differences were observed in recurrence ( hazard ratio [ HR ] : 1.27 ; 95 % confidence interval [ CI ] : 0.69 - 2.36 ; p=0.4 ) or cancer-specific survival ( p=0.4 ) . No difference in overall survival was observed ( p=0.8 ) . However , the pattern of first recurrence demonstrated a nonstatistically significant increase in metastatic sites for those undergoing ORC ( sub-HR [ sHR ] : 2.21 ; 95 % CI : 0.96 - 5.12 ; p=0.064 ) and a greater number of local/abdominal sites in the RARC-treated patients ( sHR : 0.34 ; 95 % CI : 0.12 - 0.93 ; p=0.035 ) . The major limitation to this study is that the trial was not powered to determine differences in cancer recurrences , survival outcomes , or patterns of recurrence . CONCLUSIONS The secondary outcomes from our r and omized trial did not definitively demonstrate differences in cancer outcomes in patients treated with ORC or RARC . However , differences in observed patterns of first recurrence highlight the need for future studies . PATIENT SUMMARY Of 118 patients r and omly assigned to undergo radical cystectomy/pelvic lymphadenectomy and urinary diversion , half were assigned to open surgery and half to robot-assisted techniques . We found no difference in risk of recurring or dying of bladder cancer between the two groups |
13,613 | 23,955,465 | The available evidence is limited , but suggests that adjunctive G-CSF treatment in people with a diabetic foot infection , including infected ulcers , does not appear to increase the likelihood of resolution of infection or healing of the foot ulcer .
However , it does appear to reduce the need for surgical interventions , especially amputations , and the duration of hospitalisation .
Clinicians might consider adding G-CSF to the usual treatment of diabetic foot infections , especially in patients with a limb-threatening infection , but it is not clear which patients might benefit | BACKGROUND Granulocyte-colony stimulating factor ( G-CSF ) increases the release of neutrophil endothelial progenitor cells from the bone marrow and improves neutrophil functions , which are often impaired in people with diabetes .
OBJECTIVES To examine the effects of adjunctive G-CSF compared with placebo or no growth factor added to usual care on rates of infection , cure and wound healing in people with diabetes who have a foot infection . | Abstract Aims /hypothesis . To re-evaluate the use of Granulocyte-Colony Stimulating Factor ( G-CSF ) in the treatment of infected diabetic foot ulcers . Methods . Thirty-seven diabetic subjects were r and omised to Granulocyte-Colony Stimulating Factor ( G-CSF ) ( n=20 ) or placebo ( n=17 ) . The primary endpoint was resolution of cellulitis , which was evaluated clinical ly and with an infection summary score . Patients were hospitalised for 10 days and received subcutaneously either 5 µg/kg G-CSF or placebo daily . Ulcers were treated with a st and ard wound protocol and the patients were instructed to stay in bed . All subjects received antibiotics ( clindamycin and ciprofloxacin ) intravenously until the inflammation had subsided . Results . Patients who received G-CSF did not have an earlier resolution of clinical ly defined cellulitis ( p=0.57 ) . The infection summary score declined , but comparably , in both groups ( G-CSF : 29.5±18.4 to 6.7±6.3 p<0.001 , placebo : 24.2±16.9 to 8.9±7.2 p<0.001 ) . The ulcer volume , which was not greater among placebo patients , was reduced by 59 % in G-CSF and by 35 % in placebo patients . Conclusion /interpretation . We conclude that antibiotic and non weight-bearing therapy ( bed rest ) accelerated the resolution of cellulitis in infected foot ulcers . Additional treatment with G-CSF had no further beneficial effect EXECUTIVE SUMMARY : 1 . Foot infections in patients with diabetes cause substantial morbidity and frequent visits to health care professionals and may lead to amputation of a lower extremity . 2 . Diabetic foot infections require attention to local ( foot ) and systemic ( metabolic ) issues and coordinated management , preferably by a multidisciplinary foot-care team ( A-II ) . The team managing these infections should include , or have ready access to , an infectious diseases specialist or a medical microbiologist ( B-II ) . 3 . The major predisposing factor to these infections is foot ulceration , which is usually related to peripheral neuropathy . Peripheral vascular disease and various immunological disturbances play a secondary role . 4 . Aerobic Gram-positive cocci ( especially Staphylococcus aureus ) are the predominant pathogens in diabetic foot infections . Patients who have chronic wounds or who have recently received antibiotic therapy may also be infected with Gram-negative rods , and those with foot ischemia or gangrene may have obligate anaerobic pathogens . 5 . Wound infections must be diagnosed clinical ly on the basis of local ( and occasionally systemic ) signs and symptoms of inflammation . Laboratory ( including microbiological ) investigations are of limited use for diagnosing infection , except in cases of osteomyelitis ( B-II ) . 6 . Send appropriately obtained specimens for culture before starting empirical antibiotic therapy in all cases of infection , except perhaps those that are mild and previously untreated ( B-III ) . Tissue specimens obtained by biopsy , ulcer curettage , or aspiration are preferable to wound swab specimens ( A-I ) . 7 . Imaging studies may help diagnose or better define deep , soft-tissue purulent collection s and are usually needed to detect pathological findings in bone . Plain radiography may be adequate in many cases , but MRI ( in preference to isotope scanning ) is more sensitive and specific , especially for detection of soft-tissue lesions ( A-I ) . 8 . Infections should be categorized by their severity on the basis of readily assessable clinical and laboratory features ( B-II ) . Most important among these are the specific tissues involved , the adequacy of arterial perfusion , and the presence of systemic toxicity or metabolic instability . Categorization helps determine the degree of risk to the patient and the limb and , thus , the urgency and venue of management . 9 . Available evidence does not support treating clinical ly uninfected ulcers with antibiotic therapy ( D-III ) . Antibiotic therapy is necessary for virtually all infected wounds , but it is often insufficient without appropriate wound care . 10 . Select an empirical antibiotic regimen on the basis of the severity of the infection and the likely etiologic agent(s ) ( B-II ) . Therapy aim ed solely at aerobic Gram-positive cocci may be sufficient for mild-to-moderate infections in patients who have not recently received antibiotic therapy ( A-II ) . Broad-spectrum empirical therapy is not routinely required but is indicated for severe infections , pending culture results and antibiotic susceptibility data ( B-III ) . Take into consideration any recent antibiotic therapy and local antibiotic susceptibility data , especially the prevalence of methicillin-resistant S. aureus ( MRSA ) or other resistant organisms . Definitive therapy should be based on both the culture results and susceptibility data and the clinical response to the empirical regimen ( C-III ) . 11 . There is only limited evidence with which to make informed choices among the various topical , oral , and parenteral antibiotic agents . Virtually all severe and some moderate infections require parenteral therapy , at least initially ( C-III ) . Highly bioavailable oral antibiotics can be used in most mild and in many moderate infections , including some cases of osteomyelitis ( A-II ) . Topical therapy may be used for some mild superficial infections ( B-I ) . 12 . Continue antibiotic therapy until there is evidence that the infection has resolved but not necessarily until a wound has healed . Suggestions for the duration of antibiotic therapy are as follows : for mild infections , 12 weeks usually suffices , but some require an additional 12 weeks ; for moderate and severe infections , usually 24 weeks is sufficient , depending on the structures involved , the adequacy of debridement , the type of soft-tissue wound cover , and wound vascularity ( A-II ) ; and for osteomyelitis , generally at least 46 weeks is required , but a shorter duration is sufficient if the entire infected bone is removed , and probably a longer duration is needed if infected bone remains ( B-II ) . 13 . If an infection in a clinical ly stable patient fails to respond to 1 antibiotic courses , consider discontinuing all antimicrobials and , after a few days , obtaining optimal culture specimens ( C-III ) . 14 . Seek surgical consultation and , when needed , intervention for infections accompanied by a deep abscess , extensive bone or joint involvement , crepitus , substantial necrosis or gangrene , or necrotizing fasciitis ( A-II ) . Evaluating the limb 's arterial supply and revascularizing when indicated are particularly important . Surgeons with experience and interest in the field should be recruited by the foot-care team , if possible . 15 . Providing optimal wound care , in addition to appropriate antibiotic treatment of the infection , is crucial for healing ( A-I ) . This includes proper wound cleansing , debridement of any callus and necrotic tissue , and , especially , off-loading of pressure . There is insufficient evidence to recommend use of a specific wound dressing or any type of wound healing agents or products for infected foot wounds . 16 . Patients with infected wounds require early and careful follow-up observation to ensure that the selected medical and surgical treatment regimens have been appropriate and effective ( B-III ) . 17 . Studies have not adequately defined the role of most adjunctive therapies for diabetic foot infections , but systematic review s suggest that granulocyte colony-stimulating factors and systemic hyperbaric oxygen therapy may help prevent amputations ( B-I ) . These treatments may be useful for severe infections or for those that have not adequately responded to therapy , despite correcting for all amenable local and systemic adverse factors . 18 . Spread of infection to bone ( osteitis or osteomyelitis ) may be difficult to distinguish from noninfectious osteoarthropathy . Clinical examination and imaging tests may suffice , but bone biopsy is valuable for establishing the diagnosis of osteomyelitis , for defining the pathogenic organism(s ) , and for determining the antibiotic susceptibilities of such organisms ( B-II ) . 19 . Although this field has matured , further research is much needed . The committee especially recommends that adequately powered prospect i ve studies be undertaken to eluci date and vali date systems for classifying infection , diagnosing osteomyelitis , defining optimal antibiotic regimens in various situations , and clarifying the role of surgery in treating osteomyelitis ( A-III ) Abstract Objective : To calculate costs for the management of deep foot infections and to identify the most important factors related to treatment costs . Design : Costs for in-hospital care , surgery , investigations , antibacterials , visits to the foot-care team , orthopaedic appliances and topical treatment were calculated retrospectively from diagnosis until healing or death . Multiple regression analysis was used to identify factors that independently affect costs . Setting : A multidisciplinary foot-care team . Patients : 220 prospect ively followed patients with diabetes mellitus and deep foot infections who were referred to the team from 1986 to 1995 . Main Outcome Measures and Results : Total cost for healing without amputation was Swedish kronor (SEK)136 600 per patient , while the corresponding cost for healing with minor amputation was SEK260 000 and with major amputation was SEK234 500 . All costs were quoted in SEK at 1997 price levels ( £ 1 sterling and $ US1 equalled approximately SEK12.50 and SEK7.64 , respectively ) . The cost of antibacterials was 4%of total costs . The cost of topical treatment was 51 % of total costs and related to wound healing time . Number of weeks between diagnosis of deep foot infection and healing , and number of surgical procedures were variables that explained 95 % of costs in the multiple regression analysis . It was not possible to find any parameters present at diagnosis that could contribute to an explanation of total treatment costs . Conclusions : Topical treatment accounted for the largest proportion of total costs and the most important cost driving factors were wound healing duration and repeated surgery . Costs of antibacterials should not be used as an argument in the choice between early amputation and conservative treatment BACKGROUND The purpose of this study was to determine whether treatment with granulocyte colony-stimulating factor ( G-CSF ) , which mobilizes endothelial progenitor cells from bone marrow , can safely improve the clinical outcomes of patients with atherosclerotic peripheral artery disease ( PAD ) . METHODS AND RESULTS Thirty-nine patients with intractable PAD were r and omly assigned to 3 groups : a negative control group ( n=12 ) treated with conventional drug therapy ; a positive control group ( n=13 ) treated with conventional drug therapy plus bone marrow transplantation ( BMT ) ; and a G-CSF group ( n=14 ) treated with conventional therapy plus subcutaneous injection of 2 - 5 microg/kg of recombinant human G-CSF once daily for 10 days . One month after treatment , subjective symptoms improved significantly in the G-CSF and BMT groups . Ankle-brachial pressure index and transcutaneous oxygen pressure increased significantly in the BMT and G-CSF groups , but no such improvements were seen in the group receiving conventional therapy alone . CONCLUSIONS G-CSF improves the clinical signs and symptoms of patients with intractable PAD to the same degree as BMT does . This noninvasive treatment may thus represent a useful new approach to managing the disease AIMS Foot infections and the subsequent amputation of a lower extremity are the most common cause of hospitalization among patients with diabetes mellitus . Although there are several reasons for susceptibility to infection in diabetic patients , white blood cell dysfunction is considered to be an important cause for this tendency . Granulocyte-colony stimulating factor ( G-CSF ) increases the release of neutrophils from the bone marrow and improves neutrophil functions . Based on this knowledge , the aim of the present study was to investigate the effects of addition of G-CSF to the treatment of foot infections in diabetic patients . METHODS Thirty diabetic patients with foot infection were included in the study . Fifteen of the patients received st and ard treatment consisting of local wound care and antibiotics ( st and ard group ) , and the other 15 patients received G-CSF besides st and ard treatment ( G-CSF group ) . The objectives of this study were to determine the time to resolution of infection , time to hospital discharge , need for surgical intervention , and the effects of G-CSF on phagocytosis and respiratory burst of neutrophils . RESULTS Treatment with G-CSF led to significantly higher neutrophil counts on the 5th and 10th days , and at the end of treatment in the G-CSF treated group compared to the st and ard group . Respiratory burst of neutrophils increased significantly in both the G-CSF group ( from 1.6 + /- 0.3 to 2.3 + /- 0.5 , p = 0.001 ) and the st and ard group ( from 2.0 + /- 0.4 to 2.3 + /- 0.4 , p = 0.02 ) with treatment . But , while phagocytosis of neutrophils increased significantly in the G-CSF group ( from 70.4 + /- 2.0 to 74.5 + /- 1.9 , p = 0.004 ) , it did not change significantly in the st and ard group ( from 68.1 + /- 0.2 to 69.4 + /- 1.9 , p = 0.3 ) with treatment . Duration of hospitalization ( 26.9 + /- 2.0 vs. 28.3 days , p < 0.05 ) , duration of parenteral antibiotic administration ( 22.9 + /- 2.0 vs. 23.3 + /- 1.9 days , p < 0.05 ) , time to resolution of infection ( 23.6 + /- 1.8 vs. 22.3 + /- 1.7 days , p < 0.05 ) , and need for amputation ( 13.3 % vs. 20 % , p > 0.05 ) were similar between the G-CSF and the st and ard groups . CONCLUSIONS Although G-CSF improves neutrophil function as well as increasing the absolute numbers , this improvement is not associated with shortening of duration of antibiotic administration , duration of hospital stay or need for amputation in diabetic foot infection BACKGROUND Diabetic foot infections cause substantial morbidity and mortality . Neutrophil superoxide generation , a crucial part of neutrophil bactericidal activity , is impaired in diabetes . Granulocyte-colony stimulating factor ( G-CSF ) increases the release of neutrophils from the bone marrow and improves neutrophil function . We assessed G-CSF as adjuvant therapy for the treatment of severe foot infections in diabetic patients . METHODS 40 diabetic patients with foot infections were enrolled in a double-blind placebo-controlled study . On admission , patients were r and omly assigned G-CSF ( filgrastim ) therapy ( n = 20 ) or placebo ( n = 20 ) for 7 days . Both groups received similar antibiotic and insulin treatment . Neutrophils from the peripheral blood of these participants and from healthy controls were stimulated with opsonised zymosan , and superoxide production was measured by a spectrophotometric assay ( reduction of ferricytochrome C ) . FINDINGS G-CSF therapy was associated with earlier eradication of pathogens from the infected ulcer ( median 4 [ range 2 - 10 ] vs 8 [ 2 - 79 ] days in the placebo group ; p = 0.02 ) , quicker resolution of cellulitis ( 7 [ 5 - 20 ] vs 12 [ 5 - 93 ] days ; p = 0.03 ) , shorter hospital stay ( 10 [ 7 - 31 ] vs 17.5 [ 9 - 100 ] days ; p = 0.02 ) , and a shorter duration of intravenous antibiotic treatment ( 8.5 [ 5 - 30 ] vs 14.5 [ 8 - 63 ] days ; p = 0.02 ) . No G-CSF-treated patient needed surgery , whereas two placebo recipients underwent to amputation and two had extensive debridement under anaesthesia . After 7 days ' treatment , neutrophil superoxide production was significantly higher in the G-CSF group than in the placebo group ( 16.1 [ 4.2 - 24.2 ] vs 7.3 [ 2.1 - 11.5 ] nmol per 10(6 ) neutrophils in 30 min ; p < 0.0001 ) . G-CSF therapy was generally well tolerated . INTERPRETATION G-CSF treatment was associated with improved clinical outcome of foot infection in diabetic patients . This improvement may be related to an increase in neutrophil superoxide production Recently , animal studies have demonstrated the efficacy of endothelial progenitor cell ( EPC ) therapy for diabetic wound healing . Based on these pre clinical studies , we performed a prospect i ve clinical trial phase I/IIa study of autologous G-CSF-mobilized peripheral blood ( PB ) CD34 + cell transplantation for nonhealing diabetic foot patients . Diabetic patients with nonhealing foot ulcers were treated with 2 × 107 cells of G-CSF-mobilized PB CD34 + cells as EPC-enriched population . Safety and efficacy ( wound closure and vascular perfusion ) were evaluated 12 weeks posttherapy and further followed for complete wound closure and recurrence . A total of five patients were enrolled . Although minor amputation and recurrence were seen in three out of five patients , no death , other serious adverse events , or major amputation was seen following transplantation . Complete wound closure was observed at an average of 18 weeks with increased vascular perfusion in all patients . The outcomes of this prospect i ve clinical study indicate the safety and feasibility of CD34 + cell therapy in patients with diabetic nonhealing wounds This study assessed the safety and efficacy of filgrastim ( r-metHuG-CSF [ recombinant human methionine granulocyte colony-stimulating factor ] ) , when combined with intravenous ( IV ) antibiotics , in the treatment of hospitalized adult patients with multilobar community-acquired pneumonia ( CAP ) . Four hundred eighty patients were r and omized to receive placebo ( n=243 ) or filgrastim 300 microg/day ( n=237 ) , in addition to st and ard therapy . Treatment with study drug was continued for 10 days , until the peak white blood cell ( WBC ) count reached 75x109/L , until discharge from the hospital , until death , or until IV antibiotics were discontinued . Study -related observations continued through day 29 . Filgrastim increased WBC counts ( baseline median , 13.3x109/L ; median peak , 43 . 8x109/L ) . The 2 treatment groups were not statistically different with respect to the study end points ; however , there was a trend toward reduction of mortality in patients with pneumococcal bacteremia . Although further studies will be required to vali date this observation , filgrastim was safe and well tolerated when administered to patients with multilobar CAP |
13,614 | 28,594,069 | AUTHORS ' CONCLUSIONS This review suggests that people who receive intensive glycaemic control for treatment of diabetes had comparable risks of kidney failure , death and major cardiovascular events as people who received less stringent blood glucose control , while experiencing small clinical benefits on the onset and progression of microalbuminuria and myocardial infa rct ion . | BACKGROUND Diabetes is the leading cause of end-stage kidney disease ( ESKD ) around the world .
Blood pressure lowering and glucose control are used to reduce diabetes-associated disability including kidney failure .
However there is a lack of an overall evidence summary of the optimal target range for blood glucose control to prevent kidney failure .
OBJECTIVES To evaluate the benefits and harms of intensive ( HbA1c < 7 % or fasting glucose levels < 120 mg/dL versus st and ard glycaemic control ( HbA1c ≥ 7 % or fasting glucose levels ≥ 120 mg/dL for preventing the onset and progression of kidney disease among adults with diabetes . | Basic fibroblast growth factor ( bFGF ) is a potent endothelial cell mitogen that does not normally circulate , but increases in microalbuminuric adult type 2 diabetes mellitus . Earlier work indicated an unexpected association between low levels of plasma bFGF immunoreactivity and the subsequent 4-year need for laser treatment in 172 patients from the Veterans Affairs Diabetes Trial ( mean : age , 59 years ; diabetes duration , 11 years ; baseline hemoglobin A(1c ) , 9.5 % ) . In the present study , we tested for an association between endothelial cell inhibitory autoantibodies in plasma and the need for laser treatment . Inhibitory activity in endothelial cells from the immunoglobulin G fractions of plasma was significantly associated ( P = .002 ) with low plasma bFGF immunoreactivity . There was a significant association ( P = .003 ) between endothelial cell inhibitory autoantibodies in baseline plasma and the time to occurrence of first laser treatment after 4 years of study treatment . After adjusting for other risk factors , endothelial cell inhibitory activity greater than 90 % vs less than or equal to 90 % ( hazard ratio , 0.2 ; P = .003 ) and low-density lipoprotein cholesterol concentration ( hazard ratio , 0.98 ; P = .02 ) were each significant predictors of the time to first postr and omization laser occurrence . These results suggest that circulating autoantibodies inhibitory in endothelial cells may contribute to the need for laser treatment in adult men with advanced type 2 diabetes mellitus . Among the possible risk factors evaluated , baseline insulin use was the only variable significantly inversely ( P = .02 ) associated with the baseline occurrence of inhibitory endothelial cell autoantibodies . It could not be determined whether insulin use may decrease the occurrence of endothelial cell inhibitory autoantibodies in advancing adult type 2 diabetes mellitus Type 2 diabetes mellitus and cognitive impairment are 2 of the most common chronic conditions found in persons aged > or = 60 years . Clinical studies have shown a greater prevalence of global cognitive impairment , incidence of cognitive decline , and incidence of Alzheimer disease in patients with type 2 diabetes . To date , there have been no r and omized trials of the effects of long-term glycemic control on cognitive function and structural brain changes in patients with type 2 diabetes . The primary aim of the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) Memory in Diabetes Study ( ACCORD-MIND ) is to test whether there is a difference in the rate of cognitive decline and structural brain change in patients with diabetes treated with st and ard-care guidelines compared with those treated with intensive-care guidelines . This comparison will be made in a sub sample of 2,977 patients with diabetes participating in the ongoing ACCORD trial , a clinical trial sponsored by the National Heart , Lung , and Blood Institute ( NHLBI ) with support from the National Institute on Aging ( NIA ) . Data from this ACCORD sub study on the possible beneficial or adverse effects of intensive treatment on cognitive function will be obtained from a 30-minute test battery , administered at baseline and 20-month and 40-month visits . In addition , full-brain magnetic resonance imaging will be performed on 630 participants at baseline and at 40 months to assess the relation between the ACCORD treatments and structural brain changes . The general aim of ACCORD-MIND is to determine whether the intensive treatment of diabetes , a major risk factor for Alzheimer disease and vascular dementia , can reduce the early decline in cognitive function that could later evolve into more cognitively disabling conditions . This report presents the design , rationale , and methods of the ACCORD-MIND sub study CONTEXT Macular edema contributes to visual impairment , and albuminuria is associated with increased cardiovascular mortality in adults with type 2 diabetes mellitus . These microvascular complications result from increased capillary leakage of plasma proteins whose causation is not completely understood . OBJECTIVE The objective of the present study was to test whether plasma from type 2 diabetes with maculopathy/albuminuria or control subjects contains autoantibodies that can induce apoptosis or activate Rho kinase ( ROCK ) in endothelial cells . DESIGN A cohort of Veterans Affairs Diabetes Trial adults ( > 40 yr of age ) was r and omized to st and ard vs. intensive glycemic treatment lasting 5 - 7.5 yr . SETTING The study was conducted in outpatient clinics . PATIENTS Case and age-matched control subjects who differed for the baseline presence of significant diabetic maculopathy and /or progression to macro-albuminuria were included in the study . INTERVENTION Pharmacological and lifestyle interventions in the Veterans Affairs Diabetes Trial generally result ed in substantially improved glycemic , blood pressure , and lipid levels . RESULTS Autoantibodies from patients with macular edema or progression to albuminuria potently induced caspase-dependent apoptosis in endothelial cells ( up to 60 % ) , whereas IgG from age-matched normal plasma caused much less apoptosis ( < 10 % ; P < 0.0001 ) . The active inhibitory autoantibodies triggered stress fiber formation in endothelial cells likely through the activation of Rho guanosine 5'-triphosphatase , which could be nearly completed inhibited by 10 microm Y27632 , a specific ROCK inhibitor . CONCLUSIONS These results suggest that autoantibodies from a subset of advanced type 2 diabetes may contribute to diabetic vascular complications by activating ROCK , inducing stress fiber formation and apoptosis in endothelial cells OBJECTIVE We explore the effect of r and omized treatment , comparing intensive to st and ard glucose-lowering strategies on major cardiovascular outcomes , death , and severe adverse events in older versus younger participants in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial . RESEARCH DESIGN AND METHODS Participants with type 2 diabetes ( n = 10,251 ) with a mean age of 62 years , a median duration of diabetes of 10 years , and a median A1C of 8.1 % ( 65 mmol/mol ) were r and omized to treatment strategies targeting either A1C < 6.0 % ( 42 mmol/mol ) or 7.0–7.9 % ( 53–63 mmol/mol ) and followed for a mean of 3.7 years . Outcomes were analyzed within subgroups defined by baseline age ( < 65 vs. ≥65 years ) . RESULTS Older and younger ACCORD participants achieved similar intensive-arm A1C levels and between-arm A1C differences . Within the older subgroup , similar hazards of the cardiovascular primary outcome and total mortality were observed in the two arms . While there was no intervention effect on cardiovascular mortality in the older subgroup , there was an increased risk in the intensive arm for the younger subgroup ( older hazard ratio [ HR ] = 0.97 ; younger HR = 1.71 ; P = 0.03 ) . Regardless of intervention arm , the older subgroup experienced higher annualized rates of severe hypoglycemia ( 4.45 % intensive and 1.36 % st and ard ) than the younger subgroup ( 2.45 % intensive and 0.80 % st and ard ) . CONCLUSIONS Intensive glucose lowering increased the risk of cardiovascular disease and total mortality in younger participants , whereas it had a neutral effect in older participants . The intensive to st and ard relative risk of severe hypoglycemia was similar in both age subgroups , with higher absolute rates in older participants within both treatment arms Urinary albumin was studied in 45 patients with insulin-dependent diabetes in a 4-year prospect i ve r and omized trial , comparing continuous sc insulin infusion ( CSII ) , multiple insulin injections , and conventional treatment with twice daily injections . Strict blood glucose control was obtained with CSII and multiple injections , better than with conventional treatment ( 2P less than 0.01 ) : mean glycosylated haemoglobin ( % HbA1 + /- SEM ) after 4 years : CSII 9.0 + /- 0.4 % ; multiple injections 9.4 + /- 0.4 % ; conventional treatment 10.5 + /- 0.5 . A total of 696 24-h urine specimens were collected . After 4 years of CSII from the time of r and omization , urinary albumin excretion was reduced ( 26 + /- 5 to 16 + /- 4 mg/24 h , mean + /- SEM , 2P less than 0.01 ) , when compared with conventional treatment ( 2P = 0.01 ) , when compared with conventional treatment ( 2P = 0.01 ) where no change was observed ( 21 + /- 4 to 22 + /- 6 mg/24 h , n.s . ) . The reduction observed during multiple injection treatment was not significant ( 17 + /- 3 to 14 + /- 3 mg/24 h ) . Long-term near-normoglycaemia may influence the mechanisms leading to albuminuria in diabetes , if introduced at an early stage of the disease OBJECTIVE To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications , an 8-year prospect i ve study of Japanese patients with type 2 diabetes was performed . RESEARCH DESIGN AND METHODS A total of 110 patients with type 2 diabetes ( 55 with no retinopathy [ the primary prevention cohort ] and 55 with simple retinopathy [ the secondary intervention cohort ] ) were r and omly assigned to multiple insulin injection therapy ( MIT ) groups and administered three or more daily insulin injections or assigned to conventional insulin injection therapy ( CIT ) groups and administered one or two daily intermediate-acting insulin injections . Worsening of microvascular complications was regularly assessed during 8 years . Two or more steps up in the 19 stages of the modified Early Treatment of Diabetic Retinopathy Study classification in retinopathy and one or more stages up among three stages in nephropathy ( normoalbuminuria , microalbuminuria , and albuminuria ) were defined as worsening of complications . RESULTS In both primary prevention and secondary intervention cohorts , the cumulative percentages of worsening in retinopathy and nephropathy were significantly lower ( P < 0.05 ) in the MIT group than in the CIT group . In neurological tests after 8 years , the MIT group showed significant improvement ( P < 0.05 ) in the median nerve conduction velocities ( motor and sensory nerves ) , whereas the CIT group showed significant deterioration ( P < 0.05 ) in the nerve conduction velocities and vibration threshold . From this study , the glycemic threshold to prevent the onset and progression of diabetic microvascular complications was as follows : HbA1c < 6.5 % , fasting blood glucose concentration < 110 mg/dl , and 2-h postpr and ial blood glucose concentration < 180 mg/dl . CONCLUSIONS Intensive glycemic control can delay the onset and progression of the early stages of diabetic microvascular complications in Japanese patients with type 2 diabetes Background — We report relationships between cardiovascular disease risk factors and myocardial structure , function , and scar in patients with type 1 diabetes mellitus in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications ( DCCT/EDIC ) study . Methods and Results — Cardiac magnetic resonance was obtained in 1017 patients with type 1 diabetes mellitus . Gadolinium cardiac magnetic resonance was also obtained in 741 patients . The mean age was 49±7 years ; 52 % were men ; and mean duration of diabetes mellitus was 28±5 years . Associations of cardiovascular disease risk factors with cardiac magnetic resonance parameters were examined with linear and logistic regression models . History of macroalbuminuria was positively associated with left ventricular mass ( by 14.8 g ) , leading to a significantly higher ratio of left ventricular mass to end-diastolic volume ( by 8 % ) . Mean hemoglobin A1c levels over the preceding 22 years were inversely associated with end-diastolic volume ( −3.0 mL per unit mean hemoglobin A1c percent ) and stroke volume ( −2.3 mL per unit mean hemoglobin A1c percent ) and positively related to the ratio of elevated left ventricular mass to end-diastolic volume ( 0.02 g/mL per unit ) . The overall prevalence of myocardial scar was 4.3 % by cardiac magnetic resonance and 1.4 % by clinical adjudication of myocardial infa rct ion . Both mean hemoglobin A1c ( odds ratio , 1.5 [ 95 % confidence interval , 1.0–2.2 ] per unit ) and macroalbuminuria ( odds ratio , 3.5 [ 95 % confidence interval , 1.2–9.9 ] ) were significantly associated with myocardial scar and traditional cardiovascular disease risk factors . Conclusions — In addition to traditional cardiovascular disease risk factors , elevated mean hemoglobin A1c and macroalbuminuria were significantly associated with alterations in left ventricular structure and function . The prevalence of myocardial scar was 4.3 % in this subcohort of DCCT/EDIC participants with relatively preserved renal function . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifiers : NCT00360893 and NCT00360815 BACKGROUND The Diabetes Control and Complications Trial ( DCCT ) showed a beneficial effect of 6.5 years of intensive glycemic control on retinopathy in patients with type 1 diabetes . METHODS Between 1983 and 1989 , a total of 1441 patients with type 1 diabetes in the DCCT were r and omly assigned to receive either intensive diabetes therapy or conventional therapy aim ed at preventing hyperglycemic symptoms . They were treated and followed until 1993 . Subsequently , 1375 of these patients were followed in the observational Epidemiology of Diabetes Interventions and Complications ( EDIC ) study . The self-reported history of ocular surgical procedures was obtained annually . We evaluated the effect of intensive therapy as compared with conventional therapy on the incidence and cost of ocular surgery during these two studies . RESULTS Over a median follow-up of 23 years , 130 ocular operations were performed in 63 of 711 patients assigned to intensive therapy ( 8.9 % ) and 189 ocular operations in 98 of 730 patients assigned to conventional therapy ( 13.4 % ) ( P<0.001 ) . After adjustment for DCCT baseline factors , intensive therapy was associated with a reduction in the risk of any diabetes-related ocular surgery by 48 % ( 95 % confidence interval [ CI ] , 29 to 63 ; P<0.001 ) and a reduction in the risk of all such ocular procedures by 37 % ( 95 % CI , 12 to 55 ; P=0.01 ) . Forty-two patients who received intensive therapy and 61 who received conventional therapy underwent cataract extraction ( adjusted risk reduction with intensive therapy , 48 % ; 95 % CI , 23 to 65 ; P=0.002 ) ; 29 patients who received intensive therapy and 50 who received conventional therapy underwent vitrectomy , retinal-detachment surgery , or both ( adjusted risk reduction , 45 % ; 95 % CI , 12 to 66 ; P=0.01 ) . The costs of surgery were 32 % lower in the intensive-therapy group . The beneficial effects of intensive therapy were fully attenuated after adjustment for mean glycated hemoglobin levels over the entire follow-up . CONCLUSIONS Intensive therapy in patients with type 1 diabetes was associated with a substantial reduction in the long-term risk of ocular surgery . ( Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others ; DCCT/EDIC Clinical Trials.gov numbers , NCT00360893 and NCT00360815 . ) Background — Recent evidence suggests that visit-to-visit variability in systolic blood pressure ( SBP ) and maximum SBP are predictors of cardiovascular disease . However , it remains uncertain whether these parameters predict the risks of macrovascular and microvascular complications in patients with type 2 diabetes mellitus . Methods and Results — The Action in Diabetes and Vascular Disease : Preterax and Diamicron Modified Release Controlled Evaluation ( ADVANCE ) was a factorial r and omized controlled trial of blood pressure lowering and blood glucose control in patients with type 2 diabetes mellitus . The present analysis included 8811 patients without major macrovascular and microvascular events or death during the first 24 months after r and omization . SBP variability ( defined as st and ard deviation ) and maximum SBP were determined during the first 24 months after r and omization . During a median 2.4 years of follow-up from the 24-month visit , 407 major macrovascular ( myocardial infa rct ion , stroke , or cardiovascular death ) and 476 microvascular ( new or worsening nephropathy or retinopathy ) events were observed . The association of major macrovascular and microvascular events with SBP variability was continuous even after adjustment for mean SBP and other confounding factors ( both P<0.05 for trend ) . Hazard ratios ( 95 % confidence intervals ) for the highest tenth of SBP variability were 1.54 ( 0.99–2.39 ) for macrovascular events and 1.84 ( 1.19–2.84 ) for microvascular events in comparison with the lowest tenth . For maximum SBP , hazard ratios ( 95 % confidence intervals ) for the highest tenth were 3.64 ( 1.73–7.66 ) and 2.18 ( 1.04–4.58 ) , respectively . Conclusion — Visit-to-visit variability in SBP and maximum SBP were independent risk factors for macrovascular and microvascular complications in type 2 diabetes mellitus . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique Identifier : NCT00145925 OBJECTIVE To investigate the association between dietary n-3 long-chain polyunsaturated fatty acids ( n-3 LC-PUFAs ) and the degree and development of albuminuria in type 1 diabetes . RESEARCH DESIGN AND METHODS We analyzed longitudinal data from 1,436 participants in the Diabetes Control and Complications Trial . We defined the average intake of eicosapentaenoic and docosahexaenoic acid from diet histories . Urinary albumin excretion rates ( UAERs ) were measured over 24 h ; incident albuminuria was considered the first occurrence of an UAER > 40 mg/24 h sustained for ≥1 year in normoalbuminuric individuals . RESULTS In a mean follow-up of 6.5 years , we observed a lower mean UAER ( difference 22.7 mg/24 h [ 95 % CI 1.6–43.8 ) ] ) in the top versus the bottom third of dietary n-3 LC-PUFAs , but we found no association with incident albuminuria . CONCLUSIONS Dietary n-3 LC-PUFAs appear inversely associated with the degree but not with the incidence of albuminuria in type 1 diabetes . These findings require further investigation in prospect i ve studies AIMS The aim of the present study was to investigate the association of high-sensitivity C-reactive protein ( CRP ) , interleukin-6 ( IL-6 ) and lipoprotein-associated phospholipase A2 ( Lp-PLA2 ) with the extent of calcified coronary atherosclerosis in patients with type 2 diabetes mellitus ( T2DM ) . MATERIAL S AND RESULTS This is a cross-sectional study of 306 subjects aged 40years or older who were enrolled into the veterans affairs diabetes trial ( VADT ) . Calcified coronary atherosclerosis was assessed using electron beam computed tomography scored by the Agatston method . Clinical parameters , traditional cardiovascular risk factors and plasma levels of CRP , IL-6 and Lp-PLA2 were measured at the time of the scan . Coronary artery calcium ( CAC ) scores increased stepwise across increasing categories of IL-6 , but did not change across increasing categories of CRP and Lp-PLA2 . After adjustment for traditional cardiovascular risk factors , IL-6 was significantly associated with CAC scores ( p=0.05 ) . The association between IL-6 and CAC was largely in those with lower ( below the median ) abdominal artery calcium ( AAC ) levels ( p=0.04 ) . CONCLUSIONS Despite a generally higher level of systemic inflammation in T2DM , the inflammatory marker IL-6 remained significantly associated with CAC score , particularly in those subjects with lower AAC scores The Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial is a r and omized , multicenter clinical trial using a double 2 x 2 factorial design in 10,251 participants with type 2 diabetes mellitus at high risk for cardiovascular disease ( CVD ) events . ACCORD is testing 3 complementary medical treatment strategies that may reduce high rates of major CVD morbidity and mortality in patients with type 2 diabetes . The ACCORD vanguard phase , conducted at 59 clinics in the United States and Canada , recruited 1,174 participants in 20 weeks from January through June 1 , 2001 , with a recruitment efficiency ( R-factor ) of 0.65 . The recruitment strategies used in this vanguard phase were almost exclusively chart and data base review within clinical practice s and institutions . Recruitment for the main trial began in February 2003 , involved 77 clinics , and result ed in an additional 9,077 participants by October 29 , 2005 ( total , 10,251 ) . The R-factor during main trial recruitment was 0.96 . Although new and refined recruitment strategies were formulated from the vanguard experience , the most powerful determinant of improved recruitment efficiency was the immediate start of enrollment by most clinics at the beginning of the main trial . Recruitment in the main trial required only a brief extension of 3 months and facilitated the nearly complete capture of the expected number of person-years of observation . Described herein are vanguard and main trial recruitment activities , including strategy implementation , screening procedures , r and omization results , problems encountered , and lessons learned OBJECTIVE Blood pressure ranges associated with cardiovascular disease ( CVD ) events in advanced type 2 diabetes are not clear . Our objective was to determine whether baseline and follow-up ( On- Study ) systolic blood pressure ( SBP ) , diastolic blood pressure ( DBP ) , and SBP combined with DBP predict CVD events in the Veterans Affairs Diabetes Trial ( VADT ) . RESEARCH DESIGN AND METHODS Participants in the VADT ( n = 1,791 ) with hypertension received stepped treatment to maintain blood pressure below the target of 130/80 mmHg in st and ard and intensive glycemic treatment groups . Blood pressure levels of all subjects at baseline and On- Study were analyzed to detect associations with CVD risk . The primary outcome was the time from r and omization to the first occurrence of myocardial infa rct ion , stroke , congestive heart failure , surgery for vascular disease , inoperable coronary disease , amputation for ischemic gangrene , or CVD death . RESULTS Separated SBP ≥140 mmHg had significant risk at baseline ( hazards ratio [ HR ] 1.508 , P < 0.001 ) and On- Study ( HR 1.469 , P = 0.002 ) . DBP < 70 mmHg increased CVD events at baseline ( HR 1.482 , P < 0.001 ) and On- Study ( HR 1.491 , P < 0.001 ) . Combined blood pressure categories indicated high risk for CVD events for SBP ≥140 with DBP < 70 mmHg at baseline ( HR 1.785 , P = 0.03 ) and On- Study ( HR 2.042 , P = 0.003 ) and nearly all SBP with DBP < 70 mmHg . CONCLUSIONS Increased risk of CVD events with SBP ≥140 mmHg emphasizes the urgency for treatment of systolic hypertension . Increased risk with DBP < 70 mmHg , even when combined with SBP in guideline -recommended target ranges , supports a new finding in patients with type 2 diabetes . The results emphasize that DBP < 70 mmHg in these patients was associated with elevated CVD risk and may best be avoided Background Errors in clinical laboratory data are rare but their potential high cost both in terms of harm to the subject as well as diluted statistical power results in a significant workload for experts , who must review large volumes of data in the search for these errors . Purpose The current research objective is to develop and evaluate a method to assist in detecting potential errors in laboratory data for an interventional clinical trial , such as Action to Control Cardiovascular Risk in Diabetes , where treatment effects may be influenced by errors in the data . Methods Utilizing data from a clinical trial investigating the effect of intensive glycemic control on major cardiovascular disease events , we constructed an algorithm that conducts probabilistic error detection called a ‘ Bayesian network ’ . Using a synthetic error model , errors were introduced into a testing data set , and the Bayesian network ’s performance in identifying those errors was compared to laboratory experts . For each laboratory result we used the Bayesian network to compute the probability , the measured value was erroneous . This probability was then used to compute a receiver operating characteristic ( ROC ) curve . Three laboratory experts were recruited and took a survey consisting of 200 laboratory results . The task was to evaluate if these results were erroneous or not and to provide a confidence rating on a 6-point subjective probability scale . Results The Bayesian network ’s overall area under the ROC curve was calculated to be 0.79 , whereas the three laboratory experts had areas under the ROC curve of 0.73 , 0.73 , and 0.72 . Perfect error prediction and r and om guessing yield a ROC of 1.00 and 0.50 , respectively . This difference in performance was statistically significant for all three experts . Human experts were also generally overconfident in their ability to detect errors . Limitations The model is , by design , specific to a novel intervention in a specific diabetic population and , therefore , the specific Bayesian network discussed may not generalize to other interventions and population s. In addition , the study is limited by the small number of expert eligible to complete the survey . Conclusions The results of this study suggest that continuous Bayesian networks , suitably constructed , may serve as an effective tool to assist experts in the review of voluminous laboratory data by flagging unlikely results for more thorough review . Clinical Trials 2010 ; 7 : 380—389 . AIM To determine if serum pigment epithelium-derived factor ( PEDF ) levels in Type 2 diabetes are related to vascular risk factors and renal function . METHODS PEDF was quantified by ELISA in a cross-sectional study of 857 male Veterans Affairs Diabetes Trial ( VADT ) subjects , and associations with cardiovascular risk factors and renal function were determined . In a subset ( n=246 ) in whom serum was obtained early in the VADT ( 2.0±0.3 years post-r and omization ) , PEDF was related to longitudinal changes in renal function over 3.1 years . RESULTS Cross-sectional study : In multivariate regression models , PEDF was positively associated with serum triglycerides , waist-to-hip ratio , serum creatinine , use of ACE inhibitors or angiotensin receptor blockers , and use of lipid-lowering agents ; it was negatively associated with HDL-C ( all p<0.05 ) . Longitudinal study : PEDF was not associated with changes in renal function over 3.1 years ( p>0.09 ) . CONCLUSIONS Serum PEDF in Type 2 diabetic men was cross-sectionally associated with dyslipidemia , body habitus , use of common drugs for blood pressure and dyslipidemia , and indices of renal function ; however , PEDF was not associated with renal decline over 3.1years OBJECTIVE To determine the occurrence of extremely low HDL cholesterol ( HDL-C ) among participants in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) Lipid Trial and to examine the relationship of this finding with treatment with fenofibrate and thiazolidinedione ( TZD ) . RESEARCH DESIGN AND METHODS The ACCORD Lipid Trial was a r and omized , double-blind , placebo-controlled study conducted in patients with type 2 diabetes at 77 clinical centers across the U.S. and Canada in a 5,518-patient subset of the larger 10,251 ACCORD Glycemia Trial . Patients were enrolled from 11 January 2001 to 29 October 2005 and followed until the end of study visits between 1 March and 30 June 2009 . Follow-up in the ACCORD Lipid Trial was 4–8 years ( mean 4.7 years ) . Patients were treated with blinded fenofibrate or placebo on a background of simvastatin therapy . The main outcome measures for these descriptive , post hoc analyses was the occurrence of extremely low HDL-C ( defined as < 25 mg/dL [ 0.647 mmol/L ] ) during the trial . RESULTS Among ACCORD Lipid Trial participants , the occurrence of extremely low HDL-C ever during study follow-up was 106 % higher among those r and omized to fenofibrate ( 10.1 % fenofibrate vs. 4.9 % placebo , P < 0.001 ) . The occurrence of low HDL-C was associated with concurrent treatment with fenofibrate and TZD ( 7.0 % for both vs. 2.2 % for neither at 48 months postr and omization ) . CONCLUSIONS Idiosyncratic and marked reduction in HDL-C can occur in some patients treated with both fenofibrate and TZD . Practitioners should recognize this important potential idiosyncratic reaction and take appropriate corrective action Diabetic retinopathy ( DR ) is a major microvascular complication of diabetes mellitus . The Action to Control Cardiovascular Risk in Diabetes Eye Study ( ACCORD-EYE ) , a prospect i ve study of a subset of patients in the r and omized controlled clinical ACCORD trial , is being conducted at enrollment and after 4 years of follow-up to assess the progression of DR with st and ardized comprehensive eye exams and fundus photography of 7 st and ard stereoscopic fields . This study aims to assess the effects of the ACCORD medical treatment strategies of tight control of glycemia and blood pressure and management of dyslipidemia on the course of DR in patients with type 2 diabetes . Photographs will be evaluated at a central ized location using the modified Early Treatment Diabetic Retinopathy Study ( ETDRS ) classification . The primary outcome of ACCORD-EYE , which will measure the development and progression of DR , is a composite of ( 1 ) progression of DR ( > or = 3 steps on the ETDRS scale ) , ( 2 ) photocoagulation for DR , or ( 3 ) vitrectomy for DR . Specifically , the following questions will be addressed : ( 1 ) Does a therapeutic strategy targeting a glycosylated hemoglobin ( HbA(1c ) ) level < 6.0 % reduce development and progression of DR more than one targeting an HbA(1c ) level of 7.0%-7.9 % ( target median level , 7.5 % ) ? ( 2 ) In the context of good glycemic control , does a strategy using a fibrate to increase high-density lipoprotein cholesterol and lower triglyceride levels and a statin to maintain the level of low-density lipoprotein ( LDL ) cholesterol at < 2.59 mmol/L ( 100 mg/dL ) reduce development and progression of DR compared with one using placebo and a statin to treat LDL cholesterol ? ( 3 ) In the context of good glycemic control , does a strategy targeting a systolic blood pressure level < 120 mm Hg reduce development and progression of DR compared with one targeting a level < 140 mm Hg ? Secondary outcome variables include various levels of loss of visual acuity at 4 years versus baseline , cataract extraction , and the development or progression of diabetic macular edema . Methods to measure DR progression have been incorporated into ACCORD , and complete baseline data have been collected on 3,537 participants . These data will provide valuable information regarding the effects of medical treatment on the prevention and progression of DR OBJECTIVE R and omized treatment comparing an intensive glycemic treatment strategy with a st and ard strategy in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial was ended early because of an unexpected excess of mortality in the intensive arm . As part of ongoing post hoc analyses of potential mechanisms for this finding , we explored whether on-treatment A1C itself had an independent relationship with mortality . RESEARCH DESIGN AND METHODS Participants with type 2 diabetes ( n = 10,251 with mean age 62 years , median duration of diabetes 10 years , and median A1C 8.1 % ) were r and omly assigned to treatment strategies targeting either A1C < 6.0 % ( intensive ) or A1C 7.0–7.9 % ( st and ard ) . Data obtained during 3.4 ( median ) years of follow-up before cessation of intensive treatment were analyzed using several multivariable models . RESULTS Various characteristics of the participants and the study sites at baseline had significant associations with the risk of mortality . Before and after adjustment for these covariates , a higher average on-treatment A1C was a stronger predictor of mortality than the A1C for the last interval of follow-up or the decrease of A1C in the first year . Higher average A1C was associated with greater risk of death . The risk of death with the intensive strategy increased approximately linearly from 6–9 % A1C and appeared to be greater with the intensive than with the st and ard strategy only when average A1C was > 7 % . CONCLUSIONS These analyses implicate factors associated with persisting higher A1C levels , rather than low A1C per se , as likely contributors to the increased mortality risk associated with the intensive glycemic treatment strategy in ACCORD Patients with insulin-dependent diabetes mellitus ( IDDM ) , non-proliferative retinopathy and unsatisfactory blood glucose control were r and omized to intensified conventional treatment ( ICT , 48 patients ) or regular treatment ( RT , 54 patients ) for a 5-year study . After 18 months the glycosylated hemoglobin ( HbA1c ) was reduced in both groups , but significantly more in the ICT group ( p = 0.00005 ) . Thirty of the RT patients and 16 from the ICT group deteriorated as to retinopathy ( p = 0.024 ) . Microalbuminuria appeared more often in the RT patients ( p = 0.023 ) , and nerve conduction velocities were significantly reduced only in the RT group ( p between 0.0005 and 0.047 ) . Serious hypoglycemia was more common in the ICT patients ( p = 0.003 ) . The progression of diabetic late complications was thus slowed down by intensified treatment , but at the price of an increased frequency of serious hypoglycemia OBJECTIVE The feasibility study for the VA Cooperative Study on Glycemic Control and Complications in Type 2 Diabetes ( VA CSDM ) prospect ively studied 153 insulin-requiring type 2 diabetes patients , r and omized between an intensively treated arm and a st and ard treatment arm during a mean follow-up of 27 months . The glycemic response to each of the progressive , sequential phases of insulin treatment was assessed , along with the incidence of hypoglycemic reactions and the relative efficacy of different doses of glipizide in combination with fixed doses of insulin . RESEARCH DESIGN AND METHODS Five medical centers participated ; half of the patients were assigned to the intensive treatment arm aim ing for normal HbA1c levels . Age of patients was 60 ± 6 years , duration of diabetes 8 ± 3 years , and BMI 30.7 ± 4 kg/m2 . A fourstep management technique was used , with patients moving to the next step if the operational goals were not met : Phase I , evening intermediate or long-acting insulin ; phase II , added daytime glipizide ; phase III , two injections of insulin alone ; and phase IV multiple daily insulin injections . Home glucose monitoring measurements were done twice daily and at 3:00 A.M. once a week . Hypoglycemic reactions and home glucose monitoring results were recorded and counted in each of the treatment phases . RESULTS Baseline HbA1c was 9.3 ± 1.8 % , and fasting plus serum glucose was 11.4 ± 3.3 mmol/1 . Fasting serum glucose fell to near normal in phase I , and remained so in the other treatment phases . An HbA1c separation of 2.1 % between the arms was maintained during the course of the study , while the intensive arm kept HbA1c levels below 7.3 % ( P = 0.001 ) . Most of the decrease in HbA1c occurred with one injection of insulin alone ( phase I , − 1.4 % ) or adding daytime glipizide ( phase II , −1.9 % compared with baseline ) . HbA1c did not decrease further after substituting two injections of insulin alone , with twice the insulin dose . Multiple daily injections result ed in an additional HbA1c fall ( −2.4 % compared with baseline ) . However , two-thirds of the patients were still on one or two injections a day at the end of the study Changes in home glucose monitoring levels paralleled those of the HbA1c , as did the increments in number of reported hypoglycemic reactions , virtually all either “ mild ” or “ moderate ” in character . For the combination of glipizide and insulin ( phase II ) , the only significant effect was obtained with daily doses up to 10 mg a day ; there were no significant additional benefits with up to fourfold higher daily doses , and HbA1c levels had an upward trend with doses > 20 mg/day . CONCLUSIONS A simple regime of a single injection of insulin , alone or with glipizide , seemed sufficient to obtain clinical ly acceptable levels of HbA1c for most obese , insulin-requiring type 2 diabetes patients . Further decrease of HbA1c dem and ed multiple daily injections at the expense of doubling the insulin dose and the rate of hypoglycemic events . In combination therapy , doses of glipizide > 20 mg/day offered no additional benefit Previous studies have demonstrated that intensified treatment can result in lower blood glucose concentrations and retard microvascular complications . In the Stockholm Diabetes Intervention Study , 96 patients were followed for 5 years ; 44 patients received intensified , conventional treatment and 52 patients received regular treatment . Changes in conceptions and attitudes that accompanied intensified treatment were evaluated with question naires and semistructured interviews . After education and personal tutoring , HbAlc was significantly lower in patients in the intensified treatment group compared with patients in the regular treatment group . Self-rated well-being and perceived ability to control the diabetes increased more in the patients in the intensified treatment group . Blood glucose testing became more important to the patients in the intensified treatment group , who used the blood glucose tests more frequently whenever necessary , and who acted on the test results . Microvascular complications were retarded or halted OBJECTIVE Intensive glucose-lowering therapy ( INT ) did not reduce macrovascular events in the recent r and omized trials , possibly because it did not improve or worsen other traditional or novel cardiovascular risk factors . RESEARCH DESIGN AND METHODS St and ard plasma lipids , cholesterol content of lipoprotein subfractions , and plasma inflammatory and prothrombotic markers were determined in a subgroup of the Veterans Affairs Diabetes Trial ( VADT ) participants ( n = 266 ) at baseline and after 9 months of INT or st and ard therapy . RESULTS INT lowered glycated hemoglobin ( by a median of 2 % vs. a median of 0.7 % by st and ard treatment ; P < 0.0001 ) ; increased BMI ( 4 vs. 1 % ; P < 0.001 ) , total HDL ( 9 vs. 4 % ; P < 0.05 ) , HDL2 ( 14 vs. 0 % ; P = 0.009 ) , LDL2 ( 36 vs. 1 % ; P < 0.0001 ) , and plasma adiponectin ( 130 vs. 80 % ; P < 0.01 ) ; and reduced triglycerides ( −13 vs. −4 % ; P = 0.02 ) and small , dense LDL4 ( −39 vs. −13 % ; P < 0.001 ) , but had no effect on levels of plasma apolipoproteins B-100 and B-48 , C-reactive protein , interleukin-6 , lipoprotein-associated phospholipase A2 , myeloperoxidase , fibrinogen , and plasminogen activator inhibitor 1 . Incident macrovascular events were associated with baseline interleukin-6 ( hazard ratio per each quartile increase 1.33 [ 95 % CI 1.06–1.66 ] ) , total LDL ( 1.25 [ 1.01–1.55 ] ) , apolipoprotein B-100 ( 1.29 [ 1.01–1.65 ] ) , and fibrinogen ( 1.26 [ 1.01–1.57 ] ) but not changes in any cardiovascular risk factors at 9 months . CONCLUSIONS INT was associated with improved adiponectin , lipid levels , and a favorable shift in LDL and HDL subfractions after 9 months . These data suggest that the failure of INT to lower cardiovascular outcomes occurred despite generally favorable changes in st and ard and novel risk factors early in the study Abstract Aims /hypothesisFenofibrate has been noted to cause an elevation in serum creatinine in some individuals . Participants in the Action to Control Cardiovascular Risk in Diabetes Lipid Study were studied to better characterise who is at risk of an increase in creatinine level and to determine whether those with creatinine elevation have a differential risk of adverse renal or cardiovascular outcomes . Methods A fenofibrate-associated creatinine increase ( FACI ) was defined as an increase in serum creatinine of at least 20 % from baseline to month 4 in participants assigned to fenofibrate . Baseline patient characteristics , and baseline and 4-month drug , clinical , laboratory characteristics and study outcomes were examined by FACI status . Results Of the sample , 48 % of those r and omised to receive fenofibrate had at least a 20 % increase in serum creatinine within 4 months . In multivariable analysis , participants who were older , male , used an ACE inhibitor at baseline , used a thiazolidinedione ( TZD ) at 4 months post-r and omisation , had baseline CVD , and had lower baseline serum creatinine and LDL-cholesterol levels were all more likely to meet the criteria for FACI . Participants in the FACI group were also more likely to have a decrease in their serum triacylglycerol level from baseline to 4 months . No differences in study outcomes were seen by FACI criteria . Conclusions /interpretationSeveral characteristics predict a rapid rise in serum creatinine upon starting fenofibrate . Participants who met the criteria for FACI also had a greater change in triacylglycerol levels . In the setting of careful renal function surveillance and reduction of fenofibrate dose as indicated , no increase in renal disease or cardiovascular outcome was seen in those individuals demonstrating FACI . Trial registration : ClincalTrials.gov : NCT00000620 Funding : The ACCORD Trial was supported by grants ( N01-HC-95178 , N01-HC-95179 , N01-HC-95180 , N01-HC-95181 , N01-HC-95182 , N01-HC-95183 , N01-HC-95184 , IAA-Y1-HC-9035 and IAA-Y1-HC-1010 ) from the National Heart , Lung , and Blood Institute ; by the National Institute of Diabetes and Digestive and Kidney Diseases , the National Institute on Aging , and the National Eye Institute ; by the Centers for Disease Control and Prevention ; by General Clinical Research Centers and by the Clinical and Translational Science Awards . Abbott Laboratories , Amylin Pharmaceutical , AstraZeneca Pharmaceuticals LP , Bayer HealthCare LLC , Closer Healthcare , GlaxoSmithKline Pharmaceuticals , King Pharmaceuticals , Merck , Novartis Pharmaceuticals , Novo Nordisk , Omron Healthcare , sanofi-aventis US and Takeda Pharmaceuticals provided study medications , equipment or supplies Results of the main Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial indicate that intensive glucose lowering increases cardiovascular and all-cause mortality . As the contribution of mild-to-moderate chronic kidney disease ( CKD ) to these risks is not known , we assessed the impact on cardiovascular outcomes in this population . Renal function data were available on 10,136 patients of the original ACCORD cohort . Of those , 6,506 were free of CKD at baseline and 3,636 met the criteria for CKD . Participants were r and omly assigned to a treatment strategy of either intensive or st and ard glycemic goal . The primary outcome , all-cause and cardiovascular mortality , and prespecified secondary outcomes were evaluated . Risk for the primary outcome was 87 % higher in patients with than in those without CKD ( hazard ratio of 1.866 ; 95 % CI : 1.651 - 2.110 ) . All prespecified secondary outcomes were 1.5 to 3 times more frequent in patients with than in those without CKD . In patients with CKD , compared with st and ard therapy , intensive glucose lowering was significantly associated with both 31 % higher all-cause mortality ( 1.306 : 1.065 - 1.600 ) and 41 % higher cardiovascular mortality ( 1.412 : 1.052 - 1.892 ) . No significant effects were found in patients without CKD . Thus , in high-risk patients with type II diabetes , mild and moderate CKD is associated with increased cardiovascular risk . Intensive glycemic control significantly increases the risk of cardiovascular and all-cause mortality in this population Objectives In general population s , the adverse effects of smoking on coronary risk have been demonstrated to be greater in women than in men ; whether this is true for individuals with diabetes is unclear . Design Cohort study . Setting 20 countries worldwide participating in the ADVANCE ( Action in Diabetes and Vascular Disease : Preterax and Diamicron modified release Controlled Evaluation ) trial . Participants 11 140 patients with type 2 diabetes aged ≥55 years and in cardiovascular risk at the time of r and omisation . Primary and secondary outcome measures Major cardiovascular events ( death from cardiovascular disease , non-fatal stroke or non-fatal myocardial infa rct ion ( MI ) ) , all cardiovascular events ( major cardiovascular event or peripheral arterial disease or transient ischaemic attack ) , and all-cause mortality . Secondary outcome measures were major coronary events ( fatal and non-fatal MI ) , major cerebrovascular events ( fatal and non-fatal stroke ) , nephropathy ( new or worsening renal disease ) , and all cancer . Results At baseline , 6466 ( 56 % women ) participants were never-smokers , 1550 ( 28 % women ) were daily smokers and 3124 ( 21 % women ) were former smokers . Median follow-up time was 5 years . In Cox regression models after multiple adjustments , compared with never smoking , daily smoking was associated with increased risk of all primary and secondary outcomes with the exception of major cerebrovascular disease . Only for major coronary events was there any evidence of a stronger effect in women than in men ( ratio of the adjusted HRs women : men ; 1.64 ( 0.83 to 3.26 ) p=0.08 ) . For all other outcomes considered , the hazards of smoking were similar in men and women . Quitting smoking was associated with a 30 % reduction in all-cause mortality ( p=0.001 ) in both sexes . Conclusions In individuals with diabetes , the effects of smoking on all major forms of cardiovascular disease are equally as hazardous in women and men with the possible exception of major coronary events where there was some evidence of a greater hazard in women . Trial registration number NCT00145925 Aims /hypothesisThere is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes . Here , we investigate the relationship between HbA1c and the risks of vascular complications and death in such patients . Methods Eleven thous and one hundred and forty patients were r and omised to intensive or st and ard glucose control in the Action in Diabetes and Vascular disease : Preterax and Diamicron Modified Release Controlled Evaluation ( ADVANCE ) trial . Glycaemic exposure was assessed as the mean of HbA1c measurements during follow-up and prior to the first event . Adjusted risks for each HbA1c decile were estimated using Cox models . Possible differences in the association between HbA1c and risks at different levels of HbA1c were explored using linear spline models . Results There was a non-linear relationship between mean HbA1c during follow-up and the risks of macrovascular events , microvascular events and death . Within the range of HbA1c studied ( 5.5–10.5 % ) , there was evidence of ‘ thresholds ’ , such that below HbA1c levels of 7.0 % for macrovascular events and death , and 6.5 % for microvascular events , there was no significant change in risks ( all p > 0.8 ) . Above these thresholds , the risks increased significantly : every 1 % higher HbA1c level was associated with a 38 % higher risk of a macrovascular event , a 40 % higher risk of a microvascular event and a 38 % higher risk of death ( all p < 0.0001 ) . Conclusions /interpretationIn patients with type 2 diabetes , HbA1c levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0 % and microvascular events down to a threshold of 6.5 % . There was no evidence of lower risks below these levels but neither was there clear evidence of harm . Trial Registration : Clinical Trial.gov NCT00145925 Funding : Servier and the National Health and Medical Research Council of Australia ( project grant ID 211086 and programme grant IDs 358395 and 571281 74 insulin-dependent diabetic patients with background retinopathy were r and omised to continue with usual diabetic care ( group U ) or to a more intensive programme ( group A ) using ultralente insulin as basal cover and soluble insulin at mealtimes . Group A attended the clinic more frequently , received closer dietary supervision , and were taught home blood glucose monitoring . Group A had a significantly lower mean glycosylated haemoglobin level during the study , although the mean level also fell in group U towards the end of year 2 . Renal and sensory-nerve function were significantly better preserved in group A than in group U. Significant improvements were also seen in low-density-lipoprotein-cholesterol and whole-blood low-shear viscosity . The rate of progression of retinopathy was similar in both groups . It appears that a modest improvement in diabetic control , obtainable in most clinics , has been associated with a reduction in the progression of diabetic tissue damage Objectives To investigate potential determinants of severe hypoglycaemia , including baseline characteristics , in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial and the association of severe hypoglycaemia with levels of glycated haemoglobin ( haemoglobin A1C ) achieved during therapy . Design Post hoc epidemiological analysis of a double 2 × 2 factorial , r and omised , controlled trial . Setting Diabetes clinics , research clinics , and primary care clinics . Participants 10 209 of the 10 251 participants enrolled in the ACCORD study with type 2 diabetes , a haemoglobin A1C concentration of 7.5 % or more during screening , and aged 40 - 79 years with established cardiovascular disease or 55 - 79 years with evidence of significant atherosclerosis , albuminuria , left ventricular hypertrophy , or two or more additional risk factors for cardiovascular disease ( dyslipidaemia , hypertension , current smoker , or obese ) . Interventions Intensive ( haemoglobin A1C < 6.0 % ) or st and ard ( haemoglobin A1C 7.0 - 7.9 % ) glucose control . Main outcome measures Severe hypoglycaemia was defined as episodes of “ low blood glucose ” requiring the assistance of another person and documentation of either a plasma glucose less than 2.8 mmol/l ( < 50 mg/dl ) or symptoms that promptly resolved with oral carbohydrate , intravenous glucose , or glucagon . Results The annual incidence of hypoglycaemia was 3.14 % in the intensive treatment group and 1.03 % in the st and ard glycaemia group . We found significantly increased risks for hypoglycaemia among women ( P=0.0300 ) , African-Americans ( P<0.0001 compared with non-Hispanic whites ) , those with less than a high school education ( P<0.0500 compared with college graduates ) , aged participants ( P<0.0001 per 1 year increase ) , and those who used insulin at trial entry ( P<0.0001 ) . For every 1 % unit decline in the haemoglobin A1C concentration from baseline to 4 month visit , there was a 28 % ( 95 % CI 19 % to 37 % ) and 14 % ( 4 % to 23 % ) reduced risk of hypoglycaemia requiring medical assistance in the st and ard and intensive groups , respectively . In both treatment groups , the risk of hypoglycaemia requiring medical assistance increased with each 1 % unit increment in the average up date d haemoglobin A1C concentration ( st and ard arm : hazard ratio 1.76 , 95 % CI 1.50 to 2.06 ; intensive arm : hazard ratio 1.15 , 95 % CI 1.02 to 1.21 ) . Conclusions A greater drop in haemoglobin A1C concentration from baseline to the 4 month visit was not associated with an increased risk for hypoglycaemia . Patients with poorer glycaemic control had a greater risk of hypoglycaemia , irrespective of treatment group . Identification of baseline subgroups with increased risk for severe hypoglycaemia can provide guidance to clinicians attempting to modify patient therapy on the basis of individual risk . Trial registration Clinical Trials.gov number NCT00000620 OBJECTIVE The Veterans Affairs Diabetes Trial ( VADT ) was a r and omized , prospect i ve , controlled trial of 1,791 patients with type 2 diabetes to determine whether intensive glycemic control would reduce cardiovascular events compared with st and ard control . The effect of intensive glycemic control and selected baseline variables on renal outcomes is reported . RESEARCH DESIGN AND METHODS Baseline mean age was 60.4 years , mean duration of diabetes was 11.5 years , HbA1c was 9.4 % , and blood pressure was 132/76 mmHg . The renal exclusion was serum creatinine > 1.6 mg/dL. Renal outcomes were sustained worsening of the urine albumin-to-creatinine ratio ( ACR ) and sustained worsening by one or more stages in the estimated glomerular filtration rate ( eGFR ) . RESULTS Intensive glycemic control did not independently reduce ACR progression but was associated with a significant attenuation in the progression of ACR in those who had baseline photocoagulation , cataract surgery , or both . The beneficial effect of intensive glycemic control increased with increasing BMI and with decreasing diastolic blood pressure ( DBP ) . Intensive glycemic control was associated with less worsening of eGFR with increasing baseline ACR and insulin use . Baseline systolic blood pressure , triglycerides , and photocoagulation were associated with worsening of eGFR . CONCLUSIONS Intensive glycemic control had no significant effect on the progression of renal disease in the whole cohort but was associated with some protection against increasing ACR in those with more advanced microvascular disease , lower baseline DBP , or higher baseline BMI and on worsening of eGFR in those with high baseline ACR Abstract Aims /hypothesisWe investigated skin microcirculation and its association with HbA1c and the incidence of ischaemic foot ulcer in patients with type 1 diabetes formerly r and omised ( 1982–1984 ) to intensified conventional treatment ( ICT ) or st and ard treatment ( ST ) with insulin for a mean of 7.5 years . Methods We re-determined the skin microcirculation of 72 patients ( ICT 35 vs ST 37 ) from the original Stockholm Diabetes Intervention Study with iontophoresis topically applied with the following vasoactive stimuli : acetylcholine ( ACh ) ( endothelial-dependent vasodilatation ) , sodium nitroprusside ( SNP ) ( endothelial-independent vasodilatation ) , and capsaicin ( C-nociceptive-dependent vasodilatation ) . HbA1c levels ( mean of 14 values/patient ) were prospect ively collected between 1990 and 1995 and tested for association with skin microcirculation . The patients were followed until first hospitalisation for an ischaemic foot ulcer or until 2011 . Results During the median 28 years of follow-up , three patients developed ischaemic foot ulcers in the ICT group compared with ten in the ST group ( logrank , p = 0.035 ) . At the time of iontophoresis , HbA1c was lower in the ICT group ( median 57 mmol/mol [ minimum – maximum 40–79 mmol/mol ] ) compared with the ST group ( 68 mmol/mol [ 41–96 mmol/mol ] , p < 0.01 ) ( DCCT : ICT 7.4 % [ 5.8–9.4 % ] vs ST 8.4 % [ 5.9–10.9 % ] ) . Stimulated blood flow was higher in the ICT vs ST group with significantly increased perfusion units ( PU ) for : ACh ( 8.1 PU [ 4.6–24.7 PU ] vs 5.3 PU [ 1.7–21.4 PU ] , p < 0.01 ) ; SNP ( 8.1 PU [ 2.2–20.1 PU ] vs 5.6 PU [ 2.3–19.2 PU ] , p = 0.03 ) ; and capsaicin ( 5.0 PU [ 1.7–22.9 PU ] vs 3.4 PU [ 1.5–8.4 PU ] , p < 0.01 ) . HbA1c was associated with vasodilatation induced by ACh ( b = −0.02 , p < 0.01 ) and capsaicin ( b = −0.02 , p = 0.03 ) . HbA1c was independently associated with ACh ( b = −1.48 , p < 0.01 ) and capsaicin-induced vasodilatation ( b = −1.45 , p < 0.01 ) . Conclusions /interpretationImproved glycaemic control in patients with type 1 diabetes is associated with an improvement in skin microcirculation and with a lower incidence of ischaemic foot ulcers . Trial registration : Clinical Trials.gov To determine whether a difference in HbA(1c ) could be safely sustained between a st and ard therapy ( STD ) arm and an intensive therapy ( INT ) arm , while maintaining HbA(1c ) levels in both arms within a range acceptable in community practice . The effects of intensive treatment on various parameters were studied in this feasibility trial . We report here the results of 24 months of INT on peripheral and autonomic neuropathy . A prospect i ve trial was conducted in five medical centers in 153 men of 60 + /- 6 years of age who had a known diagnosis of diabetes for 7.8 + /- 4 years . They were r and omly assigned to a st and ard insulin treatment group ( one morning injection per day ) or to an intensive therapy group design ed to attain near-normal glycemia and a clinical ly significant separation of glycohemoglobin from the st and ard arm . A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose : ( 1 ) an evening insulin injection , ( 2 ) the same injection adding daytime glipizide , ( 3 ) two injections of insulin alone , and ( 4 ) multiple daily injections . Peripheral neuropathy was diagnosed clinical ly by a history and physical examination , and by abnormal autonomic neuropathy Valsalva ratio ( VR < 1.2 ) and RR variation ( RRV < 10 ) . An average HbA(1c ) separation of 2.07 % was achieved with INT , having HbA(1c ) at or below 7.3 % ( p = 0 . 001 versus STD ) . Baseline prevalence of peripheral neuropathy was 53 % in STD , and 48 % in INT . By 24 months , the prevalence increased to 69 % in STD ( p = 0.005 versus baseline ) , and to 64 % in INT ( p = 0 . 008 versus baseline , but no different than STD ) . Though INT did not reverse all elements of peripheral neuropathy , there was a decreased prevalence of cranial neuropathy ( p = 0.053 versus STD ) and more frequent preservation of touch sensation in the upper extremities ( p = 0.03 versus STD ) in INT . At baseline , an abnormal Valsalva ratio and /or RR variation was seen in 38 % of STD and 31 % of INT . By 24 months in STD , the prevalence rose to 55 % ( p = 0.0067 versus baseline ) , and in INT , to 48 % ( p = 0.012 versus baseline and no different from STD ) . The prevalence of erectile dysfunction increased from 53 % at baseline to 73 % at 2 years , p = 0.002 in STD , and from 51 % to 73 % at 2 years ( p = 0.003 versus baseline ) and no different from STD . There was no change in the frequency of abnormal gastrointestinal or sweating symptoms . Our conclusion was that 2 years of meticulous glycemic control did not decrease overall prevalence of peripheral or autonomic neuropathy . In fact , the prevalence rose equivalently and significantly in both treatment arms . There was some benefit , however , in decreased frequency of cranial neuropathy and better preservation of touch sensation in INT BACKGROUND The Veterans Affairs Cooperative Study in Type II Diabetes Mellitus prospect ively studied insulin-treated patients with type 2 ( non-insulin-dependent ) diabetes mellitus , achieving 2.1 % glycosylated hemoglobin separation between intensive- and st and ard-treatment arms ( P<.001 ) for 2 years . OBJECTIVE To assess the effect of intensive therapy on serum fibrinogen and lipid levels , compared with st and ard treatment . METHODS One hundred fifty-three male subjects with type 2 diabetes mellitus and who required insulin treatment were recruited from 5 Veterans Affairs medical centers . The subjects were divided into intensive- and st and ard-treatment arms for a r and omized prospect i ve study . Dyslipidemia was managed identically in both arms ( diet , drugs ) . Fibrinogen levels and lipid fractions were measured in the full cohort . Lipid fractions are separately reported in patients not treated with hypolipidemic agents . RESULTS There were no baseline differences between arms . Fibrinogen levels rose in the intensive-treatment arm at 1 year ( from 3.34+/-0.12 to 3.75+/-0.15 g/L ; P<.001 ) but returned to baseline at 2 years ( 3.47+/-0.12 g/L ) . There was no change in the st and ard-treatment arm . Triglyceride levels decreased in the intensive-treatment arm from 2.25+/-0.27 to 1.54+/-0.14 mmol/L ( 199+/-24 to 136+/-12 mg/ dL ) at 1 year ( P = .004 ) and to 1.74+/-0.18 mmol/L ( 154+/-16 mg/dL ) at 2 years ( P = .03 ) ; there was no change in the st and ard-treatment arm . Cholesterol levels decreased in the intensive-treatment arm at 1 year from 5.4+/-0.21 to 4.99+/-0.13 mmol/L ( 207+/-8 to 193+/-5 mg/dL ) ( P = .02 ) ; there was no change in the st and ard-treatment arm . Levels of low- and high-density lipoprotein cholesterol decreased in the st and ard-treatment arm only by 2 years , from 3.44+/-0.13 to 3.16+/-0.10 mmol/L ( 133+/-5 to 122+/-4 mg/ dL ) ( P = .02 ) and from 1.10+/-0.03 to 1.00+/-0.03 mmol/L ( 42+/-1 to 38+/-1 mg/dL ) ( P<.001 ) for low-density and high-density lipoprotein cholesterol , respectively . Levels of apolipoprotein B decreased in both treatment arms ( P<.001 ) , and apolipoprotein A1 levels decreased in the st and ard-treatment arm ( P<.01 ) . Lipoprotein ( a ) levels did not change in either treatment arm . Lipid results were essentially identical whether examined in the full cohort or excluding those patients receiving hypolipidemic agents . CONCLUSIONS Intensive insulin therapy led to a potentially beneficial reduction in serum triglyceride levels and preservation of high-density lipoprotein cholesterol and apolipoprotein A1 levels . However , it caused transient elevation in plasma fibrinogen levels , a possible thrombogenic effect OBJECTIVE To test the hypothesis that high levels of plasminogen-activating inhibitor (PAI)-1 and fibrinogen at baseline were associated with the onset or progression of diabetic retinopathy ( DR ) during the Veterans Affairs Diabetes Trial ( VADT ) . RESEARCH DESIGN AND METHODS The VADT was an open-label , prospect i ve , r and omized controlled trial to test the effect of st and ard glycemic control ( STD ) compared with intensive control ( INT ) on cardiovascular events in patients with advanced type 2 diabetes mellitus ( T2DM ) . Diabetic retinopathy ( DR ) outcomes were also collected . Incidence and progression of DR were assessed by grading seven-field stereoscopic fundus photographs at baseline and 5 years later taken in 858 of a total of 1,791 participants who completed both eye examinations . RESULTS Assignment to INT was not independently associated with decreased risk of onset of DR . However , after adjustment for multiple covariates , baseline level of PAI-1 was an independent risk factor for the onset of DR . The risk for incidence of DR increased by 12 % for each 10 ng/dL increase in baseline PAI-1 concentration ( odds ratio [ OR ] 1.012 [ 95 % CI 1.00–1.024 ] , P = 0.042 ) . Assignment to INT was not independently associated with decreased risk of progression of DR . However , there was an interaction between glycemic treatment assignment and fibrinogen level at baseline . INT was associated with decreased progression of retinopathy in those with fibrinogen < 296 mg/dL ( OR 0.55 [ 95 % CI 0.31–1.00 ] , P = 0.03 ) . CONCLUSIONS The results require confirmation but are consistent with greater hypercoagulabilty and inflammation , as measured by higher levels of PAI-1 and fibrinogen , being related to DR and responsiveness to INT Background Health utility ( HU ) measures are used as overall measures of quality of life and to determine quality adjusted life years ( QALYs ) in economic analyses . We compared baseline values of three HUs including Short Form 6 Dimensions ( SF-6D ) , and Health Utilities Index , Mark II and Mark III ( HUI2 and HUI3 ) and the feeling thermometer ( FT ) among type 2 diabetes participants in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial . We assessed relationships between HU and FT values and patient demographics and clinical variables . Methods ACCORD was a r and omized clinical trial to test if intensive controls of glucose , blood pressure and lipids can reduce the risk of major cardiovascular disease ( CVD ) events in type 2 diabetes patients with high risk of CVD . The health-related quality of life ( HRQOL ) sub- study includes 2,053 r and omly selected participants . Interclass correlations ( ICCs ) and agreement between measures by quartile were used to evaluate relationships between HU ’s and the FT . Multivariable regression models specified relationships between patient variables and each HU and the FT . Results The ICCs were 0.245 for FT/SF-6D , 0.313 for HUI3/SF-6D , 0.437 for HUI2/SF-6D , 0.338 for FT/HUI2 , 0.337 for FT/HUI3 and 0.751 for HUI2/HUI3 ( P < 0.001 for all ) . Common classification by quartile was found for the majority ( 62 % ) of values between HUI2 and HUI3 , which was significantly ( P < 0.001 ) higher than between other HUs and the FT : SF-6D/HUI3 = 40.8 % , SF-6D/HUI2 = 40.9 % , FT/HUI3 = 35.0 % , FT/HUI2 = 34.9 % , and FT/SF-6D = 31.9 % . Common classification was higher between SF-6D/HUI2 and SF-6D/HUI3 ( P < 0.001 ) than between FT/SF-6D , FT/HUI2 , and FT/HUI3 . The mean difference in HU values per patient ranged from −0.024 ± 0.225 for SF-6D/ HUI3 to −0.124 ± 0.133 for SF-6D/HUI2 . Regression models were significant ; clinical and demographic variables explained 6.1 % ( SF-6D ) to 7.7 % ( HUI3 ) of the variance in HUs . Conclusions The agreements between the different HUs were poor except for the two HUI measures ; therefore HU values derived different measures may not be comparable . The FT had low agreement with HUs . The relationships between HUs and demographic and clinical measures demonstrate how severity of diabetes and other clinical and demographic factors are associated with HUs and FT measures .Trial registration Clinical Trials.gov Identifier : Many clinical trials incorporate a system for monitoring emerging data that utilizes a committee composed of individuals who are independent of the investigators conducting the study . Although this is a common practice , there is a paucity of publications examining the operating methods of these groups . This paper describes the composition , functions , and procedures of the Data , Safety and Quality Review Group ( DSQ ) of the Diabetes Control and Complications Trial ( DCCT ) . The DSQ is not masked to emerging data and the voting membership is made up of individuals with a wide diversity of expertise that reflects the needs of the trial . There are also nonvoting exofficio members who represent other components of the study organization . In addition to data monitoring , the DSQ provides external review of coordinating center operations . A distinctive aspect of the DCCT 's DSQ is the creation of a free-st and ing operations manual for the DSQ 's use during the trial and the involvement of the study investigators in developing certain sections of this document . Utilizing a process that allowed participation of the investigators was considered critical to achieving a mutual underst and ing regarding the planned uses and interpretations of the study data prior to the study 's completion so as to minimize the chances of major disagreements regarding the conclusions drawn . Equally important , the existence of such a manual provides documentable reassurance to all interested parties that both scientific integrity and patient safety are being closely watched and gives the study investigators confidence that the results of the study will be scientifically credible and clinical ly important OBJECTIVE Intensive therapy targeting normal blood glucose increased mortality compared with st and ard treatment in a r and omized clinical trial of 10,251 participants with type 2 diabetes at high-risk for cardiovascular disease ( CVD ) events . We evaluated whether the presence of cardiac autonomic neuropathy ( CAN ) at baseline modified the effect of intensive compared with st and ard glycemia treatment on mortality outcomes in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial participants . RESEARCH DESIGN AND METHODS CAN was assessed by measures of heart rate variability ( HRV ) and QT index ( QTI ) computed from 10-s resting electrocardiograms in 8,135 ACCORD trial participants with valid measurements ( mean age 63.0 years , 40 % women ) . Prespecified CAN definitions included a composite of the lowest quartile of HRV and highest QTI quartile in the presence or absence of peripheral neuropathy . Outcomes were all-cause and CVD mortality . Associations between CAN and mortality were evaluated by proportional hazards analysis , adjusting for treatment group allocation , CVD history , and multiple prespecified baseline covariates . RESULTS During a mean 3.5 years follow-up , there were 329 deaths from all causes . In fully adjusted analyses , participants with baseline CAN were 1.55–2.14 times as likely to die as participants without CAN , depending on the CAN definition used ( P < 0.02 for all ) . The effect of allocation to the intensive group on all-cause and CVD mortality was similar in participants with or without CAN at baseline ( Pinteraction > 0.7 ) . CONCLUSIONS Whereas CAN was associated with increased mortality in this high-risk type 2 diabetes cohort , these analyses indicate that participants with CAN at baseline had similar mortality outcomes from intensive compared with st and ard glycemia treatment in the ACCORD cohort Basic fibroblast growth factor ( bFGF ) is a potent endothelial and smooth muscle cell mitogen that does not normally circulate . Plasma bFGF-like bioactivity was increased in association with persistent microalbuminuria ( a risk marker for cardiovascular disease ) in adult type 2 diabetes mellitus . In the present study , we tested whether baseline plasma bFGF immunoreactivity ( IR ) predicts the occurrence of a subset of cardiovascular disease outcomes in adults with advanced type 2 diabetes mellitus from the Veterans Affairs Diabetes Trial ( mean : age , 59 years ; diabetes duration , 11 years ; baseline hemoglobin A(1c ) , 9.5 % ) . Plasma bFGF-IR was determined with a sensitive and specific 2-site enzyme-linked immunoassay in 399 patients at the baseline visit . These results were then evaluated as possible predictors of the occurrence of prespecified cardiovascular or coronary heart disease end points . There was a borderline-significant association ( P = .07 ) between plasma bFGF-IR and the main study cardiovascular disease outcome ( myocardial infa rct ion , congestive heart failure , cerebrovascular accident , amputation , cardiovascular death , coronary , cerebrovascular or peripheral revascularization , and inoperable coronary artery disease ) . Plasma bFGF-IR was significantly associated with the occurrence of coronary heart disease ( P = .01 ) . After adjusting for clinical risk factors , bFGF ( hazard ratio [ HR ] , 1.013 ; 95 % confidence interval [ CI ] , 1.007 - 1.019 ; P < .0001 ) , prior macrovascular event ( HR , 3.55 ; 95 % CI , 2.154 - 5.839 ; P < .0001 ) , and duration of diabetes ( HR , 1.041 ; 95 % CI , 1.012 - 1.071 ; P = .0055 ) were all significantly associated with time to first postr and omization coronary heart disease occurrence . These results suggest that increased plasma bFGF-IR may be a novel risk marker for coronary heart disease occurrence in adult men with advanced type 2 diabetes mellitus BACKGROUND Tools are needed to predict which individuals with diabetes will develop kidney disease and its complications . STUDY DESIGN An observational analysis of a r and omized controlled trial . SETTING & PARTICIPANTS The ADVANCE ( Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ) Study followed up 11,140 participants with type 2 diabetes for 5 years . PREDICTOR Readily available baseline demographic and clinical variables . OUTCOMES ( 1 ) Major kidney-related events ( doubling of serum creatinine to ≥2.26 mg/dL [ ≥200 μmol/L ] , renal replacement therapy , or renal death ) in all participants , and ( 2 ) new-onset albuminuria in participants with baseline normoalbuminuria . MEASUREMENTS Cox proportional hazard regression models predicting the outcomes were used to generate risk scores . Discrimination of the risk prediction models was compared with that of models based on estimated glomerular filtration rate ( eGFR ) alone , urinary albumin-creatinine ratio ( ACR ) alone , and their combination . RESULTS Risk scores for major kidney-related events and new-onset albuminuria were derived from 7- and 8-variable models , respectively . Baseline eGFR and ACR were dominant although models based on the 2 factors , alone or combined , had less discrimination ( P<0.05 ) than the risk prediction models containing additional variables ( risk prediction model C statistics of 0.847 [ 95 % CI , 0.815 - 0.880 ] for major kidney-related events , and 0.647 [ 95 % CI , 0.637 - 0.658 ] for new-onset albuminuria ) . Novel risk factors for new-onset albuminuria included Asian ethnicity and greater waist circumference , and for major kidney-related events , less education . The risk prediction models had acceptable calibration for both outcomes ( modified Hosmer-Lemeshow test , P=0.9 and P=0.06 , respectively ) . LIMITATIONS The follow-up period was limited to 5 years . Results are applicable to people with type 2 diabetes at risk of vascular disease . CONCLUSIONS Risk scores have been developed for early and late events in diabetic nephropathy . Although eGFR and urinary ACR are important components of the prediction models , the extra variables considered add significantly to discrimination and , in the case of new-onset albuminuria , are required to achieve satisfactory calibration BACKGROUND Intensified multifactorial intervention - with tight glucose regulation and the use of renin-angiotensin system blockers , aspirin , and lipid-lowering agents - has been shown to reduce the risk of nonfatal cardiovascular disease among patients with type 2 diabetes mellitus and microalbuminuria . We evaluated whether this approach would have an effect on the rates of death from any cause and from cardiovascular causes . METHODS In the Steno-2 Study , we r and omly assigned 160 patients with type 2 diabetes and persistent microalbuminuria to receive either intensive therapy or conventional therapy ; the mean treatment period was 7.8 years . Patients were subsequently followed observationally for a mean of 5.5 years , until December 31 , 2006 . The primary end point at 13.3 years of follow-up was the time to death from any cause . RESULTS Twenty-four patients in the intensive-therapy group died , as compared with 40 in the conventional-therapy group ( hazard ratio , 0.54 ; 95 % confidence interval [ CI ] , 0.32 to 0.89 ; P=0.02 ) . Intensive therapy was associated with a lower risk of death from cardiovascular causes ( hazard ratio , 0.43 ; 95 % CI , 0.19 to 0.94 ; P=0.04 ) and of cardiovascular events ( hazard ratio , 0.41 ; 95 % CI , 0.25 to 0.67 ; P<0.001 ) . One patient in the intensive-therapy group had progression to end-stage renal disease , as compared with six patients in the conventional-therapy group ( P=0.04 ) . Fewer patients in the intensive-therapy group required retinal photocoagulation ( relative risk , 0.45 ; 95 % CI , 0.23 to 0.86 ; P=0.02 ) . Few major side effects were reported . CONCLUSIONS In at-risk patients with type 2 diabetes , intensive intervention with multiple drug combinations and behavior modification had sustained beneficial effects with respect to vascular complications and on rates of death from any cause and from cardiovascular causes . ( Clinical Trials.gov number , NCT00320008 . The effect of intensive glucose control on major kidney outcomes in type 2 diabetes remains unclear . To study this , the ADVANCE trial r and omly assigned 11,140 participants to an intensive glucose-lowering strategy ( hemoglobin A1c target 6.5 % or less ) or st and ard glucose control . Treatment effects on end-stage renal disease ( ( ESRD ) , requirement for dialysis or renal transplantation ) , total kidney events , renal death , doubling of creatinine to above 200 μmol/l , new-onset macroalbuminuria or microalbuminuria , and progression or regression of albuminuria , were then assessed . After a median of 5 years , the mean hemoglobin A1c level was 6.5 % in the intensive group , and 7.3 % in the st and ard group . Intensive glucose control significantly reduced the risk of ESRD by 65 % ( 20 compared to 7 events ) , microalbuminuria by 9 % ( 1298 compared to 1410 patients ) , and macroalbuminuria by 30 % ( 162 compared to 231 patients ) . The progression of albuminuria was significantly reduced by 10 % and its regression significantly increased by 15 % . The results were almost identical in analyses taking account of potential competing risks . The number of participants needed to treat over 5 years to prevent one ESRD event ranged from 410 in the overall study to 41 participants with macroalbuminuria at baseline . Thus , improved glucose control will improve major kidney outcomes in patients with type 2 diabetes The impact of prolonged near-normoglycemia on platelet reactivity ( spontaneous and induced platelet aggregation ) , factor VIII , and von Willebr and factor in patients with insulin-dependent diabetes mellitus ( IDDM ) was evaluated in a prospect i ve , r and omized , controlled clinical trial . Twenty IDDM patients with no or only minor clinical signs of microvascular disease were r and omly assigned to 1 year of continuous subcutaneous insulin infusion ( CSII ) or unchanged conventional insulin treatment ( CIT ) . Hemoglobin A1c declined during the 12 month observation period from 7.3 + /- 1.2 % to 6.4 + /- 0.9 % ( 2p less than 0.01 ) in the CSII group , while this measure of glycemic control was unchanged in the CIT group : 7.2 + /- 1.1 % vs 8.0 + /- 1.6 % ( NS ) . Platelet reactivity , factor VIII , and von Willebr and factor concentrations were identical in the two groups at entry into the study , and no significant changes in these variables were seen in either group . Thus , the present results do not support the concept of increased platelet reactivity following CSII treatment OBJECTIVE Low heart rate variability ( HRV ) is , in several patient groups , related to poor prognosis . The underlying mechanisms are still unclear . The aim was to study if there is a relationship between HRV , which is a measure of baroreceptor function , and atherosclerosis . DESIGN The relationship between heart rate variability and carotid arterial wall stiffness was studied in subjects with type 1 diabetes mellitus in which autonomic dysfunction and early atherosclerosis are common . HRV was assessed from power spectral analysis of 24-h Holter recordings and arterial wall stiffness was assessed from an ultrasound study of the right common carotid artery . SETTING A university hospital . SUBJECTS Fifty-nine patients ( 41 + /- 8 years ) from the Stockholm Diabetes Intervention Study ( SDIS ) were investigated . These patients were r and omized to intensified conventional treatment or st and ard treatment approximately 12 years before this study . RESULTS Patients with stiffer arteries had lower HRV in all spectral b and s ( r = -0.32 to -0.40 , P = 0.06 - 0.001 ) . This relation remained on correcting for age . All spectral parameters of HRV correlated with the mean HbA1c from 10 years of study ( r = -0.37 to -0.40 , P = 0.004 - 0.001 ) . CONCLUSIONS In patients with type 1 diabetes mellitus , heart rate variability and arterial wall stiffness are related to each other . The results suggests that the autonomic nervous system could be a link between diabetes and vascular disease OBJECTIVE This study investigated the long-term effects of intensive diabetic treatment on the progression of atherosclerosis , measured as common carotid artery intima-media thickness ( IMT ) . RESEARCH DESIGN AND METHODS A total of 1,116 participants ( 52 % men ) in the Epidemiology of Diabetes Interventions and Complications ( EDIC ) trial , a long-term follow-up of the Diabetes Control and Complications Trial ( DCCT ) , had carotid IMT measurements at EDIC years 1 , 6 , and 12 . Mean age was 46 years , with diabetes duration of 24.5 years at EDIC year 12 . Differences in IMT progression between DCCT intensive and conventional treatment groups were examined , controlling for clinical characteristics , IMT reader , and imaging device . RESULTS Common carotid IMT progression from EDIC years 1 to 6 was 0.019 mm less in intensive than in conventional ( P < 0.0001 ) , and from years 1 to 12 was 0.014 mm less ( P = 0.048 ) ; but change from years 6 to 12 was similar ( intensive − conventional = 0.005 mm , P = 0.379 ) . Mean A1C levels during DCCT and DCCT/EDIC were strongly associated with progression of IMT , explaining most of the differences in IMT progression between DCCT treatment groups . Albuminuria , older age , male sex , smoking , and higher systolic blood pressure were significant predictors of IMT progression . CONCLUSIONS Intensive treatment slowed IMT progression for 6 years after the end of DCCT but did not affect IMT progression thereafter ( 6–12 years ) . A beneficial effect of prior intensive treatment was still evident 13 years after DCCT ended . These differences were attenuated but not negated after adjusting for blood pressure . These results support the early initiation and continued maintenance of intensive diabetes management in type 1 diabetes to retard atherosclerosis OBJECTIVE To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-st and ing type 2 diabetes . RESEARCH DESIGN AND METHODS This was a multicenter , factorial r and omized trial of perindopril-indapamide versus placebo ( double-blind comparison ) and intensive glucose control with a gliclazide MR – based regimen ( target A1C ≤6.5 % ) versus st and ard glucose control ( open comparison ) in 11,140 participants with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ( ADVANCE ) trial . Annual event rates and risks of major macrovascular and microvascular events considered jointly and separately , renal events , and death during an average 4.3 years of follow-up were assessed , using Cox proportional hazards models . RESULTS There was no interaction between the effects of routine blood pressure lowering and intensive glucose control for any of the prespecified clinical outcomes ( all P > 0.1 ) : the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale . Compared with neither intervention , combination treatment reduced the risk of new or worsening nephropathy by 33 % ( 95 % CI 12–50 % , P = 0.005 ) , new onset of macroalbuminuria by 54 % ( 35–68 % , P < 0.0001 ) , and new onset of microalbuminuria by 26 % ( 17–34 % ) . Combination treatment was associated with an 18 % reduction in the risk of all-cause death ( 1–32 % , P = 0.04 ) . CONCLUSIONS The effects of routine blood pressure lowering and intensive glucose control were independent of one another . When combined , they produced additional reductions in clinical ly relevant outcomes Antibodies to the smaller isoform of glutamic acid decarboxylase ( GAD65Ab ) have been linked to the presence of neuropathy in Type 1 diabetes in several small studies . We attempted to confirm this association by measuring GAD65Ab , GAD65Ab epitopes and IA-2Ab in 511 patients who participated in the Diabetes Control and Complications Trial ( DCCT ) . We also tested for correlations between these autoantibodies and C-peptide and glycemic control . We only included patients for whom serum was available from the first 4 years of their illness . The presence or absence of neuropathy was determined by electrophysiological studies , autonomic testing and clinical evaluation at baseline and 5 years into the trial or at close out . Sample s from controls ( patients without neuropathy at 5 years ) were selected for patients who had similar C-peptide responses to a st and ardized meal at baseline . The GAD65Ab index correlated with HgbA(1c ) only in the adult participants and only at baseline . The adults initially in poor control ( upper tertile for glycemia ) had higher GAD65Ab and lower C-peptides . The GAD65Ab index was not significantly different in patients with confirmed clinical neuropathy at 5 years versus controls matched for C-peptide ( .248+/-.03 versus .278+/-.03 ) . Epitope analysis , based on the blocking of conformational epitopes by recombinant Fab , revealed that the binding to multiple epitopes was decreased in the patients with neuropathy BACKGROUND An impaired glomerular filtration rate ( GFR ) leads to end-stage renal disease and increases the risks of cardiovascular disease and death . Persons with type 1 diabetes are at high risk for kidney disease , but there are no interventions that have been proved to prevent impairment of the GFR in this population . METHODS In the Diabetes Control and Complications Trial ( DCCT ) , 1441 persons with type 1 diabetes were r and omly assigned to 6.5 years of intensive diabetes therapy aim ed at achieving near-normal glucose concentrations or to conventional diabetes therapy aim ed at preventing hyperglycemic symptoms . Subsequently , 1375 participants were followed in the observational Epidemiology of Diabetes Interventions and Complications ( EDIC ) study . Serum creatinine levels were measured annually throughout the course of the two studies . The GFR was estimated with the use of the Chronic Kidney Disease Epidemiology Collaboration formula . We analyzed data from the two studies to determine the long-term effects of intensive diabetes therapy on the risk of impairment of the GFR , which was defined as an incident estimated GFR of less than 60 ml per minute per 1.73 m(2 ) of body-surface area at two consecutive study visits . RESULTS Over a median follow-up period of 22 years in the combined studies , impairment of the GFR developed in 24 participants assigned to intensive therapy and in 46 assigned to conventional therapy ( risk reduction with intensive therapy , 50 % ; 95 % confidence interval , 18 to 69 ; P=0.006 ) . Among these participants , end-stage renal disease developed in 8 participants in the intensive-therapy group and in 16 in the conventional-therapy group . As compared with conventional therapy , intensive therapy was associated with a reduction in the mean estimated GFR of 1.7 ml per minute per 1.73 m(2 ) during the DCCT study but during the EDIC study was associated with a slower rate of reduction in the GFR and an increase in the mean estimated GFR of 2.5 ml per minute per 1.73 m(2 ) ( P<0.001 for both comparisons ) . The beneficial effect of intensive therapy on the risk of an impaired GFR was fully attenuated after adjustment for glycated hemoglobin levels or albumin excretion rates . CONCLUSIONS The long-term risk of an impaired GFR was significantly lower among persons treated early in the course of type 1 diabetes with intensive diabetes therapy than among those treated with conventional diabetes therapy . ( Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others ; DCCT/EDIC Clinical Trials.gov numbers , NCT00360815 and NCT00360893 . ) BACKGROUND Intensive glucose lowering has previously been shown to increase mortality among persons with advanced type 2 diabetes and a high risk of cardiovascular disease . This report describes the 5-year outcomes of a mean of 3.7 years of intensive glucose lowering on mortality and key cardiovascular events . METHODS We r and omly assigned participants with type 2 diabetes and cardiovascular disease or additional cardiovascular risk factors to receive intensive therapy ( targeting a glycated hemoglobin level below 6.0 % ) or st and ard therapy ( targeting a level of 7 to 7.9 % ) . After termination of the intensive therapy , due to higher mortality in the intensive-therapy group , the target glycated hemoglobin level was 7 to 7.9 % for all participants , who were followed until the planned end of the trial . RESULTS Before the intensive therapy was terminated , the intensive-therapy group did not differ significantly from the st and ard-therapy group in the rate of the primary outcome ( a composite of nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes ) ( P=0.13 ) but had more deaths from any cause ( primarily cardiovascular ) ( hazard ratio , 1.21 ; 95 % confidence interval [ CI ] , 1.02 to 1.44 ) and fewer nonfatal myocardial infa rct ions ( hazard ratio , 0.79 ; 95 % CI , 0.66 to 0.95 ) . These trends persisted during the entire follow-up period ( hazard ratio for death , 1.19 ; 95 % CI , 1.03 to 1.38 ; and hazard ratio for nonfatal myocardial infa rct ion , 0.82 ; 95 % CI , 0.70 to 0.96 ) . After the intensive intervention was terminated , the median glycated hemoglobin level in the intensive-therapy group rose from 6.4 % to 7.2 % , and the use of glucose-lowering medications and rates of severe hypoglycemia and other adverse events were similar in the two groups . CONCLUSIONS As compared with st and ard therapy , the use of intensive therapy for 3.7 years to target a glycated hemoglobin level below 6 % reduced 5-year nonfatal myocardial infa rct ions but increased 5-year mortality . Such a strategy can not be recommended for high-risk patients with advanced type 2 diabetes . ( Funded by the National Heart , Lung and Blood Institute ; Clinical Trials.gov number , NCT00000620 . ) OBJECTIVE To assess the reversibility of the elevation of serum creatinine levels in patients with diabetes after 5 years of continuous on-trial fenofibrate therapy . RESEARCH DESIGN AND METHODS An on-drug/off-drug ancillary study to the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) Lipid Trial to investigate posttrial changes in serum creatinine and cystatin C. Eligible participants were recruited into a prospect i ve , nested , three-group study based on retrospective on-trial serum creatinine levels : fenofibrate case subjects ( n = 321 , ≥20 % increase after 3 months of therapy ) ; fenofibrate control subjects ( n = 175 , ≤2 % increase ) ; and placebo control subjects ( n = 565 ) . Serum creatinine and cystatin C were measured at trial end and 6–8 weeks after discontinuation of trial therapy . RESULTS At trial end , case subjects had the highest adjusted serum creatinine ( ± SE ) mg/dL ( 1.11 ± 0.02 ) and the lowest adjusted estimated glomerular filtration rate ( eGFR ) ( ± SE ) mL/min/1.73 m2 ( 68.4 ± 1.0 ) versus control subjects ( 1.01 ± 0.02 ; 74.8 ± 1.3 ) and placebo subjects ( 0.98 ± 0.01 ; 77.8 ± 0.7 ) . After 51 days off-drug , serum creatinine in case subjects was still higher ( 0.97 ± 0.02 ) and eGFR still lower ( 77.8 ± 1.0 ) than control subjects ( 0.90 ± 0.02 ; 81.8 ± 1.3 ) but not different from placebo subjects ( 0.99 ± 0.01 ; 76.6 ± 0.7 ) . Changes in serum cystatin C recapitulated the serum creatinine changes . CONCLUSIONS Participants with significant initial on-trial increases in serum creatinine ( ≥20 % ) returned to the same level of renal function as participants receiving placebo while participants who had ≤2 % increase in serum creatinine had net preservation of renal function compared with the same unselected placebo reference group . The fenofibrate-associated on-trial increases in serum creatinine were reversible , and the reversal was complete after 51 days off-drug . The similarity of the cystatin C results suggests that the mechanism of this change is not specific for serum creatinine OBJECTIVE Blood pressure ( BP ) control for renal protection is essential for patients with type 2 diabetes . Our objective in this analysis of Veterans Affairs Diabetes Trial ( VADT ) data was to learn whether on- study systolic BP ( SBP ) , diastolic BP ( DBP ) , and pulse pressure ( PP ) affected renal outcomes measured as albumin-to-creatinine ratio ( ACR ) and estimated glomerular filtration rate ( eGFR ) . RESEARCH DESIGN AND METHODS The VADT was a prospect i ve , r and omized study of 1,791 veterans with type 2 diabetes to determine whether intensive glucose control prevented major cardiovascular events . In this post hoc study , time-varying covariate survival analyses and hazard ratios ( HR ) were used to determine worsening of renal outcomes . RESULTS Compared with SBP 105–129 mmHg , the risk of ACR worsening increased significantly for SBP 130–139 mmHg ( HR 1.88 [ 95 % CI 1.28–2.77 ] ; P = 0.001 ) and for SBP ≥140 mmHg ( 2.51 [ 1.66–3.78 ] ; P < 0.0001 ) . Compared with a PP range of 40–49 mmHg , PP < 40 was associated with significantly lowered risk of worsening ACR ( 0.36 [ 0.15–0.87 ] ; P = 0.022 ) and PP ≥60 with significantly increased risk ( 2.38 [ 1.58–3.59 ] ; P < 0.0001 ) . Analyses of BP ranges associated with eGFR worsening showed significantly increased risk with rising baseline SBP and an interaction effect between SBP ≥140 mmHg and on- study A1C . These patients were 15 % more likely than those with SBP < 140 mmHg to experience eGFR worsening ( 1.15 [ 1.00–1.32 ] ; P = 0.045 ) for each 1 % ( 10.9 mmol/mol ) A1C increase . CONCLUSIONS SBP ≥130 mmHg and PP > 60 mmHg were associated with worsening ACR . The results suggest that treatment of SBP to < 130 mmHg may lessen ACR worsening . The interaction between SBP ≥140 mmHg and A1C suggests that the effect of glycemic control on reducing progression of renal disease may be greater in hypertensive patients OBJECTIVE This study investigated the hypothesis that baseline calcified coronary atherosclerosis may determine cardiovascular disease events in response to intensive glycemic control within the Veterans Affairs Diabetes Trial ( VADT ) . RESEARCH DESIGN AND METHODS At baseline , 301 type 2 diabetic participants in the VADT , a r and omized trial comparing the effects of intensive versus st and ard glucose lowering on cardiovascular events , had baseline coronary atherosclerosis assessed by coronary artery calcium ( CAC ) measured by computed tomography . Participants were followed over the 7.5-year study for development of cardiovascular end points . RESULTS During a median follow-up duration of 5.2 years , 89 cardiovascular events occurred . Although intensive glucose-lowering therapy did not significantly reduce cardiovascular events in the sub study cohort as a whole , there was evidence that the response was modified by baseline CAC , as indicated by significant P values for treatment by log(CAC + 1 ) interaction terms in unadjusted and multivariable-adjusted models ( 0.01 and 0.03 , respectively ) . Multivariable-adjusted hazard ratios ( HRs ) for the effect of treatment indicated a progressive diminution of benefit with increasing CAC . Subgroup analyses were also conducted for clinical ly relevant CAC categories : those above and below an Agatston score of 100 . Among those r and omized to intensive treatment , for the subgroup with CAC > 100 , 11 of 62 individuals had events , while only 1 of 52 individuals with CAC ≤100 had an event . The multivariable HR for intensive treatment for those with CAC > 100 was 0.74 ( 95 % CI 0.46–1.20 ; P = 0.21 ) , while for the subgroup with CAC ≤100 , the corresponding HR was 0.08 ( 0.008–0.77 ; P = 0.03 ) , with event rates of 39 and 4 per 1,000 person-years , respectively . CONCLUSIONS These data indicate that intensive glucose lowering reduces cardiovascular events in those with less extensive calcified coronary atherosclerosis OBJECTIVE We examined the impact of intensive versus conventional diabetes treatment upon menopause among women with type 1 diabetes in the Diabetes Control and Complications Trial ( DCCT ) , a r and omized controlled trial of intensive diabetes treatment , and its observational follow-up , the Epidemiology of Diabetes Interventions and Complications ( EDIC ) study . RESEARCH DESIGN AND METHODS In a secondary analysis of women in the DCCT/EDIC ( n = 657 ) , outcomes were the cumulative incidences of natural menopause and surgical menopause . Cox regression analyses were used to examine associations with treatment group , time-varying estimates of hemoglobin A1c ( HbA1c ) , insulin dosage , BMI , and microvascular complications ( retinopathy , nephropathy , and neuropathy ) . RESULTS By EDIC year 18 , after an average of 28 years of follow-up , 240 ( 38 % ) women had experienced natural menopause and 115 ( 18 % ) women had experienced surgical menopause . Age at natural menopause was similar in the intensive versus conventional groups ( 49.9 vs. 49.0 years ; P = 0.28 ) , and age at surgical menopause was similar in the intensive versus conventional groups ( 40.8 vs. 42.0 years ; P = 0.31 ) . In multivariable models , treatment group , HbA1c , and microvascular complications were not associated with risk of natural or surgical menopause . Each 10 unit/day increase in insulin dosage decreased risk of natural menopause ( hazard ratio [ HR ] 0.91 , 95 % CI 0.75–0.98 ) and each kg/m2 increase in BMI increased risk of surgical menopause ( HR 1.08 , 95 % CI 1.00–1.16 ) . CONCLUSIONS In the DCCT/EDIC , intensive versus conventional treatment group and HbA1c level were not associated with menopause risk . Greater insulin dose was associated with lower menopause risk Forty five insulin dependent diabetics were r and omised to treatment with continuous subcutaneous insulin infusion ( CSII ) , multiple insulin injections ( five or six daily ) , or conventional twice daily insulin injections . Near normoglycaemia was obtained with CSII and multiple injections but not with conventional treatment ( p less than 0.01 ) . Hypoglycaemic coma was observed less frequently with CSII than with multiple injections and conventional treatment ( p less than 0.001 ) , but blood glucose concentrations below 2.5 mmol/l ( 45 mg/100 ml ) were more common . After two years fewer retinal microaneurysms and haemorrhages had developed in the patients given CSII and multiple injections compared with those given conventional treatment , in whom the number had increased significantly ( p less than 0.01 ) . Motor nerve conduction velocity deteriorated in the patients given conventional treatment ; in those given CSII it was unchanged during the first year but had improved after two years ( p less than 0.01 ) . Glomerular hyperfiltration was reduced with CSII , but no change occurred in urine albumin excretion rates . Long term near normoglycaemia may prevent the progression of early stages of late diabetic complications BACKGROUND The effects of intensive glucose control on cardiovascular events in patients with long-st and ing type 2 diabetes mellitus remain uncertain . METHODS We r and omly assigned 1791 military veterans ( mean age , 60.4 years ) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or st and ard glucose control . Other cardiovascular risk factors were treated uniformly . The mean number of years since the diagnosis of diabetes was 11.5 , and 40 % of the patients had already had a cardiovascular event . The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level , as compared with the st and ard-therapy group . The primary outcome was the time from r and omization to the first occurrence of a major cardiovascular event , a composite of myocardial infa rct ion , stroke , death from cardiovascular causes , congestive heart failure , surgery for vascular disease , inoperable coronary disease , and amputation for ischemic gangrene . RESULTS The median follow-up was 5.6 years . Median glycated hemoglobin levels were 8.4 % in the st and ard-therapy group and 6.9 % in the intensive-therapy group . The primary outcome occurred in 264 patients in the st and ard-therapy group and 235 patients in the intensive-therapy group ( hazard ratio in the intensive-therapy group , 0.88 ; 95 % confidence interval [ CI ] , 0.74 to 1.05 ; P=0.14 ) . There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause ( hazard ratio , 1.07 ; 95 % CI , 0.81 to 1.42 ; P=0.62 ) . No differences between the two groups were observed for microvascular complications . The rates of adverse events , predominantly hypoglycemia , were 17.6 % in the st and ard-therapy group and 24.1 % in the intensive-therapy group . CONCLUSIONS Intensive glucose control in patients with poorly controlled type 2 diabetes had no significant effect on the rates of major cardiovascular events , death , or microvascular complications with the exception of progression of albuminuria ( P = 0.01 ) [ added ] . ( Clinical Trials.gov number , NCT00032487 . OBJECTIVE Self-management of type 2 diabetes including avoidance of hypoglycemia is complex , but the impact of cognition on safe self-management is not well understood . This study aim ed to assess the effect of baseline cognitive function and cognitive decline on subsequent risk of severe hypoglycemia and to assess the effect of different glycemic strategies on these relationships . RESEARCH DESIGN AND METHODS Prospect i ve cohort analysis of data from the ACCORD trial included 2,956 adults aged ≥55 years with type 2 diabetes and additional cardiovascular risk factors . Cognitive tests ( Digit Symbol Substitution Test [ DSST ] , Rey Auditory Verbal Learning Test , Stroop Test , and Mini Mental Status Examination ) were conducted at baseline and 20 months . Study outcomes were incident confirmed severe hypoglycemia requiring medical assistance ( HMA ) and hypoglycemia requiring any assistance ( HAA ) . RESULTS After a median 3.25-year follow-up , a 5-point-poorer baseline score on the DSST was predictive of a first episode of HMA ( hazard ratio 1.13 [ 95 % CI 1.08–1.18 ] ) . Analyses of the other cognitive tests and of HAA were consistent with the DSST results . Cognitive decline over 20 months increased the risk of subsequent hypoglycemia to a greater extent in those with lower baseline cognitive function ( Pinteraction = 0.037 ) . R and omization to an intensive versus st and ard glycemic strategy had no impact on the relationship between cognitive function and the risk of severe hypoglycemia . CONCLUSIONS Poor cognitive function increases the risk of severe hypoglycemia in patients with type 2 diabetes . Clinicians should consider cognitive function in assessing and guiding their patients regarding safe diabetes self-management regardless of their glycemic targets BACKGROUND The Veterans Affairs Diabetes Trial previously showed that intensive glucose lowering , as compared with st and ard therapy , did not significantly reduce the rate of major cardiovascular events among 1791 military veterans ( median follow-up , 5.6 years ) . We report the extended follow-up of the study participants . METHODS After the conclusion of the clinical trial , we followed participants , using central data bases to identify procedures , hospitalizations , and deaths ( complete cohort , with follow-up data for 92.4 % of participants ) . Most participants agreed to additional data collection by means of annual surveys and periodic chart review s ( survey cohort , with 77.7 % follow-up ) . The primary outcome was the time to the first major cardiovascular event ( heart attack , stroke , new or worsening congestive heart failure , amputation for ischemic gangrene , or cardiovascular-related death ) . Secondary outcomes were cardiovascular mortality and all-cause mortality . RESULTS The difference in glycated hemoglobin levels between the intensive-therapy group and the st and ard-therapy group averaged 1.5 percentage points during the trial ( median level , 6.9 % vs. 8.4 % ) and declined to 0.2 to 0.3 percentage points by 3 years after the trial ended . Over a median follow-up of 9.8 years , the intensive-therapy group had a significantly lower risk of the primary outcome than did the st and ard-therapy group ( hazard ratio , 0.83 ; 95 % confidence interval [ CI ] , 0.70 to 0.99 ; P=0.04 ) , with an absolute reduction in risk of 8.6 major cardiovascular events per 1000 person-years , but did not have reduced cardiovascular mortality ( hazard ratio , 0.88 ; 95 % CI , 0.64 to 1.20 ; P=0.42 ) . No reduction in total mortality was evident ( hazard ratio in the intensive-therapy group , 1.05 ; 95 % CI , 0.89 to 1.25 ; P=0.54 ; median follow-up , 11.8 years ) . CONCLUSIONS After nearly 10 years of follow-up , patients with type 2 diabetes who had been r and omly assigned to intensive glucose control for 5.6 years had 8.6 fewer major cardiovascular events per 1000 person-years than those assigned to st and ard therapy , but no improvement was seen in the rate of overall survival . ( Funded by the VA Cooperative Studies Program and others ; VADT Clinical Trials.gov number , NCT00032487 . ) BACKGROUND Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention . We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes . METHODS We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes , using Cox proportional-hazards models with adjustment for covariates measured at baseline and after r and omization . RESULTS During a median follow-up period of 5 years , 231 patients ( 2.1 % ) had at least one severe hypoglycemic episode ; 150 had been assigned to intensive glucose control ( 2.7 % of the 5571 patients in that group ) , and 81 had been assigned to st and ard glucose control ( 1.5 % of the 5569 patients in that group ) . The median times from the onset of severe hypoglycemia to the first major macrovascular event , the first major microvascular event , and death were 1.56 years ( interquartile range , 0.84 to 2.41 ) , 0.99 years ( interquartile range , 0.40 to 2.17 ) , and 1.05 years ( interquartile range , 0.34 to 2.41 ) , respectively . During follow-up , severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events ( hazard ratio , 2.88 ; 95 % confidence interval [ CI ] , 2.01 to 4.12 ) , major microvascular events ( hazard ratio , 1.81 ; 95 % CI , 1.19 to 2.74 ) , death from a cardiovascular cause ( hazard ratio , 2.68 ; 95 % CI , 1.72 to 4.19 ) , and death from any cause ( hazard ratio , 2.69 ; 95 % CI , 1.97 to 3.67 ) ( P<0.001 for all comparisons ) . Similar associations were apparent for a range of nonvascular outcomes , including respiratory , digestive , and skin conditions ( P<0.01 for all comparisons ) . No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death . CONCLUSIONS Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes . It is possible that severe hypoglycemia contributes to adverse outcomes , but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events . ( Funded by Servier and the National Health and Medical Research Council of Australia ; Clinical Trials.gov number , NCT00145925 . ) BACKGROUND We investigated whether combination therapy with a statin plus a fibrate , as compared with statin monotherapy , would reduce the risk of cardiovascular disease in patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease . METHODS We r and omly assigned 5518 patients with type 2 diabetes who were being treated with open-label simvastatin to receive either masked fenofibrate or placebo . The primary outcome was the first occurrence of nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS The annual rate of the primary outcome was 2.2 % in the fenofibrate group and 2.4 % in the placebo group ( hazard ratio in the fenofibrate group , 0.92 ; 95 % confidence interval [ CI ] , 0.79 to 1.08 ; P=0.32 ) . There were also no significant differences between the two study groups with respect to any secondary outcome . Annual rates of death were 1.5 % in the fenofibrate group and 1.6 % in the placebo group ( hazard ratio , 0.91 ; 95 % CI , 0.75 to 1.10 ; P=0.33 ) . Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex , with a benefit for men and possible harm for women ( P=0.01 for interaction ) , and a possible interaction according to lipid subgroup , with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol ( P=0.057 for interaction ) . CONCLUSIONS The combination of fenofibrate and simvastatin did not reduce the rate of fatal cardiovascular events , nonfatal myocardial infa rct ion , or nonfatal stroke , as compared with simvastatin alone . These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority of high-risk patients with type 2 diabetes . ( Clinical Trials.gov number , NCT00000620 . BACKGROUND We investigated whether intensive glycemic control , combination therapy for dyslipidemia , and intensive blood-pressure control would limit the progression of diabetic retinopathy in persons with type 2 diabetes . Previous data suggest that these systemic factors may be important in the development and progression of diabetic retinopathy . METHODS In a r and omized trial , we enrolled 10,251 participants with type 2 diabetes who were at high risk for cardiovascular disease to receive either intensive or st and ard treatment for glycemia ( target glycated hemoglobin level , < 6.0 % or 7.0 to 7.9 % , respectively ) and also for dyslipidemia ( 160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin ) or for systolic blood-pressure control ( target , < 120 or < 140 mm Hg ) . A subgroup of 2856 participants was evaluated for the effects of these interventions at 4 years on the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study Severity Scale ( as assessed from seven-field stereoscopic fundus photographs , with 17 possible steps and a higher number of steps indicating greater severity ) or the development of diabetic retinopathy necessitating laser photocoagulation or vitrectomy . RESULTS At 4 years , the rates of progression of diabetic retinopathy were 7.3 % with intensive glycemia treatment , versus 10.4 % with st and ard therapy ( adjusted odds ratio , 0.67 ; 95 % confidence interval [ CI ] , 0.51 to 0.87 ; P=0.003 ) ; 6.5 % with fenofibrate for intensive dyslipidemia therapy , versus 10.2 % with placebo ( adjusted odds ratio , 0.60 ; 95 % CI , 0.42 to 0.87 ; P=0.006 ) ; and 10.4 % with intensive blood-pressure therapy , versus 8.8 % with st and ard therapy ( adjusted odds ratio , 1.23 ; 95 % CI , 0.84 to 1.79 ; P=0.29 ) . CONCLUSIONS Intensive glycemic control and intensive combination treatment of dyslipidemia , but not intensive blood-pressure control , reduced the rate of progression of diabetic retinopathy . ( Funded by the National Heart , Lung , and Blood Institute and others ; Clinical Trials.gov numbers , NCT00000620 for the ACCORD study and NCT00542178 for the ACCORD Eye study . Background Peripheral arterial disease ( PAD ) is known to be associated with high cardiovascular risk , but the individual impact of PAD presentations on risk of macrovascular and microvascular events has not been reliably compared in patients with type 2 diabetes . We aim ed to evaluate the impact of major PAD , and its different presentations , on the 10-year risk of death , major macrovascular events , and major clinical microvascular events in these patients . Methods Participants in the action in diabetes and vascular disease : PreterAx and DiamicroN modified-release controlled evaluation ( ADVANCE ) trial and the ADVANCE-ON post-trial study were followed for a median of 5.0 ( in-trial ) , 5.4 ( post-trial ) , and 9.9 ( overall ) years . Major PAD at baseline was subdivided into lower-extremity chronic ulceration or amputation secondary to vascular disease and history of peripheral revascularization by angioplasty or surgery . Results Among 11,140 participants , 516 ( 4.6 % ) had major PAD at baseline : 300 ( 2.7 % ) had lower-extremity ulceration or amputation alone , 190 ( 1.7 % ) had peripheral revascularization alone , and 26 ( 0.2 % ) had both presentations . All-cause mortality , major macrovascular events , and major clinical microvascular events occurred in 2265 ( 20.3 % ) , 2166 ( 19.4 % ) , and 807 ( 7.2 % ) participants , respectively . Compared to those without PAD , patients with major PAD had increased rates of all-cause mortality ( HR 1.35 , 95 % CI 1.15–1.60 , p = 0.0004 ) , and major macrovascular events ( 1.47 [ 1.23–1.75 ] , p < 0.0001 ) , after multiple adjustments for region of origin , cardiovascular risk factors and treatments , peripheral neuropathy markers , and r and omized treatments . We have also observed a trend toward an association of baseline PAD with risk of major clinical microvascular events [ 1.31 ( 0.96–1.78 ) , p = 0.09 ] . These associations were comparable for patients with a lower-extremity ulceration or amputation and for those with a history of peripheral revascularization . Furthermore , the risk of retinal photocoagulation or blindness , but not renal events , increased in patients with lower-extremity ulceration or amputation [ 1.53 ( 1.01–2.30 ) , p = 0.04 ] . Conclusions Lower-extremity ulceration or amputation , and peripheral revascularization both increased the risks of death and cardiovascular events , but only lower-extremity ulceration or amputation increased the risk of severe retinopathy in patients with type 2 diabetes . Screening for major PAD and its management remain crucial for cardiovascular prevention in patients with type 2 diabetes ( Clinical Trials.gov number , NCT00949286 ) OBJECTIVE The Veterans Affairs Diabetes Trial ( VADT ) cohort is enriched with approximately 20 % Hispanics and 20 % African Americans , affording a unique opportunity to study ethnic differences in retinopathy . RESEARCH DESIGN AND METHODS Cross-sectional analyses on the baseline seven-field stereo fundus photos of 1,283 patients are reported here . Diabetic retinopathy scores are grouped into four classes of increasing severity : none ( 10 - 14 ) , minimal nonproliferative diabetic retinopathy ( NPDR ) ( 15 - 39 ) , moderate to severe NPDR ( 40 - 59 ) , and proliferative diabetic retinopathy ( 60 + ) . These four groups have also been dichotomized to none or minimal ( 10 - 39 ) and moderate to severe diabetic retinopathy ( 40 + ) . RESULTS The prevalence of diabetic retinopathy scores > 40 was higher for Hispanics ( 36 % ) and African Americans ( 29 % ) than for non-Hispanic whites ( 22 % ) . The difference between Hispanics and non-Hispanic whites was significant ( P < 0.05 ) . Similarly , the prevalence of diabetic retinopathy scores > 40 was significantly higher in African Americans than in non-Hispanic whites ( P < 0.05 ) . These differences could not be accounted for by an imbalance in traditional risk factors such as age , duration of diagnosed diabetes , HbA(1c ) ( A1C ) , and blood pressure . Diabetic retinopathy severity scores were also significantly associated with increasing years of disease duration , A1C , systolic and diastolic blood pressure , the degree of microalbuminuria , fibrinogen , and the percentage of patients with amputations . There was no relationship between retinopathy severity and the percentage of people who had strokes or cardiac revascularization procedures . There was an inverse relationship between retinopathy severity and total cholesterol , triglycerides , and plasminogen activator inhibitor-1 as well as with smoking history . Diabetic retinopathy scores were not associated with age . CONCLUSIONS In addition to many well-known associations with retinopathy , a higher frequency of severe diabetic retinopathy was found in the Hispanic and African-American patients at entry into the VADT that is not accounted for by traditional risk factors for diabetic retinopathy , and these substantial ethnic differences remain to be explained OBJECTIVE To compare effects of combinations of st and ard and intensive treatment of glycemia and either blood pressure ( BP ) or lipids in the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial . RESEARCH DESIGN AND METHODS ACCORD enrolled 10,251 type 2 diabetes patients aged 40–79 years at high risk for cardiovascular disease ( CVD ) events . Participants were r and omly assigned to hemoglobin A1c goals of < 6.0 % ( < 42 mmol/mol ; intensive glycemia ) or 7.0–7.9 % ( 53–63 mmol/mol ; st and ard glycemia ) and then r and omized a second time to either 1 ) systolic BP goals of < 120 mmHg ( intensive BP ) or < 140 mmHg ( st and ard BP ) or 2 ) simvastatin plus fenofibrate ( intensive lipid ) or simvastatin plus placebo ( st and ard lipid ) . Proportional hazards models were used to assess combinations of treatment assignments on the composite primary ( deaths due to CVD , nonfatal myocardial infa rct ion [ MI ] , and nonfatal stroke ) and secondary outcomes . RESULTS In the BP trial , risk of the primary outcome was lower in the groups intensively treated for glycemia ( hazard ratio [ HR ] 0.67 ; 95 % CI 0.50–0.91 ) , BP ( HR 0.74 ; 95 % CI 0.55–1.00 ) , or both ( HR 0.71 ; 95 % CI 0.52–0.96 ) compared with combined st and ard BP and glycemia treatment . For secondary outcomes , MI was significantly reduced by intensive glycemia treatment and stroke by intensive BP treatment ; most other HRs were neutral or favored intensive treatment groups . In the lipid trial , the general pattern of results showed no evidence of benefit of intensive regimens ( whether single or combined ) compared with combined st and ard lipid and glycemia treatment . The mortality HR was 1.33 ( 95 % CI 1.02–1.74 ) in the st and ard lipid/intensive glycemia group compared with the st and ard lipid/st and ard glycemia group . CONCLUSIONS In the ACCORD BP trial , compared with combined st and ard treatment , intensive BP or intensive glycemia treatment alone improved major CVD outcomes , without additional benefit from combining the two . In the ACCORD lipid trial , neither intensive lipid nor glycemia treatment produced an overall benefit , but intensive glycemia treatment increased mortality BACKGROUND The risks and benefits of intensive therapy in non-insulin-dependent diabetes mellitus ( NIDDM ) need to be defined . In preparation for a long-term trial , a feasibility study of 153 men in 5 medical centers compared st and ard vs intensive insulin therapy . OBJECTIVE To assess the rate of development of new cardiovascular events and their correlates . METHODS Patients with a mean + /- SD age of 60 + /- 6 years and diagnosis of NIDDM for 7.8 + /- 4.0 years were r and omly assigned to a st and ard ( 1 insulin injection every morning ) or to an intensive treatment arm ( stepped plan from 1 evening injection of insulin , alone or with glipizide , to multiple daily injections ) design ed to attain near-normal glycemia levels . A 2.07 % separation of glycosylated hemoglobin ( HbA1c ) was sustained for a mean follow-up of 27 months ( P < .001 ) . Predefined cardiovascular events were assessed by a committee unaware of treatment assignment . RESULTS Mild and moderate hypoglycemic events were more frequent in the intensive than in the st and ard treatment arm ( 16.5 vs 1.5 per patient per year , respectively ) . Mean insulin dose was 23 % lower in the st and ard treatment arm ( P < .001 ) . There were 61 new cardiovascular events in 24 patients ( 32 % ) in the intensive treatment arm and in 16 patients ( 20 % ) in the st and ard treatment arm ( P = .10 ) . There was no difference in total and cardiovascular mortality ( n = 5 and n = 3 in the intensive and st and ard treatment arms , respectively ) or in new events in patients with cardiovascular history ( n = 10 in each arm ) . In Cox regression analysis , the only significant correlate for new cardiovascular events was previous cardiovascular disease ( P = .04 ) . Entering in the analysis any baseline cardiovascular abnormality , the regression model indicated a lower HbA1c level prior to the event as the only correlate for new cardiovascular events ( P = .05 ) . CONCLUSION A long-term prospect i ve trial is needed to assess the risk-benefit ratio of intensive insulin therapy for NIDDM in patients who require it To evaluate the cost and effectiveness of intensive insulin therapy for type 2 diabetes on the prevention of diabetes complications in Japan , we performed economic evaluation based on a r and omized controlled trial . A total of 110 patients with type 2 diabetes were r and omly assigned into two groups , a multiple insulin injection therapy ( MIT ) group or a conventional insulin injection therapy ( CIT ) group , and were followed-up for 10 years . Economic evaluation ( cost-consequences analysis ) was applied to evaluate both health and economic outcomes . As outcome measures for effectiveness of intensive insulin therapy , the frequency of complications , such as retinopathy , nephropathy , neuropathy , macrovascular event , and diabetes-related death , was used . For estimating costs , a viewpoint of the payer ( the National Health Insurance ) was adopted . Direct medical costs associated with diabetes care during 10 years were calculated and evaluated . In a base case analysis , all costs were discounted to the present value at an annual rate of 3 % . Sensitivity analyses were carried out to assess the robustness of the results to changes in the values of important variables . MIT reduced the relative risk in the progression of retinopathy by 67 % , photocoagulation by 77 % , progression of nephropathy by 66 % , albuminuria by 100 % and clinical neuropathy by 64 % , relative to CIT . Moreover , MIT prolonged the period in which patients were free of complications , including 2.0 years for progression of retinopathy ( P<0.0001 ) , 0.3 years for photocoagulation ( P<0.05 ) , 1.5 years for progression of nephropathy ( P<0.01 ) and 2.2 years for clinical neuropathy ( P<0.0001 ) . The total cost ( discounted at 3 % ) per patient during the 10-year period for each group was $ 30310 and 31525 , respectively . The reduction of total costs in MIT over CIT was mainly due to reduced costs for management of diabetic complications . Our results show that MIT is more beneficial than CIT in both cost and effectiveness . Therefore , MIT is recommended for the treatment of type 2 diabetic patients who require insulin therapy as early as possible from the perspective of both patients and health policy AIMS Individuals with diabetes and chronic kidney disease ( CKD ) are at high risk for cardiovascular disease . In these analyses of the ADVANCE trial , we assessed the effects of a fixed combination of perindopril-indapamide on renal and cardiovascular outcomes in patients with type 2 diabetes according to baseline CKD stage . METHODS AND RESULTS Patients with type 2 diabetes were r and omized to perindopril-indapamide ( 4 mg/1.25 mg ) or placebo . Treatment effects on cardiovascular ( cardiovascular death , myocardial infa rct ion , or stroke ) and renal outcomes were compared in subgroups defined by baseline Kidney Disease Outcome Quality Initiative CKD stage . Homogeneity in treatment effect was tested by adding interaction terms to the relevant Cox models . The study included 10 640 participants with known CKD status , of whom 6125 did not have CKD , 2482 were classified as CKD stage 1 or 2 , and 2033 as CKD stage ≥3 . The relative treatment effects on major cardiovascular events were similar across all stages of CKD , with no heterogeneity in the magnitude of the effects for any outcome . In contrast , the absolute treatment effects approximately doubled in those with CKD stage ≥3 when compared to those with no CKD . For every 1000 patients with CKD stage ≥3 treated for 5 years , active treatment prevented 12 cardiovascular events when compared with six events per 1000 patients with no CKD . CONCLUSION The treatment benefits of a routine administration of a fixed combination of perindopril-indapamide to patients with type 2 diabetes on cardiovascular and renal outcomes , and death , are consistent across all stages of CKD at baseline . Absolute risk reductions are larger in patients with CKD highlighting the importance of blood pressure-lowering in this population Summary Blood glucose values close to normal reduce the microvascular complications of insulin-dependent diabetes mellitus . The Stockholm study of this effect continued after the initial 7.5-year period in order to see what happened when intensively treated patients were left to control their own treatment while treatment was intensified in the control group . Forty-three patients with insulin-dependent diabetes r and omised to intensified conventional treatment ( ICT ) and 48 patients r and omised to st and ard treatment ( ST ) were followed-up for 10 years . Vascular complications , treatment side-effects and well-being were studied . Risk factors for complications were sought . HbA1c ( normal range 3.9–5.7 % ) was reduced from 9.5 ± 1.4 % ( mean ± SD ) in the ICT group and 9.4 ± 1.2 % in the ST group to a mean ( during 10 years ) of 7.2 ± 0.6 % and 8.3 ± 1.0 % , respectively ( p < 0.001 ) . Serious retinopathy ( 63 vs 33 % , p = 0.003 ) , nephropathy ( 26 vs 7 % , p = 0.012 ) and symptoms of neuropathy ( 32 vs 14 % , p = 0.041 ) were more common in the ST group after 10 years . HbA1c and age were the only risk factors for complications . Self-reported well-being increased to a greater degree and severe hypoglycaemia was more common in the ICT group . Cognitive function after 10 years was similar in both treatment groups , and was not related to the number of severe hypoglycaemic episodes . Intensified insulin treatment leads to reduced long-term complications and increased well-being without causing undue side-effects . [ Diabetologia ( 1996 ) 39 : 1483–1488 Altogether , 102 patients were r and omized to intensified conventional treatment ( ICT ) ( n = 48 ) or st and ard treatment ( ST ) ( n = 54 ) . After 7.5 years , 89 patients remained , and it was shown that microangiopathy was retarded by the lower blood glucose concentrations seen in the patients in the ICT group . HbA1c was reduced from ( means ± SE ) 9.5 ± 0.2 % to 7.1 ± 0.1 % in the ICT group and from 9.4 ± 0.2 % to 8.5 ± 0.1 % in the ST group ( P < 0.001 ) . Of the patients , 4 in the ICT group and 3 in the ST group died . Mortality was predicted by albuminuria , the amplitude of the sural nerve action potential , and the test of arm blood flow during contraction of the contralateral h and ( sympathetic nerve function ) at baseline ( P < 0.05 ) . Weight increased by 4.4 ± 1.1 kg in the ICT group and 1.8 ± 0.7 kg in the ST group ( P = 0.05 ) . Atherosclerosis , measured with digital pulse plethysmography , was ∼ the same in the groups at baseline and after five years . In each group , 3 patients had myocardial infa rct ions , and 2 from each group had ketoacidosis once . There was a mean of 1.1 episodes per patient and per year of serious hypoglycemia in the ICT group and 0.4 episodes per patient and per year in the ST group . No adverse incidents or accidents were observed in either group , and there were no differences between the groups with regard to cognitive function measured with a battery of tests . retarded the microvascular complications , caused some weight gain and an almost threefold increase of the frequency of serious hypoglycemia , but brain function did not deteriorate AIMS Diabetic retinopathy ( DR ) is associated with a higher risk of renal and cardiovascular events . We sought to compare the risk for renal versus cardiovascular ( CV ) outcomes , stratified by retinopathy severity . METHODS ACCORD was a r and omized trial of people with type 2 diabetes , at high-risk for CV disease . A subgroup ( n=3,369 from 71 clinics ) had stereoscopic fundus photographs grade d central ly . Participants were stratified at baseline to moderate/severe DR or no/mild DR and were monitored for renal and CV outcomes at follow-up visits over 4 years . The composite renal outcome was composed of serum creatinine doubling , macroalbuminuria , or end-stage renal disease . The composite CV outcome was the ACCORD trial primary outcome . Competing risk techniques were used to estimate the relative risk ( RR ) of renal versus CV composite outcomes within each DR stratum . RESULTS The hazards ratio for doubling of serum creatinine and incident CV event in the moderate/severe DR versus no/mild DR strata were : 2.31 ( 95 % CI : 1.25 - 4.26 ) and 1.98 ( 95 % CI : 1.49 - 2.62 ) , respectively . The RR of the two composite outcomes was highly similar in the no/mild DR stratum ( adjusted RR at 4 years for CV versus renal events=0.96 , 95 % CI : 0.72 - 1.28 ) and the moderate/severe DR stratum ( adjusted RR=0.92 , 95 % CI : 0.64 - 1.31 ) . CONCLUSIONS Thus , in people with type 2 diabetes at high risk for cardiovascular disease , incident CV versus renal events was similar , irrespective of the severity of the DR . Further evaluation of the specificity of DR for microvascular versus macrovascular events in other population s is warranted The Action to Control Cardiovascular Disease in Diabetes ( ACCORD ) blood pressure trial is an unmasked , open-label , r and omized trial with a sample size of 4,733 participants . This report describes the rationale , design , and methods of the blood pressure interventions in ACCORD . Participants eligible for the blood pressure trial are r and omized to 1 of 2 groups with different treatment goals : systolic blood pressure < 120 mm Hg for the more intensive goal and systolic blood pressure < 140 mm Hg for the less intensive goal . The primary outcome measure for the trial is the first occurrence of a major cardiovascular disease ( CVD ) event , specifically nonfatal myocardial infa rct ion or stroke , or cardiovascular death during a follow-up period ranging from 4 - 8 years . The ACCORD blood pressure trial should provide the first definitive clinical trial data on the possible benefit of treating to a more aggressive systolic blood pressure goal in reducing CVD events in patients with diabetes mellitus OBJECTIVE It is not clear whether intensive pharmacological therapy can be effectively sustained in non-insulin-dependent diabetes mellitus ( NIDDM ) . The relative risks and benefits of intensive insulin therapy in NIDDM are not well defined . Accordingly , we design ed a feasibility study that compared st and ard therapy and intensive therapy in a group of NIDDM men who required insulin due to sustained hyperglycemia . RESEARCH DESIGN AND METHODS A prospect i ve trial was conducted in five medical centers in 153 men of 60 ± 6 years of age who had a known diagnosis of diabetes for 7.8 ± 4 years . They were r and omly assigned to a st and ard insulin treatment group ( one morning injection per day ) or to an intensive therapy group design ed to attain near-normal glycemia and a clinical ly significant separation of glycohemoglobin from the st and ard arm . A four-step plan was used in the intensive therapy group along with daily self-monitoring of glucose : 1 ) an evening insulin injection , 2 ) the same injection adding daytime glipizide , 3 ) two injections of insulin alone , and 4 ) multiple daily injections . Patient accrual and adherence , glycohemoglobin ( HbA1c ) , side effects , and measurements of endpoints for a prospect i ve long-term trial were assessed . RESULTS Accrual goals were met , mean follow-up time was 27 months ( range 18–35 months ) , and patients kept 98.6 % of scheduled visits . After 6 months , the mean HbA1c in the intensive therapy group was at or below 7.3 % and remained 2 % lower than the st and ard group for the duration of the trial . Most of the decrease in the mean HbA1c in the intensive group was obtained by a single injection of evening intermediate insulin , alone or with daytime glipizide . By the end of the trial , 64 % of the patients had advanced to two or more injections of insulin a day , aim ing for normal HbA1c . However , only a small additional fall in HbA1c was attained . Severe hypoglycemia was rare ( two events per 100 patients per year ) and not significantly different between the groups , nor were changes in weight , blood pressure , or plasma lipids . There were 61 new cardiovascular events in 40 patients and 10 deaths ( 6 due to cardiovascular causes ) . CONCLUSIONS Intense stepped insulin therapy in NIDDM patients who have failed glycemic control on pharmacological therapy is effective in maintaining near-normal glycemic control for > 2 years without excessive severe hypoglycemia , weight gain , hypertension , or dyslipidemia . Cardiovascular event rates are high at this stage of NIDDM . A long-term prospect i ve trial is needed to assess the risk-benefit ratio of intensified treatment of hyperglycemia in NIDDM patients requiring insulin BACKGROUND Blood pressure is an important determinant of the risks of macrovascular and microvascular complications of type 2 diabetes , and guidelines recommend intensive lowering of blood pressure for diabetic patients with hypertension . We assessed the effects of the routine administration of an angiotensin converting enzyme ( ACE ) inhibitor-diuretic combination on serious vascular events in patients with diabetes , irrespective of initial blood pressure levels or the use of other blood pressure lowering drugs . METHODS The trial was done by 215 collaborating centres in 20 countries . After a 6-week active run-in period , 11 140 patients with type 2 diabetes were r and omised to treatment with a fixed combination of perindopril and indapamide or matching placebo , in addition to current therapy . The primary endpoints were composites of major macrovascular and microvascular events , defined as death from cardiovascular disease , non-fatal stroke or non-fatal myocardial infa rct ion , and new or worsening renal or diabetic eye disease , and analysis was by intention-to-treat . The macrovascular and microvascular composites were analysed jointly and separately . This trial is registered with Clinical Trials.gov , number NCT00145925 . FINDINGS After a mean of 4.3 years of follow-up , 73 % of those assigned active treatment and 74 % of those assigned control remained on r and omised treatment . Compared with patients assigned placebo , those assigned active therapy had a mean reduction in systolic blood pressure of 5.6 mm Hg and diastolic blood pressure of 2.2 mm Hg . The relative risk of a major macrovascular or microvascular event was reduced by 9 % ( 861 [ 15.5 % ] active vs 938 [ 16.8 % ] placebo ; hazard ratio 0.91 , 95 % CI 0.83 - 1.00 , p=0.04 ) . The separate reductions in macrovascular and microvascular events were similar but were not independently significant ( macrovascular 0.92 ; 0.81 - 1.04 , p=0.16 ; microvascular 0.91 ; 0.80 - 1.04 , p=0.16 ) . The relative risk of death from cardiovascular disease was reduced by 18 % ( 211 [ 3.8 % ] active vs 257 [ 4.6 % ] placebo ; 0.82 , 0.68 - 0.98 , p=0.03 ) and death from any cause was reduced by 14 % ( 408 [ 7.3 % ] active vs 471 [ 8.5 % ] placebo ; 0.86 , 0.75 - 0.98 , p=0.03 ) . There was no evidence that the effects of the study treatment differed by initial blood pressure level or concomitant use of other treatments at baseline . INTERPRETATION Routine administration of a fixed combination of perindopril and indapamide to patients with type 2 diabetes was well tolerated and reduced the risks of major vascular events , including death . Although the confidence limits were wide , the results suggest that over 5 years , one death due to any cause would be averted among every 79 patients assigned active therapy BACKGROUND Long-term microvascular and neurologic complications cause major morbidity and mortality in patients with insulin-dependent diabetes mellitus ( IDDM ) . We examined whether intensive treatment with the goal of maintaining blood glucose concentrations close to the normal range could decrease the frequency and severity of these complications . METHODS A total of 1441 patients with IDDM--726 with no retinopathy at base line ( the primary -prevention cohort ) and 715 with mild retinopathy ( the secondary -intervention cohort ) were r and omly assigned to intensive therapy administered either with an external insulin pump or by three or more daily insulin injections and guided by frequent blood glucose monitoring or to conventional therapy with one or two daily insulin injections . The patients were followed for a mean of 6.5 years , and the appearance and progression of retinopathy and other complications were assessed regularly . RESULTS In the primary -prevention cohort , intensive therapy reduced the adjusted mean risk for the development of retinopathy by 76 percent ( 95 percent confidence interval , 62 to 85 percent ) , as compared with conventional therapy . In the secondary -intervention cohort , intensive therapy slowed the progression of retinopathy by 54 percent ( 95 percent confidence interval , 39 to 66 percent ) and reduced the development of proliferative or severe nonproliferative retinopathy by 47 percent ( 95 percent confidence interval , 14 to 67 percent ) . In the two cohorts combined , intensive therapy reduced the occurrence of microalbuminuria ( urinary albumin excretion of > or = 40 mg per 24 hours ) by 39 percent ( 95 percent confidence interval , 21 to 52 percent ) , that of albuminuria ( urinary albumin excretion of > or = 300 mg per 24 hours ) by 54 percent ( 95 percent confidence interval 19 to 74 percent ) , and that of clinical neuropathy by 60 percent ( 95 percent confidence interval , 38 to 74 percent ) . The chief adverse event associated with intensive therapy was a two-to-threefold increase in severe hypoglycemia . CONCLUSIONS Intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy , nephropathy , and neuropathy in patients with IDDM BACKGROUND A cause- and -effect relation between blood glucose concentrations and microvascular complications in patients with insulin-dependent diabetes mellitus has not been established . METHODS We r and omly assigned 102 patients with insulin-dependent diabetes mellitus , nonproliferative retinopathy , normal serum creatinine concentrations , and unsatisfactory blood glucose control to intensified insulin treatment ( 48 patients ) or st and ard insulin treatment ( 54 patients ) . We then evaluated them for microvascular complications after 18 months and 3 , 5 , and 7.5 years . RESULTS Mean ( + /- SD ) glycosylated hemoglobin values were reduced from 9.5 + /- 1.3 percent to 7.1 + /- 0.7 percent in the group receiving intensified treatment and from 9.4 + /- 1.4 percent to 8.5 + /- 0.7 percent in the group receiving st and ard treatment ( P = 0.001 ) . In 12 of the patients receiving intensified treatment ( 27 percent of those included in the analysis ) and 27 of those receiving st and ard treatment ( 52 percent ) , serious retinopathy requiring photocoagulation developed ( P = 0.01 ) . Visual acuity decreased in 6 patients receiving intensified treatment ( 14 percent ) and in 18 receiving st and ard treatment ( 35 percent ) ( P = 0.02 ) . Nephropathy ( urinary albumin excretion , > 200 micrograms per minute ) developed in one patient in the group receiving intensified treatment , as compared with nine patients in the group receiving st and ard treatment ( P = 0.01 ) . No patient in the intensified-treatment group had nephropathy with subnormal glomerular filtration rates , as compared with six patients in the st and ard-treatment group ( P = 0.02 ) . The conduction velocities of the ulnar , tibial , peroneal , and sural nerves decreased significantly more in the st and ard-treatment group than in the intensified-treatment group . The odds ratio for serious retinopathy was 0.4 ( 95 percent confidence interval , 0.2 to 1.0 ; P = 0.04 ) in the intensified-treatment group as compared with the st and ard-treatment group . The corresponding odds ratio for nephropathy was 0.1 ( 95 percent confidence interval , 0 to 0.8 ; P = 0.04 ) . CONCLUSIONS Long-term intensified insulin treatment , as compared with st and ard treatment , retards the development of microvascular complications in patients with insulin-dependent diabetes mellitus The Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) lipid trial aims to test whether a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ( statin ) plus a fibrate is more efficacious in reducing cardiovascular events than a statin plus placebo in patients with type 2 diabetes mellitus with defined glycemic control . This is a blinded component in a 5,518-patient subset of the ACCORD cohort . These participants were r and omized to either be ( 1 ) treated with simvastatin ( titrated to 40 mg/day if necessary to achieve a goal low-density lipoprotein [ LDL ] cholesterol level of < 2.59 mmol/L [ 100 mg/dL ] ) plus placebo or ( 2 ) treated to the same goal LDL cholesterol level with the statin plus active fenofibrate 160 mg/day or its bioequivalent ( or 54 mg/day if the estimated glomerular filtration rate ranges from 30 to < 50 mL/min per 1.73 m2 ) . Setting an upper limit of LDL cholesterol qualifying for r and omization excluded patients who would not likely achieve the LDL cholesterol goal . Recruitment for ACCORD began in January 2001 , and follow-up is scheduled to end in June 2009 . Since recruitment began , several clinical trials and consensus statements have been published that led to changes in the details of the lipid treatment algorithm and protocol . This report describes the design of the lipid protocol and modifications to the protocol during the course of the study in response to and in anticipation of these developments . The current protocol is design ed to provide an ethically justifiable test of combined statin plus fibrate treatment consistent with the highest level of safety and lipid treatment st and ards of care Atrial fibrillation ( AF ) is prevalent in patients with type 2 diabetes mellitus ( DM ) and is associated with markers of poor glycemic control ; however , the impact of glycemic control on incident AF and outcomes is unknown . The aims of this study were to prospect ively evaluate if intensive glycemic control in patients with DM affects incident AF and to evaluate morbidity and mortality in patients with DM and incident AF . A total of 10,082 patients with DM from the Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) cohort were studied in a r and omized , double-blind fashion . Participants were r and omized to an intensive therapeutic strategy targeting a glycated hemoglobin level of < 6.0 % or a st and ard strategy targeting a glycated hemoglobin level of 7.0 % to 7.9 % . Incident AF occurred in 159 patients ( 1.58 % ) over the follow-up period , at a rate of 5.9 per 1,000 patient-years in the intensive-therapy group and a rate of 6.37 per 1,000 patient-years in the st and ard-therapy group ( p = 0.52 ) . In a multivariate model , predictors of incident AF were age , weight , diastolic blood pressure , heart rate , and heart failure history . Patients with DM and new-onset AF had a hazard ratio of 2.65 for all-cause mortality ( 95 % confidence interval 1.8 to 3.86 , p < 0.0001 ) , a hazard ratio of 2.1 for myocardial infa rct ion ( 95 % confidence interval 1.33 to 3.31 , p = 0.0015 ) , and a hazard ratio of 3.80 for the development of heart failure ( 95 % confidence interval 2.48 to 5.84 , p < 0.0001 ) . In conclusion , intensive glycemic control did not affect the rate of new-onset AF . Patients with DM and incident AF had an increased risk for morbidity and mortality compared with those without AF The Diabetes Control and Complications Trial has demonstrated that intensive diabetes treatment delays the onset and slows the progression of diabetic complications in subjects with insulin-dependent diabetes mellitus from 13 to 39 years of age . We examined whether the effects of such treatment also occurred in the subset of young diabetic subjects ( 13 to 17 years of age at entry ) in the Diabetes Control and Complications Trial . One hundred twenty-five adolescent subjects with insulin-dependent diabetes mellitus but with no retinopathy at baseline ( primary prevention cohort ) and 70 adolescent subjects with mild retinopathy ( secondary intervention cohort ) were r and omly assigned to receive either ( 1 ) intensive therapy with an external insulin pump or at least three daily insulin injections , together with frequent daily blood-glucose monitoring , or ( 2 ) conventional therapy with one or two daily insulin injections and once-daily monitoring . Subjects were followed for a mean of 7.4 years ( 4 to 9 years ) . In the primary prevention cohort , intensive therapy decreased the risk of having retinopathy by 53 % ( 95 % confidence interval : 1 % to 78 % ; p = 0.048 ) in comparison with conventional therapy . In the secondary intervention cohort , intensive therapy decreased the risk of retinopathy progression by 70 % ( 95 % confidence interval : 25 % to 88 % ; p = 0.010 ) and the occurrence of microalbuminuria by 55 % ( 95 % confidence interval : 3 % to 79 % ; p = 0.042 ) . Motor and sensory nerve conduction velocities were faster in intensively treated subjects . The major adverse event with intensive therapy was a nearly threefold increase of severe hypoglycemia . We conclude that intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy and nephropathy when initiated in adolescent subjects ; the benefits outweigh the increased risk of hypoglycemia that accompanies such treatment Objectives To evaluate among individuals with diabetes whether major microvascular and macrovascular events are reduced by : ( 1 ) blood pressure lowering with a perindopril/indapamide combination compared with placebo ; ( 2 ) intensive glucose control ( targeting a haemoglobin A1c level of ≤6.5 % ) with a gliclazide MR-based regimen , compared with usual care . Methods Participants with diabetes aged 55 years and older with at least one additional vascular risk factor were r and omly assigned , using a 2 × 2 factorial design , to additional blood pressure lowering versus placebo and intensive versus st and ard glucose control . The primary outcomes were macrovascular ( cardiovascular death , non-fatal myocardial infa rct ion or non-fatal stroke ) and microvascular ( new or worsening nephropathy or retinopathy ) events jointly and separately . Results A total of 11 140 participants were r and omly assigned to the blood pressure and glucose-lowering arms , which ended after 4.3 and 5.5 years , respectively . The effects of the two interventions were independent and additive on prespecified endpoints . Compared with placebo , additional blood pressure lowering of 5.6/2.2 mmHg was associated with reductions of 9 % in the primary endpoint ( P = 0.041 ) , 18 % in cardiovascular death ( P = 0.027 ) , 14 % in total mortality ( P = 0.025 ) , and 21 % in total renal events ( P < 0.01 ) . Compared with st and ard glucose control , intensive control ( mean in-trial 0.67 percentage point reduction in haemoglobin A1c level ) was associated with reductions of 10 % in the primary endpoint ( P = 0.013 ) , 14 % in major microvascular events ( P = 0.01 ) and 11 % in total renal events ( P < 0.001 ) . Conclusion Additional blood pressure lowering and intensive glucose control , as achieved in ADVANCE , produce independent benefits and , when combined , substantially reduced cardiovascular mortality and all-cause mortality and improved renal outcomes There is an independent progressive epidemiologic relation between glycemia and cardiovascular disease ( CVD ) events ; however , whether lowering glucose levels with currently available therapies can reduce CVD events remains unknown . The Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial is design ed to answer this question in high-risk patients with type 2 diabetes mellitus . In ACCORD , 10,251 patients with type 2 diabetes and other CVD risk factors or CVD were r and omly allocated to intensive glycemic control , targeting a glycosylated hemoglobin ( HbA1c ) level < 6 % , or st and ard glycemic control , targeting an HbA1c level of 7.0%-7.9 % . All participants are provided with diabetes education , glucose-monitoring equipment , and antidiabetic medications . All participants in the intensive glycemic control group are started on > or = 2 classes of agents . Doses are intensified or a new medication class is added every month if HbA1c levels are > or = 6 % or if > 50 % of premeal or postmeal capillary glucose readings are > 5.6 mmol/L ( 100 mg/dL ) or > 7.8 mmol/L ( 140 mg/dL ) , respectively . All drug combinations are permitted , and drugs are reduced only because of side effects or contraindications . Annual training , menus of approaches for intensification , regular electronic messaging , audits of achieved glycemia , and central feedback to sites support glycemic intensification strategies in intensive participants . In participants in the st and ard glycemic control group , therapy is intensified whenever HbA1c is > or = 8 % , and antihyperglycemic drugs that promote hypoglycemia ( ie , insulin or insulin secretagogues ) are reduced if HbA1c persistently decreases to < 7 % in the setting of hypoglycemia . ACCORD addresses the hypothesis that aggressive glucose lowering prevents CVD events in patients with type 2 diabetes . It is focused on the levels of glycemia achieved using a variety of strategies , not on the specific therapies used . It will also provide information on how to safely approach near-normal levels of glucose control in clinical practice and evidence to support future clinical guidelines for diabetes management in older adults BACKGROUND In type 2 diabetes mellitus the aetiology of long-term complications is multifactorial . We carried out a r and omised trial of stepwise intensive treatment or st and ard treatment of risk factors in patients with microalbuminuria . METHODS In this open , parallel trial patients were allocated st and ard treatment ( n=80 ) or intensive treatment ( n=80 ) . St and ard treatment followed Danish guidelines . Intensive treatment was a stepwise implementation of behaviour modification , pharmacological therapy targeting hyperglycaemia , hypertension , dyslipidaemia , and microalbuminuria . The primary endpoint was the development of nephropathy ( median albumin excretion rate > 300 mg per 24 h in at least one of the two-yearly examinations ) . Secondary endpoints were the incidence or progression of diabetic retinopathy and neuropathy . FINDINGS The mean age was 55.1 years ( SD 7.2 ) and patients were followed up for 3.8 years ( 0.3 ) . Patients in the intensive group had significantly lower rates of progression to nephropathy ( odds ratio 0.27 [ 95 % CI 0 - 10 - 0.75 ] ) , progression of retinopathy ( 0.45 [ 0.21 - 0.95 ] ) , and progression of autonomic neuropathy ( 0.32 [ 0.12 - 0.78 ] ) than those in the st and ard group . INTERPRETATION Intensified multifactorial intervention in patients with type 2 diabetes and microalbuminuria slows progression to nephropathy , and progression of retinopathy and autonomic neuropathy . However , further studies are needed to establish the effect of intensified multifactorial treatment on macrovascular complications and mortality AIMS The VADT was a r and omized clinical trial design ed to assess the effect of intensive vs. st and ard glucose management on cardiovascular events in Type 2 diabetes . At the end of the study , intensive management failed to improve outcomes . We performed plasma lipoprotein subclass analyses to yield new information on the effects of study r and omization on cardiovascular risk . METHODS This is a cross-sectional study of a subset of the VADT ( 740 men : 368 intensive ; 372 st and ard ) , conducted at least six months ( mean±SD : 2.1±0.8years ) post-r and omization . Conventional lipids , apolipoprotein-defined ( ADLS ) lipoprotein subclasses , ApoCIII , ApoE , and Nuclear Magnetic Resonance ( NMR ) lipoprotein subclasses were determined . RESULTS In intensive vs. st and ard groups , conventional lipids and ADLS did not differ significantly . However , with intensive treatment , NMR-determined large and medium VLDL subclasses and VLDL diameter were lower , LDL diameter was higher , medium HDL was higher , and small HDL was lower ( all p<0.05 ) . Also , ApoCIII levels were lower ( p<0.01 ) . CONCLUSIONS In a subset of diabetic men from the VADT , intensive glucose management did not affect conventional lipids or ADLS , but had some beneficial effects on particle characteristics as defined by NMR and on ApoCIII Most patients with type 2 diabetes mellitus develop cardiovascular disease ( CVD ) , with substantial loss of life expectancy . Nonfatal CVD contributes greatly to excess healthcare costs and decreased quality of life in patients with diabetes . The current epidemic of obesity has raised expectations that CVD associated with type 2 diabetes will become an even greater public health challenge . Despite the importance of this health problem , there is a lack of definitive data on the effects of the intensive control of glycemia and other CVD risk factors on CVD event rates in patients with type 2 diabetes . The Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial is a r and omized , multicenter , double 2 x 2 factorial design study involving 10,251 middle-aged and older participants with type 2 diabetes who are at high risk for CVD events because of existing CVD or additional risk factors . ACCORD is testing the effects of 3 medical treatment strategies to reduce CVD morbidity and mortality . All participants are in the glycemia trial , which is testing the hypothesis that a therapeutic strategy that targets a glycosylated hemoglobin ( HbA1c ) level of < 6.0 % will reduce the rate of CVD events more than a strategy that targets an HbA1c level of 7.0%-7.9 % . The lipid trial includes 5,518 of the participants , who receive either fenofibrate or placebo in a double-masked fashion to test the hypothesis of whether , in the context of good glycemic control , a therapeutic strategy that uses a fibrate to increase high-density lipoprotein cholesterol and lower triglyceride levels together with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor ( statin ) to lower low-density lipoprotein cholesterol will reduce the rate of CVD events compared with a strategy that uses a statin plus a placebo . The blood pressure trial includes the remaining 4,733 participants and tests the hypothesis that a therapeutic strategy that targets a systolic blood pressure of < 120 mm Hg in the context of good glycemic control will reduce the rate of CVD events compared with a strategy that targets a systolic blood pressure of < 140 mm Hg . The primary outcome measure for all 3 research questions is the first occurrence of a major CVD event , specifically nonfatal myocardial infa rct ion , nonfatal stroke , or cardiovascular death . Upon the expected completion of participant follow-up in 2009 , the ACCORD trial should document for the first time the benefits and risks of intensive glucose control , intensive blood pressure control , and the combination of fibrate and statin drugs in managing blood lipids in high-risk patients with type 2 diabetes UNLABELLED Patients with type 2 diabetes mellitus have markedly increased risks of developing vascular diseases . These risks are reduced by lowering blood pressure in hypertensive individuals . However , the association between blood pressure and vascular risk appears continuous , with no clearly defined blood pressure level below which the risks fail to further decline . Intensive glucose lowering in these patients has also been shown to reduce microvascular disease , but effects on macrovascular disease remain uncertain . OBJECTIVES ADVANCE ( Action in Diabetes and Vascular disease ; preterAx and diamicroN-MR Controlled Evaluation ) will examine the hypotheses that intensive blood pressure lowering ( with an angiotensin-converting enzyme [ ACE ] inhibitor-diuretic combination ) and glucose control in high-risk hypertensive or non-hypertensive individuals with type 2 diabetes reduce the incidence of vascular diseases . The study will also provide an opportunity to examine the effects of blood pressure lowering against a background of ACE inhibition among such patients . DESIGN This 2 x 2 factorial r and omised controlled trial will recruit 10 000 adults with type 2 diabetes at elevated risk of vascular disease , from approximately 200 clinical centres in 20 countries worldwide . Eligible patients are r and omised to , first , the fixed combination of perindopril 2mg/indapamide 0.625 mg then perindopril 4 mg/indapamide 1.25 mg or matching placebo , and , second , to an intensive sulphonylurea-based glucose control regimen ( target glycosylated haemoglobin [ HbA(1c ) ] < /= 6.5 % ) , or usual guidelines -based therapy . Any participant in whom ACE inhibition is thought to be indicated is provided with background perindopril therapy . The scheduled period of treatment and follow-up is 4.5 years . Primary outcomes are a composite of macrovascular and a composite of microvascular events . CURRENT STATUS By mid-September 2002 , more than 8000 patients had been recruited from 17 countries , with registration s expected to be completed by December 2002 . Approximately half the participants recruited will be from Asia or from Eastern Europe . Final results are expected early in 2007 . ( Author 's note : registration closed on January 24 , 2003 , with sufficient participants to exceed the target of 10 000 r and omised subjects . OBJECTIVE To examine the effect of intensive glycemic control on cardiovascular disease events ( CVD ) among the major race/ethnic groups in a post-hoc analysis of the VADT . MATERIAL S AND METHODS Participants included 1111 non-Hispanic Whites , 307 Hispanics and 306 non-Hispanic Blacks r and omized to intensive or st and ard glucose treatment in VADT . Multivariable Cox proportional hazards models were constructed to assess the effect of intensive glucose treatment on CVD events among race/ethnic groups . RESULTS Mean age was 60.4 years and median follow-up was 5.6 years . By design , modifiable risk factors were managed equally well in both treatment arms and only differed modestly between race/ethnic groups . HbA(1c ) decreased significantly from baseline with intensive glucose treatment in each race/ethnic group , with a trend for a greater response in Hispanics ( P=0.02 for overall comparison between groups ) . Intensive glucose treatment was associated with reduced risk of CVD events for Hispanics but not for others ( hazard ratios ranged from 0.54 to 0.75 for Hispanics whereas they were consistently close to 1 for others ) . Sensitivity analyses with different definitions of race/ethnicity or limited to individuals free of previous known CVD yielded similar results . CONCLUSIONS The results of these analyses support the hypothesis that race/ethnicity is worthy of consideration when tailoring intensive treatment for individuals with long-st and ing type 2 diabetes . However , additional studies are needed to confirm the findings of this post-hoc analysis Summary We evaluated the impact of some putative progression promoters on kidney function in albuminuric Type 2 ( non-insulin-dependent ) diabetic patients with biopsyproven diabetic glomerulosclerosis . Twenty-six patients ( 1 female ) with a mean age of 52 ( st and ard error 2 ) years and a known mean duration of diabetes of 9 ( 1 ) years were followed-up prospect ively for a mean of 5.2 ( range 1.0–7.0 ) years . Twenty-one patients received antihypertensive treatment . During the observation period the glomerular filtration rate decreased from 83 ( 24–146 ) to 58 ( 2–145 ) ml·min−1·1.73 m−2 ( mean ( range ) ) ( p<0.001 ) . The mean rate of decline in glomerular filtration rate was 5.7 ( −3.5 to 22.0 ) ml/min per year . Albuminuria increased from 1.2 ( 0.3–7.2 ) to 2.3 ( 0.4–8.0 ) g/24 h ( geometric mean ( range ) ) ( p<0.001 ) . Arterial blood pressure remained unchanged : 162/93 ( SE 4/3 ) and 161/89 ( 4/2 ) mm Hg . Univariate analysis showed the rate of decline in glomerular filtration rate to correlate with systolic blood pressure ( r=0.71,p<0.001 ) , mean blood pressure ( r=0.56,p<0.005 ) , albuminuria ( r=0.58,p<0.005 ) and the initial glomerular filtration rate ( r=−0.49,p<0.02 ) . The rate of decline in glomerular filtration rate did not correlate significantly with dietary protein intake , total cholesterol , high-density lipoprotein cholesterol or HbA1c . Three patients died from uraemia and four patients died from cardiovascular disease . Two patients required renal replacement therapy at the end of the observation period . Our prospect i ve observational study revealed that one-fifth of the patients developed end-stage renal failure during the 5-year observation period . The decline in glomerular filtration rate varied considerably between patients . Increase in arterial blood pressure to a hypertensive level is an early feature of diabetic nephropathy . Elevated systolic blood pressure accelerates the progression of diabetic nephropathy in Type 2 diabetic patients To investigate the relation between blood glucose control on the one h and and an increased glomerular filtration rate and enlarged kidneys on the other , we studied 12 patients with insulin-dependent diabetes and an increased glomerular filtration rate for a year after they were r and omly assigned either to continuous subcutaneous insulin infusion or to unchanged conventional therapy . Glycemic control , measured by mean plasma concentrations of glucose and glycosylated hemoglobin , was rapidly and significantly improved ( P less than 0.001 ) in the pump group but did not change in the conventional-treatment group . In the pump group , the glomerular filtration rate fell significantly in the study period ( P less than 0.001 ) and became normal in four of the six patients . It did not change in the conventional-treatment group . There was no change in kidney volume in either group . At the end of a year , a return to conventional insulin treatment in the pump group result ed in both metabolic deterioration and a significant rise in the mean glomerular filtration rate toward base-line values . We conclude that in patients with established insulin-dependent diabetes , strict glycemic control normalizes the glomerular filtration rate , although the kidneys may remain enlarged BACKGROUND Among patients with type 1 diabetes mellitus , intensive therapy ( with the aim of achieving near-normal blood glucose and glycosylated hemoglobin concentrations [ hemoglobin A1c ] ) markedly reduces the risk of microvascular complications as compared with conventional therapy . To assess whether these benefits persist , we compared the effects of former and intensive conventional therapy on the recurrence and severity of retinopathy and nephropathy for four years after the end of the Diabetes Control and Complications Trial ( DCCT ) . METHODS At the end of the DCCT , the patients in the conventional-therapy group were offered intensive therapy , and the care of all patients was transferred to their own physicians . Retinopathy was evaluated on the basis of central ly grade d fundus photographs in 1208 patients during the fourth year after the DCCT ended , and nephropathy was evaluated on the basis of urine specimens obtained from 1302 patients during the third or fourth year , approximately half of whom were from each treatment group . RESULTS The difference in the median glycosylated hemoglobin values between the conventional-therapy and intensive-therapy groups during the 6.5 years of the DCCT ( average , 9.1 percent and 7.2 percent , respectively ) narrowed during follow-up ( median during 4 years , 8.2 percent and 7.9 percent , respectively , P<0.001 ) . Nevertheless , the proportion of patients who had worsening retinopathy , including proliferative retinopathy , macular edema , and the need for laser therapy , was lower in the intensive-therapy group than in the conventional-therapy group ( odds reduction , 72 percent to 87 percent , P<0.001 ) . The proportion of patients with an increase in urinary albumin excretion was significantly lower in the intensive-therapy group . CONCLUSIONS The reduction in the risk of progressive retinopathy and nephropathy result ing from intensive therapy in patients with type 1 diabetes persists for at least four years , despite increasing hyperglycemia OBJECTIVE Microalbuminuria can reflect the progress of microvascular complications and may be predictive of macrovascular disease in type 2 diabetes . The effect of intensive glycemic control on microalbuminuria in patients in the U.S. who have had type 2 diabetes for several years has not previously been evaluated . RESEARCH DESIGN AND METHODS We r and omly assigned 153 male patients to either intensive treatment ( INT ) ( goal HbA(1c ) 7.1 % ) or to st and ard treatment ( ST ) ( goal HbA(1c ) 9.1 % ; P = 0.001 ) , and data were obtained during a 2-year period . Mean duration of known diabetes was 8 years , mean age of the patients was 60 years , and patients were well matched at baseline . We obtained 3-h urine sample s for each patient at baseline and annually and defined microalbuminuria as an albumin : creatinine ratio of 0.03 - 0.30 . All patients were treated with insulin and received instructions regarding diet and exercise . Hypertension and dyslipidemia were treated with similar goals in each group . RESULTS A total of 38 % of patients had microalbuminuria at entry and were evenly assigned to both treatment groups . INT retarded the progression of microalbuminuria during the 2-year period : the changes in albumin : creatinine ratio from baseline to 2 years of INT versus ST were 0.045 vs. 0.141 , respectively ( P = 0.046 ) . Retardation of progressive urinary albumin excretion was most pronounced in those patients who entered the study with microalbuminuria and were r and omized to INT . Patients entering with microalbuminuria had a deterioration in creatinine clearance at 2 years regardless of the intensity of glycemic control . In the group entering without microalbuminuria , the subgroup receiving ST had a lower percentage of patients with a macrovascular event ( 17 % ) than the subgroup receiving INT ( 36 % ) ( P = 0.03 ) . Use of ACE inhibitors or calcium-channel blockers was similarly distributed among the groups . CONCLUSIONS Intensive glycemic control retards microalbuminuria in patients who have had type 2 diabetes for several years but may not lessen the progressive deterioration of glomerular function . Increases in macrovascular event rates in the subgroup entering without albuminuria who received INT remain unexplained but could reflect early worsening , as observed with microvascular disease in the Diabetes Control and Complications Trial AIMS To determine whether tighter cardiovascular risk factor control with structured education in individuals with type 2 diabetes ( T2DM ) and microalbuminuria benefits cardiovascular risk factors . METHODS Participants from a multiethnic population , recruited from primary care and specialist clinics were r and omised to intensive intervention with structured patient ( DESMOND model ) education ( n=94 ) or usual care by own health professional ( n=95 ) . PRIMARY OUTCOME change in HbA1c at 18months . SECONDARY OUTCOMES changes in blood pressure ( BP ) , cholesterol , albuminuria , proportion reaching risk factor targets , modelled cardiovascular risk scores . RESULTS Mean ( SD ) age and diabetes duration of participants were 61.5 ( 10.5 ) and 11.5 ( 9.3 ) years , respectively . At 18months , intensive intervention showed significant improvements in HbA1c ( 7.1(1.0 ) vs. 7.8(1.4)% , p<0.0001 ) , systolic BP ( 129(16 ) vs. 139(17 ) mmHg , p<0.0001 ) , diastolic BP ( 70(11 ) vs. 76(12 ) mmHg , p<0.001 ) , total cholesterol ( 3.7(0.8 ) vs. 4.1(0.9 ) mmol/l , p=0.001 ) . Moderate and severe hypoglycaemia was 11.2 vs. 29.0 % ; p=0.001 and 0 vs. 6.3 % ; p=0.07 , respectively . More intensive participants achieved ≥3 risk factor targets with greater reductions in cardiovascular risk scores . CONCLUSIONS Intensive intervention showed greater improvements in metabolic control and cardiovascular risk profile with lower rates of moderate and severe hypoglycaemia . Intensive glycaemic interventions should be underpinned by structured education promoting self-management in T2DM The effect of prolonged restoration of near-normoglycemia on the progression of diabetic nephropathy was evaluated in a controlled study in which 10 insulin-dependent ( type 1 ) diabetic patients with clinical proteinuria were r and omized to continue with conventional insulin treatment ( CIT ) or to undertake more intensive diabetic therapy using continuous subcutaneous insulin infusion ( CSII ) . The patients , mean age 33 + /- 8 yr , mean duration of diabetes 15 + /- 4 yr , were studied before and during 12 months of either CIT or CSII therapy . Glycemic control was assessed by means of mean blood glucose ( MBG ) + /- St and ard deviation ( SD ) , urinary glucose excretion and glycosylated hemoglobin , while renal function was assessed by albumin , IgG and beta-2-microglobulin urinary excretion rates , serum creatinine and creatinine clearance . Blood glucose level , urinary glucose excretion and glycosylated hemoglobin fell significantly in the CSII group , while no differences were found in the CIT group after the 12 months observation period . Both groups showed a deterioration in all indices of renal function , as illustrated by an increase of protein excretion rates and of serum creatinine , and by a decline in creatinine clearance . Comparison of the rate of increase of urinary albumin and IgG excretion and of serum creatinine and of the rate of fall in creatinine clearance between CIT and CSII groups demonstrated that the rate of progression of diabetic nephropathy may be slowed by correction of hyperglycemia . Our study , with due reservations because of the small number of examined patients and differences in kidney function at the beginning of the trial shows that intensive diabetic care may play a role in the proteinuric stage of diabetes in slowing further destruction of residual glomerular structure and in delaying end stage renal failure OBJECTIVE Few studies have examined the relationship between vitamin D levels and incident cardiovascular events in large well-characterized patient cohorts . Therefore , our objective was to determine if low vitamin D levels predicted vascular complications of diabetes . METHODS Prospect i ve analysis of 936 veterans with type 2 diabetes ( 59.7 ± 8.4 years , 96.9 % male ) who participated in the Veteran Affairs Diabetes Trial ( VADT ) was conducted . 25(OH)-vitamin D was measured a median of two years after entry and participants were subsequently followed 3.7 years . Hazard ratios ( HRs ) were calculated for cardiovascular endpoints in relation to 25(OH)-vitamin D quartile . For microvascular endpoints , logistic regression was used to calculate odds ratios . RESULTS After adjusting for age , minority status , treatment arm and history of prior event , individuals in the lowest vitamin D quartile ( i.e. , 1 - 15.9 ng/ml ) were at similar risk of MI [ HR = 1.13 ( 95 % CI : 0.53 , 2.42 ) ] , CHD [ HR = 0.87 ( 95 % CI : 0.49 , 1.55 ) ] , congestive heart failure [ HR = 1.44 ( 95 % CI : 0.67 , 3.06 ) ] , and death from any cause [ HR = 1.04 ( 95 % CI : 0.53 , 2.04 ) ] as individuals in the highest vitamin D quartile ( i.e. , 29.9 - 77.2 ng/ml ) . Similarly , there were no differences in the odds associated with retinopathy or renal disease onset or progression in the lowest versus highest vitamin D quartile . CONCLUSIONS These data indicate that vitamin D status had no significant impact on the incidence of vascular events in a cohort of high-risk veterans with diabetes in which traditional risk factors were managed according to current treatment guidelines AIMS To determine whether intensive risk factor management reduced markers of inflammation in middle-aged and older people with type 2 diabetes who either had , or were at risk for cardiovascular disease ( CVD ) , and whether these effects were mediated by adiposity . METHODS The Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) trial was a multicenter double 2 by 2 factorial r and omized controlled trial of 10,251 middle-aged and older people who had type 2 diabetes , a GHbA1c of 7.5 % or greater , and evidence of CVD or CVD risk factors . Biomarkers were assessed in a subset of 562 participants . Intervention effects on high-sensitivity C-reactive protein ( hs-CRP ) , interleukin-6 ( IL-6 ) , and tumor necrosis factor-alpha ( TNF-alpha ) were tested using linear regression models . RESULTS A significantly lower average hs-CRP was noted in the intensive versus the st and ard glycemic group ( p=0.029 ) . Adjusting for change in BMI or waist circumference result ed in larger differences in adjusted hs-CRP ( p<0.001 and p<0.002 , respectively ) between the glycemic intervention groups . CONCLUSIONS Intensive glycemic control was associated with a reduction in hs-CRP in this study population . Intervention associated increases in adiposity suppressed the beneficial effect of intensive glycemic control on lowering hs-CRP BACKGROUND AND OBJECTIVES The objective of this study was to compare r and om urine albumin-creatinine ratio ( ACR ) with timed urine albumin excretion rate ( AER ) in patients with type 1 diabetes . DESIGN , SETTING , PARTICIPANTS , & MEASUREMENTS A total of 1186 participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications ( DCCT/EDIC ) Study provided spot urine specimens concurrent with 4-hour timed urine collection s. ACR and AER were compared using Bl and -Altman plots , cross-classification of albuminuria status and its change over time , and within-person variability . RESULTS Despite moderate correlation ( r=0.62 ) , ACR levels ( mg/g ) were lower than AER levels ( mg/24 hr ) . This difference was greatest for men . Gender-specific estimated AER ( eAER ) values were empirically derived from ACR . Comparing the eAER with measured AER , agreement of prevalent microalbuminuria and macroalbuminuria classification was fair to moderate , and classification of change in albuminuria status over time was different . Intraclass correlations were 0.697 for ACR and 0.803 for AER . Effects of DCCT intensive versus conventional diabetes therapy on urine albumin excretion or classification of albuminuria were similar using the eAER versus measured AER , as were the effects of the previous glycosylated hemoglobin . CONCLUSIONS Systematic differences exist between urine ACR and AER , related to gender and other determinants of muscle mass . Use of ACR ( or eAER ) versus AER yields differences in classification of prevalent albuminuria states and changes in albuminuria states over time . These findings support the use of consistent ascertainment methods over time and further efforts to st and ardize and optimally interpret measurement of urine albumin excretion OBJECTIVE The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus was conducted in NIDDM patients to determine if a significant difference in HbA1c could be achieved between groups receiving st and ard and intensive treatment . We observed differences in the response to exogenous insulin between African-Americans and other intensively treated patients . Therefore , we assessed the variations of response and correlated factors that might explain such differences . RESEARCH DESIGN AND METHODS One hundred fifty-three men aged 40–69 years with NIDDM for ≤15 years were r and omized to either the st and ard therapy ( n = 78 ) or the intensive therapy ( n = 75 ) arm . Of the 75 patients in the intensive therapy group , 57 completed the study on insulin therapy alone . Of these , 18 were African-Americans and 39 were non-African-Americans . We conducted an analysis of the data collected to determine differences in baseline characteristics , glycemic response , insulin requirement , body weight , exercise , and basal C-peptide level , factors that may explain a difference in response to insulin therapy . RESULTS Glycemic control improved in all patients with intensive insulin therapy . African-Americans achieved a greater improvement in HbA1c compared with non-African-Americans with a similar increment in insulin . This difference could not be explained by differences in body weight , activity , concomitant use of other medicines , or insulin-secretory capacity of the pancreas . CONCLUSIONS We conclude that ethnic differences may exist in the response to insulin therapy . A knowledge of such differences may aid in achieving good glycemic control , especially since minorities have a greater prevalence of and burden from the microvascular complications of diabetes Objective and rationale ADVANCE ( Action in Diabetes and Vascular disease : preterAx and diamicroN-MR Controlled Evaluation ) is a large-scale trial design ed to investigate the benefits of blood pressure lowering and intensive glucose control in patients with type 2 diabetes , and to address a number of unresolved issues : whether blood pressure-lowering therapy and intensive glucose control therapy will reduce the risk of major vascular disease regardless of initial blood pressure or glucose concentration ; whether more intensive glucose control targeting a haemoglobin A1c ( HbA1c ) level of 6.5 % or less will confer greater protection against microvascular disease ; and whether the benefits of the two interventions are additive . Design and methods ADVANCE is a 2 × 2 factorial r and omized clinical trial evaluating the risks and benefits of the low-dose fixed combination of perindopril and indapamide versus placebo to lower blood pressure and of an intensive gliclazide-MR-based glucose control regimen , targeting an HbA1c of 6.5 % or less versus st and ard guidelines based therapy for glucose control . There are two primary outcomes : a composite macrovascular endpoint and a composite microvascular endpoint . Results A total of 12 878 participants from 215 centres in 20 countries entered a 6-week run-in phase between June 2001 and January 2003 , and 11 140 patients were r and omly assigned by March 2003 . The average ( SD ) systolic and diastolic blood pressure fell from 145 (22)/81 ( 11 ) to 137 (20)/78 ( 10 ) mmHg during the 6-week run-in phase , during which participants received one tablet of open-labelled perindopril 2 mg/indapamide 0.625 mg . Of the 12 878 patients who entered the run-in , only 3.6 % withdrew because of suspected intolerance to perindopril/indapamide . The study is half way through follow-up and both the study medications ( perindopril 2 mg/indapamide 0.625 mg and gliclazide-MR ) continue to be well tolerated . Completion is expected in 2007 . Conclusion Safe and effective blood pressure lowering with the fixed low-dose combination of perindopril and indapamide was confirmed during the run-in phase in 11 140 patients with type 2 diabetes , who were subsequently r and omly assigned . Post-r and omization study treatments have been well tolerated , and the completion of follow-up is scheduled in 2007 AIMS Autonomic neuropathy is a serious diabetic complication , probably contributing to the death of many young people with Type 1 diabetes mellitus . It is often not diagnosed . METHODS Patients with Type 1 diabetes from the Stockholm Diabetes Intervention Study were investigated with power spectral analysis ( n = 88 ) , heart rate and blood pressure reactions to tilting ( n = 66 ) , and heart rate variability during deep breathing ( n = 70 ) a mean of 11.4 years after r and omization to intensified conventional treatment ( ICT ) or st and ard treatment ( ST ) , the treatment groups similar with regard to age , duration of diabetes and metabolic control at baseline ( HbA1c 9.4 (1.3)% , mean ( SD ) ) . Blood glucose levels ( mean of 29 HbA1c values ) during the 10 years were lower in the patients from the ICT group ( 7.2 ( 0.6 ) vs. 8.3 (1.0)% , P = 0.001 ) . RESULTS Heart rate variability ( HRV ) in the high frequency range ( P = 0.034 ) , the expiration-inspiration ratio ( P = 0.020 ) , and the brake index during tilt ( P = 0.044 ) were lower in the ST group , indicating more pronounced parasympathetic insufficiency . Systolic blood pressure fell by 10 ( 16 ) mmHg in the ST group , and by 2.5 ( 15 ) mmHg in the ICT group 8 min after rising from the supine to a 70 degrees upright position ( P = 0.034 ) . A decreased autonomic function was associated with age and higher HbA1c . CONCLUSION Better autonomic nerve function is associated with lower HbA1c and lower age which were both the same in the intensively and the conventionally treatment groups at baseline . After a mean of 11.4 years autonomic function was better in the intensively treated group OBJECTIVE The main goal of the study of 153 male veterans was to determine whether a statistically and clinical ly significant difference in HbA1c could be achieved between a st and ard therapy and an intensively treated group of patients with type II diabetes . A second major goal was to assess the feasibility of collecting reliable high- quality endpoint data , including microvascular and macrovascular events . Retinopathy was defined as a key microvascular endpoint . RESEARCH DESIGN AND METHODS This was a r and omized prospect i ve trial of 153 men between the ages of 40 and 69 years , with type II diabetes for 15 years or less . Of the patients , 78 were assigned to the st and ard therapy arm and 75 to the intensive therapy arm . The goal of st and ard therapy was good general medical care and well-being and avoiding excessive hyperglycemia , glycosuria , ketonuria , or hypoglycemia . This was generally accomplished with one shot of insulin per day . The goal of intensive therapy was to obtain an HbA1c within two st and ard deviations of the mean of nondiabetic subjects ( 4.0–6.1 % ) . This was obtained by a four-step management technique , with patients moving to the next step only if operational goals were not met . The steps were as follows : step 1 : evening intermediate or long-acting insulin only ; step 2 : evening insulin with daytime glipizide ; step 3 : insulin , twice a day , no glipizide ; and step 4 : more than two injections of insulin , no glipizide . Retinopathy was assessed at baseline , 12 , and 24 months by seven-field stereo fundus photography done at each of the five participating VA medical centers and read at the Central Reading Center at the Department of Ophthalmology , University of Wisconsin Medical School , Madison . Visual acuity was determined by ophthalmologists at each of the participating hospitals . RESULTS After the 6th month of the 24-month study , an average HbA1c of ∼7.1 % in the intensively treated group was sustained for the full study and was significantly lower than that seen in the st and ard group ( 9.2 % , P < 0.001 ) . Compliance in obtaining fundus photographs was excellent . Near normalization of glycemia did not cause transient worsening of retinal morphology nor did it prevent the onset or delay the progression of retinopathy . There was no effect on visual acuity . CONCLUSIONS 1 ) A glycemic control intervention study in people with type II diabetes is feasible and safe ; 2 ) intensive control did not cause transient deterioration of retinopathy ; and 3 ) although no improvement was seen in retinopathy , the follow-up was 24 months , an interval shorter than the 3 years or more of intensive therapy before improvement is seen in type 1 diabetic studies . This does not rule out the possibility that longer periods of intensive therapy would have improved retinopathy . A full-scale intervention trial in type II diabetes is needed to resolve this issue OBJECTIVE The Veterans Affairs Cooperative Study in Diabetes Mellitus Type 2 Feasibility Trial ( VA CSDM ) studied st and ard and intensive glycemic treatment groups , achieving and maintaining for 27 months a difference in HbA1c of 2.1 % ( 9.2 % vs. 7.1 % , respectively ) . A sub study planned in advance examined health status as assessed by a health status question naire obtained at baseline and 24 months . DESIGN AND METHODS A r and omized , prospect i ve trial was carried out at five VA Medical Centers from 1990 to 1993 . The sample involved 153 male veterans 40 - 69 years of age and with diabetes duration of 8+/-4 years , who were suboptimally controlled with st and ard glucose lowering treatment . The participants were r and omized to intensive and st and ard treatment groups . In addition to a variety of indicators of glycemic control and complications , health-related qualify of life data were assessed using a 20- question version of the Medical Outcome Study instrument . Scores were evaluated at baseline and 24 months for changes between the treatment groups . RESULTS The two groups were similar at baseline with respect to age , duration of diabetes , complications , comorbidities , and reported physical activity . The intensive treatment group had more frequent , m and atory self-glucose monitoring ( vs. occasional measurement in the st and ard ) and received two or more daily insulin injections ( only one in the st and ard ) . This group had three times the number of clinic visits and 10-fold higher reported incidence of mild/moderate hypoglycemia . There were no significant changes in the health status over time in either the st and ard or intensive treatment groups , nor was there a difference between the two groups . CONCLUSIONS Intensive glucose control in advanced Type 2 diabetes mellitus ( DM ) has no effect on health status over 2 years . The successful lowering of glycemia does not improve health-related quality of life nor do the increased dem and s of an intensive therapy regimen worsen it A reduction of either blood pressure or glycemia decreases some microvascular complications of type 2 diabetes , and we studied here their combined effects . In total , 4733 older adults with established type 2 diabetes and hypertension were r and omly assigned to intensive ( systolic blood pressure less than 120 mm Hg ) or st and ard ( systolic blood pressure less than 140 mm Hg ) blood pressure control , and separately to intensive ( HbA1c less than 0.060 ) or st and ard ( HbA1c 0.070 - 0.079 ) glycemic control . Prespecified microvascular outcomes were a composite of renal failure and retinopathy and nine single outcomes . Proportional hazard regression models were used without correction for type I error due to multiple tests . During a mean follow-up of 4.7 years , the primary outcome occurred in 11.4 % of intensive and 10.9 % of st and ard blood pressure patients ( hazard ratio 1.08 ) , and in 11.1 % of intensive and 11.2 % of st and ard glycemia control patients . Intensive blood pressure control only reduced the incidence of microalbuminuria ( hazard ratio 0.84 ) , and intensive glycemic control reduced the incidence of macroalbuminuria and a few other microvascular outcomes . There was no interaction between blood pressure and glycemic control , and neither treatment prevented renal failure . Thus , in older patients with established type 2 diabetes and hypertension , intensive blood pressure control improved only 1 of 10 prespecified microvascular outcomes . None of the outcomes were significantly reduced by simultaneous intensive treatment of glycemia and blood pressure , signifying the lack of an additional beneficial effect from combined treatment OBJECTIVE Patients with type 2 diabetes ( T2DM ) are at increased risk of fracture . High prevalence of chronic kidney disease ( CKD ) in T2DM may contribute to bone fragility , but whether dynamic change in kidney function is associated with fracture risk is unclear . RESEARCH DESIGN AND METHODS To evaluate the association of pre-r and omization baseline estimated glomerular filtration ( eGFR ) and its change over time with subsequent fracture risk in the Bone sub study of Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) Trial , we conducted an observational study of 2262 women and 4737 men with T2DM and with at least 2 eGFR values . RESULTS During a mean follow-up of 4.40±1.54 years , 235 women and 223 men sustained a new non-vertebral fracture . In multivariable adjusted sex-specific models , pre-r and omization baseline eGFR was not a significant predictor of fracture risk in either men or women . However , a steeper decline in eGFR was associated with greater risk of fracture in women ( hazard ratio [ HR ] per st and ard deviation [ SD ] decrement in eGFR slope , 1.30 ; 95 % CI 1.17 - 1.44 ) but not men ( HR per SD decrement in eGFR slope , 0.97 ; 95%CI 0.82 - 1.13 ) . Accounting for competing risk of death modestly attenuated the association in women ( HR per SD decrement in eGFR slope , 1.19 ; 95 % CI 1.04 - 1.37 ) , with the relationship in men remaining non-significant ( HR per SD decrement in eGFR slope , 0.96 ; 95 % CI 0.77 - 1.18 ) . CONCLUSIONS Declining kidney function predicts fracture risk in women but not in men with T2DM . Future studies should investigate the mechanisms for these associations BP is an important determinant of kidney disease among patients with diabetes . The recommended thresholds to initiate treatment to lower BP are 130/80 and 125/75 mmHg for people with diabetes and nephropathy , respectively . We sought to determine the effects of lowering BP below these currently recommended thresholds on renal outcomes among 11,140 patients who had type 2 diabetes and participated in the Action in Diabetes and Vascular disease : preterAx and diamicroN-MR Controlled Evaluation ( ADVANCE ) study . Patients were r and omly assigned to fixed combination perindopril-indapamide or placebo , regardless of their BP at entry . During a mean follow-up of 4.3 yr , active treatment reduced the risk for renal events by 21 % ( P < 0.0001 ) , which was driven by reduced risks for developing microalbuminuria and macroalbuminuria ( both P < 0.003 ) . Effects of active treatment were consistent across subgroups defined by baseline systolic or diastolic BP . Lower systolic BP levels during follow-up , even to < 110 mmHg , was associated with progressively lower rates of renal events . In conclusion , BP-lowering treatment with perindopril-indapamide administered routinely to individuals with type 2 diabetes provides important renoprotection , even among those with initial BP < 120/70 mmHg . We could not identify a BP threshold below which renal benefit is lost INTRODUCTION Long-term glycemic control trials in type 2 diabetes show as the main clinical benefit a difference in retinal photocoagulation ( 3/1000 in the UK Prospect i ve Diabetes Study [ UKPDS ] ) , but no effect on visual acuity or renal failure . No intensive glycemic control trial has yet affected cardiovascular ( CV ) events , the main cause of morbidity and mortality . By contrast , modest blood pressure reduction has protective effects on visual acuity , renal function , CV events , and mortality . Optimal glycemic control goals are not established in elderly , obese persons with advanced complications , the most common patients in the Veterans Affairs ( VA ) system . The earlier feasibility trial in such patients ( VA-CSDM ) suggested potentially worse CV outcomes with lower attained hemoglobin A1c ( HbA1c ) levels . OBJECTIVES The primary objective of the Veterans Affairs Diabetes Trial ( VADT ) is the assessment of the effect of intensive glycemic treatment on CV events . Other objectives are effects on microangiopathy , quality of life , and cost effectiveness . RESEARCH DESIGN AND METHODS The VADT , started in December 2000 , is enrolling 1700 men and women previously uncontrolled on insulin or maximum doses of oral agents at 20 VA medical centers . Accrual is 2 years and follow-up is 5 - 7 years , with visits every 1.5 months . The study has a power of 86 % to detect a 21 % relative reduction in major CV events ( CV death , myocardial infa rct ion [ MI ] , cerebrovascular accident [ CVA ] , congestive heart failure [ CHF ] , revascularization and amputation for ischemia ) . Subjects are r and omized to an intensive arm aim ing at normal HbA1c levels or to a st and ard arm with usual , improved glycemic control . An HbA1c separation of > 1.5 % is to be maintained ( expected 2 % ) . Both arms receive step therapy : glimepiride or metformin plus rosiglitazone and addition of insulin or other oral agents to achieve goals . Strict control of blood pressure and dyslipidemia , daily aspirin , diet , and education are identical in both arms . Plasma fibrinogen , plasminogen-activating inhibitor I ( PAI-I ) , lipids , renal function parameters , and ECG are measured throughout . Stereo retinal photographs are obtained at entry and 5 years , eye examinations yearly , and intervention as needed to prevent visual deterioration . Recruitment is proceeding on schedule : the current mean HbA1c at entry is 9.4+/-1.6 % and mean duration of diagnosed diabetes 11+/-8 years Ninety-six patients with insulin-dependent diabetes mellitus ( IDDM ) and non-proliferative retinopathy were r and omized to intensified conventional treatment ( ICT ) ( n = 44 ) or regular treatment ( RT ) ( n = 52 ) , and followed up for 5 years . HbA1c decreased from 9.5 + /- 0.2 % ( mean value + /- SEM ) to 7.2 + /- 0.1 % in the ICT group , and from 9.4 + /- 0.2 % to 8.7 + /- 0.1 % in the RT group ( difference between the groups , P less than 0.001 ) . Retinopathy increased in both groups ( P less than 0.001 ) , but after 5 years it was worse in the RT group ( P less than 0.05 ) . The urinary albumin excretion rate was higher in the RT group than in the ICT group after 5 years ( 239.9 + /- 129.7 micrograms min-1 vs. 46.0 + /- 26.1 micrograms min-1 , P less than 0.05 ) . Eight RT patients developed manifest nephropathy , compared with none in the ICT group ( P less than 0.01 ) . After 5 years the conduction velocities of the sural ( P less than 0.05 ) , peroneal ( P less than 0.01 ) and tibial ( P less than 0.001 ) nerves were lower in the RT group . The respiratory sinus arrhythmia was 12.1 + /- 1.2 beats min-1 in the RT group and 16.7 + /- 1.4 beats min-1 in the ICT group at the end of the study ( P less than 0.01 ) . The increases in retinopathy ( P less than 0.01 ) , nephropathy ( P less than 0.01 ) and neuropathy ( P less than 0.001 ) were all related to the mean HbA1c value during the study . Smoking habits only influenced the progression of retinopathy ( P less than 0.05 ) . Serious hypoglycaemia occurred in 34 ICT patients and 29 RT patients ( 242 and 98 episodes , respectively ) ( P less than 0.05 ) . Whereas weight was stable in the RT group , the body mass index increased by 5.8 % in the ICT group ( P less than 0.01 ) . In conclusion , microvascular complications of diabetes were retarded by intensified conventional insulin treatment . However , such treatment increased the frequency of serious hypoglycaemia , and led to an increase in body weight BACKGROUND Intensive diabetes treatment reduces the risk of developing albuminuria in individuals with type 1 diabetes . Effects on the long-term clinical course of kidney disease remain to be defined . We aim ed to compare the long-term effects of intensive versus conventional treatment on incident albuminuria . METHODS For this long-term follow-up study of the Diabetes Control and Complications Trial ( DCCT ) we assessed the effect of intensive diabetes treatment on albuminuria during 18 years after the completion of the trial . During the DCCT ( 1983 - 1993 ) , 1441 participants with type 1 diabetes were r and omly assigned to receive either intensive treatment ( with the goal of achieving levels of glycaemia as close to the non-diabetic range as safely possible ) or conventional treatment ( aim ed at prevention of symptoms of hyperglycaemia and hypoglycaemia ) . At the end of the DCCT , all participants were instructed in intensive treatment , and all participants were invited to join the observational Epidemiology of Diabetes Interventions and Complications ( EDIC ) study . Mean HbA1c during the EDIC study was similar in the two groups of patients who differed in their treatment assignment during the DCCT . Albumin excretion rate was measured every other year during the EDIC study . Microalbuminuria was defined as an albumin excretion rate of 30 mg per 24 h or higher on two consecutive study visits and macroalbuminuria as an albumin excretion rate of 300 mg per day or higher . We estimated glomerular filtration rate from annual serum creatinine measurements throughout DCCT and the EDIC study . The DCCT is registered with Clinical Trials.gov , number NCT00360815 , and the EDIC study , with number NCT00360893 . FINDINGS During years 1 - 18 of EDIC , we noted 191 new cases of microalbuminuria ( 71 in the group receiving intensive treatment during DCCT and 120 in the group receiving conventional treatment during DCCT ; risk reduction 45 % , 95 % CI 26 - 59 ) and 117 new cases of macroalbuminuria ( 31 intensive , 86 conventional ; 61 % , 41 - 74 ) . At year 17 - 18 of EDIC , the prevalence of albumin excretion rate of 30 mg per 24 h or higher was 18·4 % in participants assigned to intensive treatment during the DCCT , compared with 24·9 % in participants assigned to conventional treatment ( p=0·02 ) . During years 1 - 18 of EDIC , we recorded 84 cases of sustained estimated glomerular filtration rate lower than 60 mL/min per 1·73m(2 ) ( 31 intensive , 53 conventional ; risk reduction 44 % , 95 % CI 12 - 64 ) . INTERPRETATION In individuals with type 1 diabetes , intensive diabetes treatment yields durable renal benefits that persist for at least 18 years after its application . Ultimately , such benefits should result in fewer patients requiring renal replacement therapy . FUNDING National Institute of Diabetes and Digestive and Kidney Disease BACKGROUND The progression of nephropathy from diagnosis of type 2 diabetes has not been well described from a single population . This study sought to describe the development and progression through the stages of microalbuminuria , macroalbuminuria , persistently elevated plasma creatinine or renal replacement therapy ( RRT ) , and death . METHODS Using observed and modeled data from 5097 subjects in the UK Prospect i ve Diabetes Study , we measured the annual probability of transition from stage to stage ( incidence ) , prevalence , cumulative incidence , ten-year survival , median duration per stage , and risk of death from all-causes or cardiovascular disease . RESULTS From diagnosis of diabetes , progression to microalbuminuria occurred at 2.0 % per year , from microalbuminuria to macroalbuminuria at 2.8 % per year , and from macroalbuminuria to elevated plasma creatinine ( > or=175 micromol/L ) or renal replacement therapy at 2.3 % per year . Ten years following diagnosis of diabetes , the prevalence of microalbuminuria was 24.9 % , of macroalbuminuria was 5.3 % , and of elevated plasma creatinine or RRT was 0.8 % . Patients with elevated plasma creatinine or RRT had an annual death rate of 19.2 % ( 95 % confidence interval , CI , 14.0 to 24.4 % ) . There was a trend for increasing risk of cardiovascular death with increasing nephropathy ( P < 0.0001 ) , with an annual rate of 0.7 % for subjects in the stage of no nephropathy , 2.0 % for those with microalbuminuria , 3.5 % for those with macroalbuminuria , and 12.1 % with elevated plasma creatinine or RRT . Individuals with macroalbuminuria were more likely to die in any year than to develop renal failure . CONCLUSIONS The proportion of patients with type 2 diabetes who develop microalbuminuria is substantial with one quarter affected by 10 years from diagnosis . Relatively fewer patients develop macroalbuminuria , but in those who do , the death rate exceeds the rate of progression to worse nephropathy Patients with insulin-dependent diabetes mellitus ( IDDM ) and non-proliferative retinopathy were r and omized to intensified conventional insulin treatment ( ICT , n = 44 ) or regular treatment ( RT , n = 51 ) . During a 3-year period the glycosylated haemoglobin ( HbA1c ) levels were reduced to a greater extent ( P = 0.00001 ) in the ICT group ( from 9.5 + /- 0.2 to 7.4 % , P = 0.0001 ) than in the RT group ( 9.4 + /- 0.2 to 9.0 + /- 0.2 , P = 0.004 ) . The urinary albumin excretion rate ( UAER ) increased significantly ( P = 0.033 ) in the RT group but not in the ICT group , and the UAER differed significantly ( P = 0.031 ) between the groups after 3 years . The mean HbA1c values during the study period independently influenced the deterioration of UAER levels ( P = 0.029 ) . Initial diastolic blood pressure ( P = 0.112 ) , the HbA1c value at entry ( P = 0.480 ) and the smoking habits ( P = 0.959 ) were not related to change of UAER levels . Manifest nephropathy after 3 years was seen almost exclusively in patients with HbA1c levels above 9 % . Improved blood glucose control , without ' near normoglycaemia ' , delayed the progression of nephropathy in patients with IDDM and retinopathy The Diabetes Control and Complications Trial ( DCCT ) is a multicenter , r and omized , clinical study design ed to determine whether an intensive treatment regimen directed at maintaining blood glucose concentrations as close to normal as possible will affect the appearance or progression of early vascular complications in patients with insulin-dependent diabetes mellitus ( IDDM ) . We present the baseline characteristics and 1-yr results of the initial cohort of 278 subjects r and omized in phase II of the trial , a phase design ed to answer several feasibility questions before initiating a full-scale trial . During phase II , recruitment was completed on schedule . The 191 adults and 87 adolescents were r and omized either to st and ard treatment ( 90 adults and 42 adolescents ) , design ed to approximate conventional diabetes treatment , or to experimental treatment ( 101 adults and 45 adolescents ) , design ed to achieve near-normal blood glucose and HbA1c concentrations . With few exceptions , baseline demographic , ophthalmologic , renal , and other medical characteristics were evenly distributed by r and omization between the two treatment groups in both age strata . Glycemic control at baseline , as assessed by HbA1c concentrations and by blood glucose profiles , was comparable between the treatment groups in both age strata . The treatment strategies employed produced statistically significant and clinical ly meaningful differences in HbA1c concentrations and blood glucose profiles between the experimental- and st and ard-group subjects for both adults and adolescents . These differences were maintained throughout the feasibility phase . Except for an increased incidence of hypoglycemia in the experimental group , the two treatment regimens maintained or improved the clinical well-being of subjects in both groups . Adherence and completeness of follow-up were excellent ( > 95 % ) , and the methods employed to measure biochemical and pathologic characteristics of IDDM proved to be reliable , reproducible , and precise . The feasibility phase of the DCCT demonstrated that a complex multicenter , r and omized study of the relationship between diabetes control and complications can be performed . The full-scale , long-term trial therefore has been initiated To examine whether intensive glycemic control could decrease the frequency or severity of diabetic microvascular complications , we performed a prospect i ve study of Japanese patients with non-insulin-dependent diabetes mellitus ( NIDDM ) treated with multiple insulin injection treatment . A total of 110 patients with NIDDM was r and omly assigned to multiple insulin injection treatment group ( MIT group ) or to conventional insulin injection treatment group ( CIT group ) . Fifty-five NIDDM patients who showed no retinopathy and urinary albumin excretions < 30 mg/24 h at the baseline were evaluated in the primary -prevention cohort , and the other 55 NIDDM patients who showed simple retinopathy and urinary albumin excretions < 300 mg/24 h were evaluated in the secondary -intervention cohort . The appearance and the progression of retinopathy , nephropathy and neuropathy were evaluated every 6 months over a 6-year period . The worsening of complications in this study was defined as an increase of 2 or more steps in the 19 stages of the modified ETDRS interim scale for retinopathy and an increase of one or more steps in 3 stages ( normoalbuminuria , microalbuminuria and albuminuria ) for nephropathy . The cumulative percentages of the development and the progression in retinopathy after 6 years were 7.7 % for the MIT group and 32.0 % for the CIT group in the primary -prevention cohort ( P = 0.039 ) , and 19.2 % for MIT group and 44.0 % for CIT group in the secondary -intervention cohort ( P = 0.049 ) . The cumulative percentages of the development and the progression in nephropathy after 6 years were 7.7 % for the MIT group and 28.0 % for the CIT group in the primary -prevention cohort ( P = 0.032 ) , and 11.5 % and 32.0 % , respectively , for the MIT and CIT groups in the secondary -intervention cohort ( P = 0.044 ) . In neurological tests after 6 years , MIT group showed significant improvement in the nerve conduction velocities , while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold . Although both postural hypotension and the coefficient of variation of R-R interval tended to improve in the MIT group , they deteriorated in the CIT group . In conclusion , intensive glycemic control by multiple insulin injection therapy can delay the onset and the progression of diabetic retinopathy , nephropathy and neuropathy in Japanese patients with NIDDM . From this study , the glycemic threshold to prevent the onset and the progression of diabetic microangiopathy is indicated as follows ; HbA1c < 6.5 % , FBG < 110 mg/dl , and 2-h post-pr and ial blood glucose concentration < 180 mg/dl BACKGROUND There is no evidence from r and omized trials to support a strategy of lowering systolic blood pressure below 135 to 140 mm Hg in persons with type 2 diabetes mellitus . We investigated whether therapy targeting normal systolic pressure ( i.e. , < 120 mm Hg ) reduces major cardiovascular events in participants with type 2 diabetes at high risk for cardiovascular events . METHODS A total of 4733 participants with type 2 diabetes were r and omly assigned to intensive therapy , targeting a systolic pressure of less than 120 mm Hg , or st and ard therapy , targeting a systolic pressure of less than 140 mm Hg . The primary composite outcome was nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The mean follow-up was 4.7 years . RESULTS After 1 year , the mean systolic blood pressure was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the st and ard-therapy group . The annual rate of the primary outcome was 1.87 % in the intensive-therapy group and 2.09 % in the st and ard-therapy group ( hazard ratio with intensive therapy , 0.88 ; 95 % confidence interval [ CI ] , 0.73 to 1.06 ; P=0.20 ) . The annual rates of death from any cause were 1.28 % and 1.19 % in the two groups , respectively ( hazard ratio , 1.07 ; 95 % CI , 0.85 to 1.35 ; P=0.55 ) . The annual rates of stroke , a prespecified secondary outcome , were 0.32 % and 0.53 % in the two groups , respectively ( hazard ratio , 0.59 ; 95 % CI , 0.39 to 0.89 ; P=0.01 ) . Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group ( 3.3 % ) and 30 of the 2371 participants in the st and ard-therapy group ( 1.3 % ) ( P<0.001 ) . CONCLUSIONS In patients with type 2 diabetes at high risk for cardiovascular events , targeting a systolic blood pressure of less than 120 mm Hg , as compared with less than 140 mm Hg , did not reduce the rate of a composite outcome of fatal and nonfatal major cardiovascular events . ( Clinical Trials.gov number , NCT00000620 . BACKGROUND The risk of microalbuminuria in patients with insulin-dependent diabetes mellitus ( IDDM ) is thought to depend on the degree of hyperglycemia , but the relation between the degree of hyperglycemia and urinary albumin excretion has not been defined . METHODS We measured urinary albumin excretion in three r and om urine sample s obtained at least one month apart from 1613 patients with IDDM . Microalbuminuria or overt albuminuria was considered to be present if the ratio of albumin ( in micrograms ) to creatinine ( in milligrams ) was 17 to 299 or > or = 300 , respectively , for men and 25 to 299 or > or = 300 , respectively , for women . Measurements of glycosylated hemoglobin ( hemoglobin A1 ) obtained up to four years before the urine testing were used as an index of hyperglycemia . Twelve percent of the patients had overt albuminuria and were excluded from subsequent analyses . RESULTS The prevalence of microalbuminuria was 18 percent in patients with IDDM . It increased with increasing postpubertal duration of diabetes and , within each six-year interval of disease duration , it increased nonlinearly with the hemoglobin A1 value . For hemoglobin A1 values below 10.1 percent , the slope of the relation was almost flat , whereas for values above 10.1 percent , the prevalence of microalbuminuria rose steeply ( P < 0.001 ) . For example , as the hemoglobin A1 value increased from 8.1 to 10.1 percent , the odds of microalbuminuria increased by a factor of 1.3 , but as the value increased from 10.1 to 12.1 percent , the odds were increased by a factor of 2.4 . CONCLUSIONS The risk of microalbuminuria in patients with IDDM increases abruptly above a hemoglobin A1 value of 10.1 percent ( equivalent to a hemoglobin A1c value of 8.1 percent ) , suggesting that efforts to reduce the frequency of diabetic nephropathy should be focused on reducing hemoglobin A1 values that are above this threshold BACKGROUND Cardiovascular morbidity is a major burden in patients with type 2 diabetes . In the Steno-2 Study , we compared the effect of a targeted , intensified , multifactorial intervention with that of conventional treatment on modifiable risk factors for cardiovascular disease in patients with type 2 diabetes and microalbuminuria . METHODS The primary end point of this open , parallel trial was a composite of death from cardiovascular causes , nonfatal myocardial infa rct ion , nonfatal stroke , revascularization , and amputation . Eighty patients were r and omly assigned to receive conventional treatment in accordance with national guidelines and 80 to receive intensive treatment , with a stepwise implementation of behavior modification and pharmacologic therapy that targeted hyperglycemia , hypertension , dyslipidemia , and microalbuminuria , along with secondary prevention of cardiovascular disease with aspirin . RESULTS The mean age of the patients was 55.1 years , and the mean follow-up was 7.8 years . The decline in glycosylated hemoglobin values , systolic and diastolic blood pressure , serum cholesterol and triglyceride levels measured after an overnight fast , and urinary albumin excretion rate were all significantly greater in the intensive-therapy group than in the conventional-therapy group . Patients receiving intensive therapy also had a significantly lower risk of cardiovascular disease ( hazard ratio , 0.47 ; 95 percent confidence interval , 0.24 to 0.73 ) , nephropathy ( hazard ratio , 0.39 ; 95 percent confidence interval , 0.17 to 0.87 ) , retinopathy ( hazard ratio , 0.42 ; 95 percent confidence interval , 0.21 to 0.86 ) , and autonomic neuropathy ( hazard ratio , 0.37 ; 95 percent confidence interval , 0.18 to 0.79 ) . CONCLUSIONS A target-driven , long-term , intensified intervention aim ed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about 50 percent IMPORTANCE Persons with type 2 diabetes mellitus ( T2DM ) are at increased risk for decline in cognitive function , reduced brain volume , and increased white matter lesions in the brain . Poor control of blood pressure ( BP ) and lipid levels are risk factors for T2DM-related cognitive decline , but the effect of intensive treatment on brain function and structure is unknown . OBJECTIVE To examine whether intensive therapy for hypertension and combination therapy with a statin plus a fibrate reduces the risk of decline in cognitive function and total brain volume ( TBV ) in patients with T2DM . DESIGN , SETTING , AND PARTICIPANTS A North American multicenter clinical trial including 2977 participants without baseline clinical evidence of cognitive impairment or dementia and with hemoglobin A1c ( HbA1c ) levels less than 7.5 % r and omized to a systolic BP goal of less than 120 vs less than 140 mm Hg ( n = 1439 ) or to a fibrate vs placebo in patients with low-density lipoprotein cholesterol levels less than 100 mg/dL ( n = 1538 ) . Participants were recruited from August 1 , 2003 , through October 31 , 2005 , with the final follow-up visit by June 30 , 2009 . MAIN OUTCOME MEASURES Cognition was assessed at baseline and 20 and 40 months . A subset of 503 participants underwent baseline and 40-month brain magnetic resonance imaging to assess for change in TBV and other structural measures of brain health . RESULTS Baseline mean HbA1c level was 8.3 % ; mean age , 62 years ; and mean duration of T2DM , 10 years . At 40 months , no differences in cognitive function were found in the intensive BP-lowering trial or in the fibrate trial . At 40 months , TBV had declined more in the intensive vs st and ard BP-lowering group ( difference , -4.4 [ 95 % CI , -7.8 to -1.1 ] cm(3 ) ; P = .01 ) . Fibrate therapy had no effect on TBV compared with placebo . CONCLUSIONS AND RELEVANCE In participants with long-st and ing T2DM and at high risk for cardiovascular events , intensive BP control and fibrate therapy in the presence of controlled low-density lipoprotein cholesterol levels did not produce a measurable effect on cognitive decline at 40 months of follow-up . Intensive BP control was associated with greater decline in TBV at 40 months relative to st and ard therapy . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00000620 The Veterans Affairs Cooperative Studies Program ( VACSP ) has just initiated a trial of the effect of intensive glucose control on cardiovascular complications in patients with type 2 diabetes . The name of the trial is “ VACSP # 465 , Glycemic Control and Complications in Diabetes Mellitus type 2 ” ( V.A. Diabetes Trial [ VADT ] ) . The trial is expected to generate discussion in the diabetes community because the central role of glucose control in preventing or delaying long-term complications is generally accepted . The data on macrovascular disease are not yet conclusive . The VADT is directed at type 2 diabetic patients with established uncontrolled diabetes . This is the population most frequently encountered by the practicing physician . Cardiovascular ( CV ) complications are the major causes of morbidity and mortality in patients with type 2 diabetes ( 1 ) . Efforts to reduce glucose levels in these patients must be balanced between risks and benefits . Consideration of intensive therapy must include effects of glucose control on microvascular complications , macrovascular complications , complications of therapy , and socioeconomic issues , including patient quality of life , compliance with therapy , and distribution of available funds for care of patients with diabetes . # # # Microvascular disease Both the Diabetes Control and Complications Trial ( DCCT ) ( type 1 diabetes ) and the UK Prospect i ve Diabetes Study ( UKPDS ) ( new-onset type 2 diabetes ) showed a significant beneficial effect of glucose control on microvascular complications ( 2,3 ) , as did the smaller Kumamoto study ( 4 ) . Basic biochemical and animal studies provide a solid foundation for these findings , as do epidemiological studies . From a clinical st and point , this issue is more complicated . Risk-to-benefit ratios must be considered . This has not been adequately addressed in older established patients with type 2 diabetes . In the UKPDS the main effect of glucose control after 10.5 years was a 3/1,000 reduction in photocoagulation for retinal disease ( from 1.1 % in the st and ard arm to 0.8 % in the BACKGROUND Microalbuminuria is a common diagnosis in the clinical care of patients with type 1 diabetes mellitus . Long-term outcomes after the development of microalbuminuria are variable . METHODS We quantified the incidence of and risk factors for long-term renal outcomes after the development of microalbuminuria in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications ( DCCT/EDIC ) study . The DCCT r and omly assigned 1441 persons with type 1 diabetes to intensive or conventional diabetes therapy , and participants were subsequently followed up during the observational EDIC study . During the DCCT/EDIC study , 325 participants developed incident persistent microalbuminuria ( albumin excretion rate , ≥30 mg/24 h at 2 consecutive study visits ) . We assessed their subsequent renal outcomes , including progression to macroalbuminuria ( albumin excretion rate , ≥300 mg/24 h at 2 consecutive visits ) , impaired glomerular filtration rate ( estimated glomerular filtration rate , < 60 mL/min/1.73 m(2 ) at 2 consecutive study visits ) , end-stage renal disease , and regression to normoalbuminuria ( albumin excretion rate , < 30 mg/24 h at 2 consecutive visits ) . RESULTS The median follow-up period after persistent microalbuminuria diagnosis was 13 years ( maximum , 23 years ) . Ten-year cumulative incidences of progression to macroalbuminuria , impaired glomerular filtration rate , end-stage renal disease , and regression to normoalbuminuria were 28 % , 15 % , 4 % , and 40 % , respectively . Albuminuria outcomes were more favorable with intensive diabetes therapy , lower glycated hemoglobin level , absence of retinopathy , female sex , lower blood pressure , and lower concentrations of low-density lipoprotein cholesterol and triglycerides . Lower glycated hemoglobin level , absence of retinopathy , and lower blood pressure were also associated with decreased risk of impaired glomerular filtration rate . CONCLUSIONS After the development of persistent microalbuminuria , progression and regression of kidney disease each commonly occur . Intensive glycemic control , lower blood pressure , and a more favorable lipid profile are associated with improved outcomes OBJECTIVE The Veterans Affairs Diabetes Trial ( VADT ) is a 20-medical center , prospect i ve , r and omized study of 1792 Type 2 diabetic individuals primarily aim ed at determining whether intensive glycemic control prevents macrovascular events . We report a comparison of fundus photographs and ophthalmologic examination at baseline , permitting an evaluation of multiple setting s similar to common clinical practice . RESEARCH DESIGN AND METHODS A 340-patient subset had both local dilated fundus examinations and central ly read seven-field stereo fundus photographs completed within 60 days of each other ( median 28 days ) . Local examiners were unaware of the stereo photographs . RESULTS Overall , agreement within one step was 76 % and exact agreement between ophthalmoscopy and central gradings of fundus photographs on a five-step retinopathy severity scale was 43 % ( weighted kappa 0.42 , CI 0.35 - 0.48 ) . In about 90 % of disagreements the severity level was higher by photographic grading . The sensitivity for ophthalmoscopy compared to grading of fundus photographs for the detection of any retinopathy was 51 % and specificity was 91 % . For proliferative diabetic retinopathy ( PDR ) , sensitivity was 61 % and specificity 98 % . Only one eye was high-risk PDR , and it was detected by both methods . For clinical ly significant macular edema , these measures were 24 % and 98 % , respectively . The disagreements were of possible clinical importance in three cases ( < 1 % ) . CONCLUSION Most disagreements occurred in eyes rated near the milder end of a category and /or result ed from small differences between the ophthalmoscopic and photographic definitions used in classifying severity . There were reasonably few disagreements of possible clinical significance OBJECTIVE The Veterans Affairs Diabetes Trial ( VADT ) will assess the effect of intensive ( INT ) vs improved st and ard ( STD ) glycaemic control on major cardiovascular ( CV ) events , treating other risk factors equally in both arms . Four-year results of main metabolic parameters are presented . RESEARCH DESIGN AND METHODS VADT is a 7.5 years prospect i ve r and omized study of 1791 patients , 20 centres , of men and women of age 60.5 + /- 8.7 years , diagnosed for 11.5 + /- 7.5 years . Their body mass index ( BMI ) at baseline was 31 + /- 4 kg/m(2 ) and mean A1C 9.4 + /- 1.5 % after maximum dose of oral agents or insulin treatment . Step treatment consists of glimepiride or metformin , rosiglitazone , insulin and other agents ; A1C goals are 8 - 9 % in STD and < 6 % in INT . Lifestyle , blood pressure and lipids are treated uniformly in both arms . RESULTS A1C improved in both arms . INT kept median A1C < 7 % all years , A1C separation is 1.5 - 1.7 % . From year 1 to 4 , mean blood pressure is < 129/74 mmHg , similar throughout . Median LDL-C was < 97 mg/dl by year 1 and triglycerides 150 or less by 2 years . Triglycerides were lower in INT ( 12 - 16 mg/dl ; p < 0.01 ) . By 4 years , 88 % are on lipid-lowering agents and 93 % are on antiplatelet/anticoagulant agents . BMI is higher in INT every year ( 0.9 - 1.6 kg/m(2 ) ; p < 0.01 ) . CONCLUSION VADT is maintaining the expected A1C in both STD and INT , and LDL-C , triglycerides and blood pressure are at target . The trial is continuing to June 2008 . It will be the first long-term completed type 2 diabetes study of the role of glycaemia on CV disease with modern treatments BACKGROUND Hyperglycaemia is associated with increased risk of cardiovascular complications in people with type 2 diabetes . We investigated whether reduction of blood glucose concentration decreases the rate of microvascular complications in people with type 2 diabetes . METHODS ACCORD was a parallel-group , r and omised trial done in 77 clinical sites in North America . People with diabetes , high HbA(1c ) concentrations ( > 7.5 % ) , and cardiovascular disease ( or > or=2 cardiovascular risk factors ) were r and omly assigned by central r and omisation to intensive ( target haemoglobin A(1c ) [ HbA(1c ) ] of < 6.0 % ) or st and ard ( 7.0 - 7.9 % ) glycaemic therapy . In this analysis , the prespecified composite outcomes were : dialysis or renal transplantation , high serum creatinine ( > 291.7 micromol/L ) , or retinal photocoagulation or vitrectomy ( first composite outcome ) ; or peripheral neuropathy plus the first composite outcome ( second composite outcome ) . 13 prespecified secondary measures of kidney , eye , and peripheral nerve function were also assessed . Investigators and participants were aware of treatment group assignment . Analysis was done for all patients who were assessed for microvascular outcomes , on the basis of treatment assignment , irrespective of treatments received or compliance to therapies . ACCORD is registered with Clinical Trials.gov , number NCT00000620 . FINDINGS 10 251 patients were r and omly assigned , 5128 to the intensive glycaemia control group and 5123 to st and ard group . Intensive therapy was stopped before study end because of higher mortality in that group , and patients were transitioned to st and ard therapy . At transition , the first composite outcome was recorded in 443 of 5107 patients in the intensive group versus 444 of 5108 in the st and ard group ( HR 1.00 , 95 % CI 0.88 - 1.14 ; p=1.00 ) , and the second composite outcome was noted in 1591 of 5107 versus 1659 of 5108 ( 0.96 , 0.89 - 1.02 ; p=0.19 ) . Results were similar at study end ( first composite outcome 556 of 5119 vs 586 of 5115 [ HR 0.95 , 95 % CI 0.85 - 1.07 , p=0.42 ] ; and second 1956 of 5119 vs 2046 of 5115 , respectively [ 0.95 , 0.89 - 1.01 , p=0.12 ] ) . Intensive therapy did not reduce the risk of advanced measures of microvascular outcomes , but delayed the onset of albuminuria and some measures of eye complications and neuropathy . Seven secondary measures at study end favoured intensive therapy ( p<0.05 ) . INTERPRETATION Microvascular benefits of intensive therapy should be weighed against the increase in total and cardiovascular disease-related mortality , increased weight gain , and high risk for severe hypoglycaemia . FUNDING US National Institutes of Health ; National Heart , Lung , and Blood Institute ; National Institute of Diabetes and Digestive and Kidney Diseases ; National Institute on Aging ; National Eye Institute ; Centers for Disease Control and Prevention ; and General Clinical Research Centers BACKGROUND The objectives of this study were to determine the influence of glucose control on lipoprotein and haemostasis variables in Type 1 diabetes mellitus patients and to evaluate the global impact of these metabolic risk factors on brachial artery reactivity and carotid artery atherosclerosis , stiffness and diameter . DESIGN Follow up of Type 1 diabetes patients r and omized to insulin-intensive conventional treatment ( ICT , n = 29 ) or insulin-st and ard treatment ( ST , n = 25 ) in the Stockholm Diabetes Intervention Study ( SDIS ) more than 14 years ago . RESULTS The intensive conventional treatment patients had lower glycosylated haemoglobin ( HbA1c ) compared with the ST patients , i.e. 7.01 ( SD 0.51 ) vs. 8.31 ( 0.97 ) , while concentrations of the lipoprotein and haemostasis variables analyzed were virtually similar . The carotid artery intima-media area was associated with high HbA1c , high serum (S)-cholesterol levels , and low high-density lipoprotein (HDL)-cholesterol levels . Carotid artery stiffness was associated with high systolic blood pressure , high HbA1c , high fibrinogen , and high HDL-cholesterol . Brachial artery endothelial reactivity was higher for women and those with low S-cholesterol . CONCLUSION In patients with Type 1 diabetes , glucose control appeared to have no effect on either lipoproteins or haemostasis variable concentrations . Poor glucose control , and high levels of S-cholesterol , systolic blood pressure and plasma fibrinogen were associated with development of atherosclerosis , thus emphasising the importance of global risk factor control in patients with Type 1 diabetes mellitus We carried out a r and omized trial of stepwise intensive treatment or st and ard treatment of risk factors in patients with type 2 diabetes and microalbuminuria . Patients were allocated st and ard treatment ( n = 80 ) or intensive treatment ( n = 80 ) . Intensive treatment was a stepwise implementation of behaviour modification , pharmacological therapy targeting hyperglycaemia , hypertension , dyslipidaemia , and microalbuminuria . The primary endpoint was development of nephropathy . Secondary endpoints were incidence or progression of diabetic retinopathy and neuropathy . Patients were followed for 3.8 years . The intensive group had significantly lower rates of progression to hephropathy ( odds ratio 0.27 [ 95 % CI 0.10 - 0.75 ] ) , progression of retinopathy ( 0.45 ( 0.21 - 0.95 ] ) , and progression of autonomic neuropathy ( 0.32 [ 0.12 - 0.78 ] ) . In conclusion , intensified multifactorial intervention in patients with type 2 diabetic mellitus and microalbuminuria has beneficial effects on long-term complications Objective The efficacy and safety of blood pressure lowering in elderly patients have not been sufficiently investigated in patients with diabetes . Using data from the Action in Diabetes and Vascular disease : preterAx and diamicroN-MR Controlled Evaluation study , we assessed the efficacy and safety of routine blood pressure lowering to prevent major clinical outcomes in elderly patients with type 2 diabetes . Methods Eleven thous and one hundred and forty patients aged at least 55 years with type 2 diabetes ( mean 66 ± 6 years ) were r and omly assigned to perindopril – indapamide or placebo . The primary endpoint was a composite of major macrovascular and microvascular disease . The effects of active treatment on outcomes were estimated in subgroups according to age : below 65 , 65–74 and at least 75 years . Results During a mean 4.3-year follow-up , 1799 ( 16.1 % ) patients experienced a major event . Active treatment produced similar relative risk reductions for the primary outcome , major macrovascular disease , death and renal events across age groups ( all P heterogeneity > 0.3 ) . Over 5 years , active treatment was estimated to prevent one primary outcome in every 21 , 71 and 118 patients of at least75 , 65–74 and below 65 years , respectively . Similar patterns of benefits were observed for secondary outcomes . There were no differences in the tolerability between r and omized allocations across age groups ( all P heterogeneity > 0.6 ) Conclusion Routine administration of perindopril – indapamide lowers blood pressure safely and reduces the risk of major clinical outcomes in patients of at least 75 years with type 2 diabetes . The greater absolute benefits in older patients in this age group were not offset by an increased risk of side effects OBJECTIVE The Veterans Affairs Cooperative Study in Type 2 Diabetes Mellitus ( VA CSDM ) was a multicenter r and omized prospect i ve study of 153 male type 2 diabetic patients to assess the ability to sustain clinical ly significant glycemic separation between intensive and st and ard treatment arms . A trend toward an excess of combined cardiovascular events in the intensive treatment arm of this trial was reported earlier . The present analysis was done to evaluate the effect of 2 years of intensive glycemic control on the left ventricular ( LV ) function . RESEARCH DESIGN AND METHODS The patients were r and omized to intensive step treatment with insulin alone or with sulfonylurea ( intensive treatment arm [ INT ] , n = 75 ) or to st and ard once-daily insulin injection ( st and ard treatment arm [ STD ] , n = 78 ) treatment . A total of 136 patients ( st and ard treatment arm [ STD ] , n = 70 ; INT , n = 66 ) had radionuclide ventriculography at entry and at 24 months for the assessment of LV function . RESULTS There was no difference in the mean LV ejection fraction ( at entry : STD 57.1+/-9.51 % ; INT 58.1+/-8.7 % ; at 24 months : STD 57.3+/-10.8 % , INT 59.5+/-10.7 % ) , peak filling rate ( at entry : STD 2.6+/-0.7 end diastolic volume per second , INT 2.4+/-0.8 end diastolic volume per second ; at 24 months : STD 2.7+/-1.0 end diastolic volume per second , INT 2.5+/-0.7 end diastolic volume per second ) , or time to peak filling rate ( at entry : STD 195.3+/-69.5 ms , INT 185.6 + /-62.4 ms ; at 24 months : STD 182.6+/-64.8 ms , INT 179.2+/-61.2 ms ) between the 2 treatment arms . A subgroup analysis of 104 patients ( STD , n = 53 ; INT , n = 51 ) that omitted individuals with intervening cardiac events/revascularization or a change in cardioactive medications also showed no difference in the LV function at entry and at 24 months between the 2 groups . Abnormal LV ejection fraction at baseline predicted cardiac events ( interval between cardiac beats [ RR ] = 2.5 ) . CONCLUSIONS Two years of intensive glycemic control does not affect the LV systolic or diastolic function in patients with type 2 diabetes BACKGROUND Epidemiologic studies have shown a relationship between glycated hemoglobin levels and cardiovascular events in patients with type 2 diabetes . We investigated whether intensive therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with type 2 diabetes who had either established cardiovascular disease or additional cardiovascular risk factors . METHODS In this r and omized study , 10,251 patients ( mean age , 62.2 years ) with a median glycated hemoglobin level of 8.1 % were assigned to receive intensive therapy ( targeting a glycated hemoglobin level below 6.0 % ) or st and ard therapy ( targeting a level from 7.0 to 7.9 % ) . Of these patients , 38 % were women , and 35 % had had a previous cardiovascular event . The primary outcome was a composite of nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes . The finding of higher mortality in the intensive-therapy group led to a discontinuation of intensive therapy after a mean of 3.5 years of follow-up . RESULTS At 1 year , stable median glycated hemoglobin levels of 6.4 % and 7.5 % were achieved in the intensive-therapy group and the st and ard-therapy group , respectively . During follow-up , the primary outcome occurred in 352 patients in the intensive-therapy group , as compared with 371 in the st and ard-therapy group ( hazard ratio , 0.90 ; 95 % confidence interval [ CI ] , 0.78 to 1.04 ; P=0.16 ) . At the same time , 257 patients in the intensive-therapy group died , as compared with 203 patients in the st and ard-therapy group ( hazard ratio , 1.22 ; 95 % CI , 1.01 to 1.46 ; P=0.04 ) . Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group ( P<0.001 ) . CONCLUSIONS As compared with st and ard therapy , the use of intensive therapy to target normal glycated hemoglobin levels for 3.5 years increased mortality and did not significantly reduce major cardiovascular events . These findings identify a previously unrecognized harm of intensive glucose lowering in high-risk patients with type 2 diabetes . ( Clinical Trials.gov number , NCT00000620 . BACKGROUND In patients with type 2 diabetes , the effects of intensive glucose control on vascular outcomes remain uncertain . METHODS We r and omly assigned 11,140 patients with type 2 diabetes to undergo either st and ard glucose control or intensive glucose control , defined as the use of gliclazide ( modified release ) plus other drugs as required to achieve a glycated hemoglobin value of 6.5 % or less . Primary end points were composites of major macrovascular events ( death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke ) and major microvascular events ( new or worsening nephropathy or retinopathy ) , assessed both jointly and separately . RESULTS After a median of 5 years of follow-up , the mean glycated hemoglobin level was lower in the intensive-control group ( 6.5 % ) than in the st and ard-control group ( 7.3 % ) . Intensive control reduced the incidence of combined major macrovascular and microvascular events ( 18.1 % , vs. 20.0 % with st and ard control ; hazard ratio , 0.90 ; 95 % confidence interval [ CI ] , 0.82 to 0.98 ; P=0.01 ) , as well as that of major microvascular events ( 9.4 % vs. 10.9 % ; hazard ratio , 0.86 ; 95 % CI , 0.77 to 0.97 ; P=0.01 ) , primarily because of a reduction in the incidence of nephropathy ( 4.1 % vs. 5.2 % ; hazard ratio , 0.79 ; 95 % CI , 0.66 to 0.93 ; P=0.006 ) , with no significant effect on retinopathy ( P=0.50 ) . There were no significant effects of the type of glucose control on major macrovascular events ( hazard ratio with intensive control , 0.94 ; 95 % CI , 0.84 to 1.06 ; P=0.32 ) , death from cardiovascular causes ( hazard ratio with intensive control , 0.88 ; 95 % CI , 0.74 to 1.04 ; P=0.12 ) , or death from any cause ( hazard ratio with intensive control , 0.93 ; 95 % CI , 0.83 to 1.06 ; P=0.28 ) . Severe hypoglycemia , although uncommon , was more common in the intensive-control group ( 2.7 % , vs. 1.5 % in the st and ard-control group ; hazard ratio , 1.86 ; 95 % CI , 1.42 to 2.40 ; P<0.001 ) . CONCLUSIONS A strategy of intensive glucose control , involving gliclazide ( modified release ) and other drugs as required , that lowered the glycated hemoglobin value to 6.5 % yielded a 10 % relative reduction in the combined outcome of major macrovascular and microvascular events , primarily as a consequence of a 21 % relative reduction in nephropathy . ( Clinical Trials.gov number , NCT00145925 . OBJECTIVE Sphingolipid metabolism is altered in diabetes and we analyzed the plasma concentrations of sphingolipid species to investigate their association with the development of albuminuria in type 1 patients with diabetes . MATERIAL S AND METHODS Sample s were collected from 497 type 1 diabetic patients during their enrollment into the Diabetes Control and Complications Trial ( DCCT ) . We determined plasma concentrations of multiple ceramide species and individual sphingoid bases and their phosphates using high performance liquid chromatography-t and em mass spectrometry and investigated their association with the development of albuminuria during 14 - 20 years of follow-up . RESULTS Patients exhibited normal albumin excretion rates ( AER < 40 mg/24h ) at the time of plasma sampling . Although the majority of patients ( N = 291 ; 59 % ) exhibited normal levels of albuminuria throughout follow-up , 141 patients ( 28 % ) progressed to microalbuminuria ( 40 mg/24h ≤ AER<300 mg/24h ) , while 65 ( 13 % ) progressed to macroalbuminuria ( AER ≥ 300 mg/24h ) . To test the association of log transformed plasma sphingolipid level with the development of albuminuria , generalized logistic regression models were used where normal , micro- and macroalbuminuria were the outcomes of interest . Models were adjusted for DCCT treatment group , baseline retinopathy , gender , baseline HbA1c % , age , AER , lipid levels , diabetes duration , and the use of ACE/ARB drugs . Increased plasma levels of very long , but not long chain ceramide species measured at DCCT baseline were associated with decreased odds to develop macroalbuminuria during the subsequent nineteen years ( DCCT Baseline to EDIC year 8) . CONCLUSION These studies demonstrate , prospect ively , that decreased plasma levels of select ceramide species are associated with the development of macroalbuminuria in type 1 diabetes OBJECTIVE The Action to Control Cardiovascular Risk in Diabetes ( ACCORD ) Blood Pressure Trial reported no differences in most cardiovascular disease ( CVD ) outcomes between intensive and st and ard blood pressure therapy in individuals with diabetes mellitus ( DM ) and hypertension . Many such individuals are central ly obese . Here we evaluate whether the trial outcomes varied by the level of central obesity . RESEARCH DESIGN AND METHODS The cohort included 4,687 people ( 47.7 % women ) with DM and hypertension . Mean age was 62.2 , and mean follow-up was 4.7 years . Participants were r and omly assigned to one of two blood pressure treatment strategies : intensive ( systolic < 120 mmHg ) or st and ard ( systolic < 140 mmHg ) . Sex-specific quartiles of waist-to-height ratio were used as the measure of central obesity . The primary ACCORD outcome ( a composite of nonfatal myocardial infa rct ion [ MI ] , nonfatal stroke , or CVD death ) and three secondary outcomes ( nonfatal MI , fatal or nonfatal stroke , and CVD death ) were examined using proportional hazard models . RESULTS There was no evidence that the effect of intensively lowering blood pressure differed by quartile of waist-to-height ratio for any of the four outcomes ( P > 0.25 in all cases ) . Controlling for waist-to-height quartile had no significant impact on previously published results for intensive blood pressure therapy . Waist-to-height ratio was significantly related to CVD mortality ( hazard ratio 2.32 [ 95 % CI 1.40–3.83 ] , P = 0.0009 comparing the heaviest to lightest quartiles ) , but not to the other outcomes ( P > 0.09 in all cases ) . CONCLUSIONS Intensive lowering of blood pressure versus st and ard treatment does not ameliorate CVD risk in individuals with DM and hypertension . These results did not vary by quartile of waist-to-height ratio OBJECTIVE The Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ( ADVANCE ) trial reported that intensive glucose control prevents end-stage kidney disease ( ESKD ) in patients with type 2 diabetes , but uncertainty about the balance between risks and benefits exists . Here , we examine the long-term effects of intensive glucose control on risk of ESKD and other outcomes . RESEARCH DESIGN AND METHODS Survivors , previously r and omized to intensive or st and ard glucose control , were invited to participate in post-trial follow-up . ESKD , defined as the need for dialysis or kidney transplantation , or death due to kidney disease , was documented overall and by baseline CKD stage , along with hypoglycemic episodes , major cardiovascular events , and death from other causes . RESULTS A total of 8,494 ADVANCE participants were followed for a median of 5.4 additional years . In-trial HbA1c differences disappeared by the first post-trial visit . The in-trial reductions in the risk of ESKD ( 7 vs. 20 events , hazard ratio [ HR ] 0.35 , P = 0.02 ) persisted after 9.9 years of overall follow-up ( 29 vs. 53 events , HR 0.54 , P < 0.01 ) . These effects were greater in earlier-stage CKD ( P = 0.04 ) and at lower baseline systolic blood pressure levels ( P = 0.01 ) . The effects of glucose lowering on the risks of death , cardiovascular death , or major cardiovascular events did not differ by levels of kidney function ( P > 0.26 ) . CONCLUSIONS Intensive glucose control was associated with a long-term reduction in ESKD , without evidence of any increased risk of cardiovascular events or death . These benefits were greater with preserved kidney function and with well-controlled blood pressure |
13,615 | 20,537,923 | Steroid prophylaxis had no effect on postoperative mortality , mechanical ventilation duration , re-exploration for bleeding , and postoperative infection .
CONCLUSIONS A systematic review of RDB trials reveals that steroid prophylaxis may reduce morbidity after cardiac surgery and does not increase the risk of postoperative infections | OBJECTIVE Cardiac surgery and cardiopulmonary bypass ( CPB ) induce an acute inflammatory response contributing to postoperative morbidity .
The use of steroids as anti-inflammatory agents in surgery using CPB has been tested in many trials and has been shown to have good anti-inflammatory effects but no clear clinical advantages for the lack of an adequately powered sample size .
The aim of this study was to evaluate the effects of steroid treatment on mortality and morbidity after cardiac surgery . | Methylprednisolone sodium succinate ( MPSS ) was given to 50 % of patients undergoing coronary artery bypass graft in a 50-patient double-blind clinical study to ascertain the beneficial effects of this glucocorticoid in decreasing ischemic injury to the heart . MPSS ( 1 gm ) was given intravenously at the start of cardiopulmonary bypass and another gram was given during the course of the open-heart procedure . Steroid-treated patients demonstrated a favorable response compared to placebo-treated controls in a variety of physiologic variables : Bypass graft flow rates measured prior to operative closure were 51 - 62 % greater ; urine output in the first 24 postoperative hours was 67 % higher ; fewer abnormalities were found in both chest x-ray and microbiology results . Thus , methylprednisolone sodium succinate treated patients exhibited more favorable trends for all critical variables measured BACKGROUND Cardiopulmonary bypass ( CPB ) induces derangements in physiology characterized by activation of blood pathways that may contribute to multiorgan dysfunction . This trial addresses the efficacy of a biocompatible surface alone and in combination with steroids in inhibiting these changes . METHODS In a factorial design , patients undergoing coronary artery bypass grafting were r and omized ( four groups ; n = 17 per group ) to CPB utilizing control circuits or a circuit prepared with a surface modifying active copolymer ( SMA-CPB ) , with or without methylprednisolone ( MPSS , 1 g intravenous ) . Leukocyte and complement activation , cytokine release , and bradykinin generation were measured . Clinical outcomes ( blood loss , transfusion , arterial pressure response , and postoperative cardiac and pulmonary functions ) were also examined . RESULTS The SMA-CPB was associated with a significant inhibition of elastase release ( p = 0.026 ) and bradykinin generation ( p = 0.027 ) during CPB . Terminal complement complex ( TCC ) generation was inhibited as an effect of SMA-CPB ( p = 0.047 ) . There was an interaction of SMA-CPB and MPSS to decrease both TCC ( p = 0.042 ) and bradykinin generation ( p = 0.028 ) . There were strong effects of MPSS in inhibiting release of interleukin 6 ( IL-6 ) ( p = 0.007 ) and IL-8 ( p < 0.001 ) and tissue plasminogen activator over time ( p = 0.009 ) as well as decreasing peak day 1 creatine kinase ( CK , p = 0.015 ) levels . Clinical effects of MPSS included decreased atrial fibrillation ( p = 0.02 ) , improved cardiac index over time , increased pulmonary compliance , and increased insulin need . CONCLUSIONS This trial suggests a potential beneficial effect for combined strategies to minimize inflammation after CPB . The specific effect of MPSS in decreasing postoperative atrial fibrillation and CK warrants further investigation of its role as a potential myocardial protective agent The purpose of this study was to evaluate the acute cardioprotective effect of high-dose methylprednisolone ( 25 mg/kg ) in the controlled in vivo model of myocardial ischemia – reperfusion injury occurring during cardiopulmonary bypass . Forty nondiabetic male patients with three-vessel disease undergoing first-time bypass surgery were enrolled for this double-blind prospect i ve study . Patients were r and omized to be given 25 mg/kg methylprednisolone ( Group I ) and saline ( Group II ) 1 h before cardiopulmonary bypass . The levels of cardiac troponin-I ( cTnI ) were used as a marker of myocardial tissue damage in myocardial ischemia – reperfusion injury . The cTnI levels were measured before surgery , at the second hour after cardiopulmonary bypass , at the 6th and 24th hours , and 5th day postoperatively . There was no significant difference between the two groups in respect to the duration of ischemia and reperfusion . The preoperative cTnI levels were 0.22 ± 0.29 ng/ml in Group I and 0.23 ± 0.28 ng/ml in Group II . cTnI levels increased to 2.40 ± 1.0 ng/ml in Group I and 3.19 ± 0.88 ng/ml in Group II at the 2nd hour after cardiopulmonary bypass . When the differences between T1 and T0 level that showed the amount of troponin release occurring due to ischemia – repefusion injury was calculated and then compared , there was a significant difference between Groups I and II ( P = 0.024 ) . The cTnI levels measured at 6 h after CPB were 1.98 ± 0.63 ng/ml in Group I and 2.75 ± 1.15 ng/ml in Group II ( P = 0.049 ) . cTnI levels decreased to 0.22 ± 0.10 ng/ml in Group I and 0.49 ± 0.25 ng/ml in Group II on the postoperative day 5 ( P = 0.0001 ) . Univalent regression analysis showed that preoperative high-dose corticosteroid usage decreased the troponin release in about 12 % and this effect was statistically significant ( R2 = 0.12 , P < 0.05 ) . A single dose of intravenous methylpredisolone ( 25 mg/kg ) given 1 h before ischemia reduced myocardial ischemia – reperfusion injury . These results demonstrated that the acute cardioprotective effect of corticosteroids has much potential in the future for reducing ischemia – reperfusion injury occurring during cardiopulmonary bypass when it is inevitable OBJECTIVE The mechanism involved in the endotoxemia frequently recognized during cardiopulmonary bypass remains unclear . It has also been suggested that endotoxin levels were higher in steroid-pretreated patients undergoing cardiopulmonary bypass . METHODS Twenty patients undergoing cardiopulmonary bypass were r and omly pretreated with steroids ( methylprednisolone , 30 mg/kg ) or placebo . Blood sample s for endotoxin measurement were drawn simultaneously from the superior and inferior venae cavae before heparin administration , 5 and 50 minutes after the onset of bypass , 5 minutes after aortic declamping , at the end of bypass , and 1 , 2 , and 20 hours after the end of cardiopulmonary bypass . RESULTS The perioperative variables in the two groups were similar . Blood endotoxin levels were higher in the inferior vena cava than in the superior vena cava immediately after the onset of bypass . Endotoxin levels in inferior vena cava blood were significantly lower in steroid-pretreated patients than those in patients not receiving steroids . CONCLUSIONS Endotoxin is released during cardiopulmonary bypass from the region drained by the inferior vena cava . Steroid pretreatment may actually reduce endotoxin release during bypass This study investigated whether the prophylactic administration of methylprednisolone sodium succinate ( MPSS ) could prevent an increase in plasma endotoxin levels during cardiac surgery with cardiopulmonary bypass . MPSS ( 1 g/patient ) or saline was given intravenously with induction in the steroid ( n = 6 ) and control ( n = 7 ) groups , respectively . Blood sample s were collected preinduction and postinduction , during and after cardiopulmonary bypass , and 1 and 24 hours postoperatively . Plasma endotoxin was determined by a chromogenic Limulus amebocyte lysate assay . There was an intraoperative increase in the level of plasma endotoxin that occurred primarily after initiation of cardiopulmonary bypass and removal of the aortic cross-clamp . Endotoxin at 1 and 24 hours postoperatively was lower than the peak intraoperative levels and approached the preinduction level in both groups . The pump prime and other administered fluids contained low levels of endotoxin that were at or below the preinduction or postinduction level of the patients . MPSS did not prevent or attenuate the degree of endotoxemia during cardiopulmonary bypass . The loss of normal gut mucosal barrier function during cardiopulmonary bypass may result in endotoxemia and /or bacterial translocation , either of which could initiate or contribute to postoperative complications The use of cardiopulmonary bypass ( CPB ) is associated with the development of a significant systemic inflammatory response syndrome ( SIRS ) which can affect patient outcomes . Multiple pathways are involved in initiating and maintaining SIRS . We studied whether a single dose of steroids ( dexamethasone ) after the induction of anesthesia could blunt the SIRS from CPB . A prospect i ve , r and omized , double-blinded , placebo control trial of 28 patients ( 13 study vs. 15 control ) . The study group received 100 mg of dexamethasone whereas the control group received sterile saline . Inclusion criteria were the following : elective coronary artery bypass grafting , less than 80 years old , normal ejection fraction , no acute myocardial infa rct ion . Serum levels of C3a , interleukin (IL)-6 , and plasma norepinephrine ( PNE ) were measured after intubation , 30 minutes after initiation of CPB , 24 and 72 hours after termination of bypass . The study group demonstrated significantly lower levels of IL-6 ( p = 0.0005 ) at 24 hours and PNE ( p = 0.05 ) at 72 hours post-CPB . There were no differences in the C3a levels between the groups . No infections occurred in either group . A single dose of dexamethasone reduces IL-6 and PNE levels associated with CPB . Despite the significant reductions in IL-6 and PNE , there was no effect on clinical outcomes . Additional studies are needed to demonstrate a clinical ly significant effect on patient outcomes Thirty-one patients who were undergoing cardiopulmonary bypass for elective aortic valve replacement were studied . The effects on some aspects of lung function of intravenous methyl prednisolone , administered immediately before bypass , were assessed by measuring alveolar-arterial oxygen differences and shunt fractions . No significant differences in pulmonary function were found between the treated and control groups . The use of methyl prednisolone in this context is not justified OBJECTIVE To compare the effects of low- and full-dose aprotinin to methylprednisolone ( MPS ) in reducing cardiopulmonary bypass (CPB)-induced interleukin-6 ( IL-6 ) release . DESIGN Prospect i ve , r and omized , blinded study . SETTING Cytokine Laboratory , pharmacology department , in a university teaching hospital . PARTICIPANTS Forty adult male human patients scheduled for myocardial revascularization were divided into four groups ( n = 10 ) : ( 1 ) control ; ( 2 ) MPS , 1 g IV before CPB ; ( 3 ) aprotinin-low-dose protocol ; and ( 4 ) aprotinin-full-dose protocol . MEASUREMENTS AND MAIN RESULTS Plasma levels of IL-6 were measured at baseline and 1 and 24 hours after CPB by enzyme-linked immunosorbent assay technique . Group 1 demonstrated a significant ( p < 0.05 ) increase in IL-6 at 1 and 24 hours post-CPB . Groups 2 and 4 demonstrated significant ( p < 0.05 ) reduction of IL-6 at 1 ( group 2 only ) and 24 ( groups 2 and 4 ) hours post-CPB when compared with group 1 at the same time periods . CONCLUSIONS These results demonstrate that MPS , 1 g before CPB , and full-dose aprotinin , but not half-dose aprotinin , achieve significant reduction in IL-6 release after CPB . These results further suggest that MPS and full-dose aprotinin may reduce reperfusion injury after CPB Background Intensive insulin therapy to maintain normoglycemia after cardiac surgery reduces morbidity and mortality . We investigated the magnitude and duration of hyperglycemia caused by dexamethasone administered after cardiopulmonary bypass . Methods A single-center before-after cohort study was performed . All consecutive patients undergoing coronary artery bypass grafting with cardiopulmonary bypass during a 6-month period were included . Insulin administration was guided by a sliding scale protocol . Halfway the observation period , the dexamethasone protocol was changed . The single dose ( 1D ) group received a pre-operative dose of dexamethasone of 1 mg/kg . The double dose group ( 2D ) received an additional dose of 0.5 mg/kg of dexamethasone post-operatively at ICU admission . Results We included 116 patients in the 1D group and 158 patients in the 2D group . There were no significant baseline differences between the groups . Median Euroscore was 5 . In univariable analysis , the glucose level was different between groups 1D and 2D at 4 , 6 , 9 , 12 and 24 hours after ICU admission ( all p < 0.001 ) . Insulin infusion was higher in the 1D group . Corrected for insulin dose in multivariable linear analysis , the difference in glucose between the 1D and 2D groups was 1.5 mmol/L ( 95 % confidence interval 1.0–2.0 , p < 0.001 ) 12 hours after ICU admission . Conclusion Dexamethasone exerts a hyperglycemic effect in cardiac surgery patients . Patients receiving high-dose corticosteroid therapy should be monitored and treated more intensively for hyperglycemic episodes OBJECTIVE The purpose of this study was to assess the effect of preoperative dexamethasone ( DEX ) on the occurrence of postoperative atrial fibrillation ( AF ) . DESIGN Prospect i ve , r and omized , double-blind , placebo-controlled clinical trial . SETTING Tertiary referral center . PARTICIPANTS Seventy-eight adult patients undergoing combined valve and coronary artery bypass graft ( CABG ) surgery were r and omized to receive either DEX or placebo . INTERVENTIONS The DEX group received dexamethasone , 0.6 mg/kg , after induction of anesthesia , and the placebo group received an equal volume of normal saline . Interleukin (IL)-6 , -8 , and -10 ; tumor necrosis factor alpha ; and endothelin (ET)-1 were measured preoperatively and on postoperative days ( POD ) 1 , 2 , and 3 . Complement ( C-4 ) and C-reactive protein ( CRP ) were measured preoperatively and on POD 2 . Exhaled nitric oxide ( NO ) was measured preoperatively , 15 minutes after aortic unclamping , and 1 hour after intensive care unit admission . MEASUREMENTS AND MAIN RESULTS No significant difference in the incidence of AF was found between the placebo ( 41 % ) and DEX groups ( 30 % ) ( 95 % confidence interval [ -11 % , 34 % ) ; p = 0.31 ) . DEX significantly reduced at least 1 postoperative level of IL-6 , IL-8 , IL-10 , CRP , and exhaled NO . DEX did not affect ET-1 or C-4 levels . IL-10 on POD 3 was positively correlated with postoperative hospital length of stay ( r = 0.30 , p = 0.01 ) . Increased levels of IL-8 and IL-10 on POD 1 were positively correlated with the intubation time ( r = 0.31 , p = 0.01 ; r = 0.30 , p = 0.01 , respectively ) . Conversely , C-4 on POD 2 was negatively correlated with the intubation time and intensive care unit length of stay ( r = -0.32 , p = 0.006 ; r = -0.30 , p = 0.01 , respectively ) . CONCLUSIONS DEX did not affect the incidence of AF in patients undergoing combined CABG and valve surgery . However , it did modulate the release of several inflammatory and acute-phase response mediators that are associated with adverse outcomes OBJECTIVE To determine the influence of methylprednisolone on the cytokine balance during cardiac surgery . DESIGN Prospect i ve , r and omized , nonblinded study . SETTING University hospital . PATIENTS Twenty-one patients on cardiopulmonary bypass undergoing aortocoronary bypass surgery . INTERVENTIONS According to a r and omized sequence , the patients either received methylprednisolone ( 30 mg/kg ) [ corrected ] before cardiopulmonary bypass and before declamping of the aorta ( MPS group , n = 11 ) or received nothing ( control group , n = 10 ) . MEASUREMENTS AND MAIN RESULTS Serum proinflammatory cytokines ( interleukin [IL]-8 , IL-6 ) and anti-inflammatory cytokines ( IL-10 , IL-1ra ) were measured by enzyme-linked immunosorbent assays . Serum IL-6 and IL-8 concentrations in the control group ( 15.2 + /- 4.1 and 14.1 + /- 1.9 pg/mL , preoperatively ) increased to 242 + /- 70.1 and 97.3 + /- 18.3 pg/mL at 60 mins after declamping of the aorta ( p < .01 , p < .01 , respectively ) . The increases were greater than those from 2.5 + /- 0.6 and 2.5 + /- 0.5 pg/mL to 109.5 + /- 29.0 and 33 + /- 4.1 pg/mL in the MPS group for IL-6 and IL-8 , respectively . Serum IL-10 concentrations increased significantly 60 mins after declamping of the aorta compared with its preoperative value in the two groups ( the control group , from 1.0 + /- 0 to 537.9 + /- 61.7 pg/mL ; the MPS group , from 0.3 + /- 0.2 to 654.9 + /- 24 pg/mL [ p < .01 , p < .01 , respectively ] ) . No difference was found between the two groups . Similarly , serum IL-1ra concentrations in the two groups increased the preoperative value in the control group from 304 + /- 120 to 44,374 + /- 14,631 pg/mL and in the MPS group from 616.5 + /- 109.6 to 35,598 + /- 9,074 pg/mL at 60 mins after declamping of the aorta ( p < .01 , p < .01 , respectively ) . There was no difference between the two groups . CONCLUSIONS Methylprednisolone reduces the production of IL-6 and IL-8 but not that of IL-10 and IL-1ra . These results suggest that one of the mechanisms of the cytoprotective effect of methylprednisolone may be to make changes in the proinflammatory and anti-inflammatory cytokine balance HYPOTHESIS Delayed or reduced polymorphonuclear leukocyte ( PMN ) apoptosis may contribute to prolongation of systemic inflammation after cardiopulmonary bypass . BACKGROUND / OBJECTIVE Preoperative administration of glucocorticoids has been used ostensibly to attenuate the systemic inflammation associated with cardiopulmonary bypass . Therefore , this study evaluated , in patients undergoing cardiopulmonary bypass , the efficacy of glucocorticoids in restoring peripheral blood PMN apoptosis and modulating PMN surface receptors ( CD95 , tumor necrosis factor receptor [ TNFR ] ) known to be involved in proapoptotic or antiapoptotic signal transduction . DESIGN R and omized control study . SETTING Medical school and affiliated tertiary care hospital . PATIENTS Thirteen patients undergoing coronary artery bypass grafting . INTERVENTION Patients were r and omly assigned to the control group ( n = 7 ) or to receive 1 g of methylprednisolone sodium succinate on anesthetic induction ( n = 6 ) . MAIN OUTCOME MEASURES Blood sample s were drawn before induction , 20 minutes after sternotomy and bypass , immediately postoperatively , and on postoperative day 1 . Isolated PMNs were incubated for 6 hours with or without the CD95 agonist CH 11 . Polymorphonuclear leukocyte apoptosis was measured using propidium iodide-RNAase staining and flow cytometry . Levels of PMN cell-associated receptors ( TNFR and CD95 ) , cytokines ( TNF-alpha , interleukin 6 [ IL-6 ] , IL-8 , and IL-10 ) , and soluble receptors ( sTNFR1 and sTNFR2 ) were measured . RESULTS In all 13 patients , spontaneous and Fas-mediated PMN apoptosis decreased more than 80 % from baseline ( P<.001 ) by postoperative day 1 . Polymorphonuclear leukocyte CD95 increased ( P<.003 ) by postoperative day 1 compared with baseline , whereas PMN TNFR was unchanged . Methylprednisolone administration did not modulate PMN apoptosis or immunocyte receptor expression ; however , such treatment did decrease postoperative IL-6 secretion ( P<.001 ) and increase postoperative IL-10 secretion ( P<.001 ) . CONCLUSIONS The complications of major surgery include persistent inflammation , which can lead to multisystem organ failure . Polymorphonuclear leukocyte resistance to apoptosis may contribute to this process . A single preoperative dose of glucocorticoids did not effect PMN apoptosis or receptor phenotype BACKGROUND Cardiopulmonary bypass ( CPB ) is associated with tissue damage mediated by adhesion molecules and cytokines . Prebypass steroid administration may modulate the inflammatory response , result ing in improved postoperative recovery . METHODS Fifty patients undergoing elective coronary operations under normothermic CPB were r and omized into two groups : group A ( n = 24 ) received intravenous methylprednisolone ( 10 mg/kg ) 4 hours preoperatively , and group B ( n = 26 ) served as controls . Cytokines ( tumor necrosis factor-alpha [ TNF-alpha ] , interleukin-2R [ IL-2R ] , IL-6 , IL-8 ) , soluble adhesion molecules ( sE-selectin , sICAM-1 ) , C-reactive protein , and leukocytes were measured before steroid application , then 24 and 48 hours , and 6 days postoperatively . Adhesion molecules were measured by enzyme-linked immunosorbent assay , cytokines by chemiluminescent immunoassay . Postoperatively , hemodynamic measurements , inotropic agent requirements , blood loss , duration of mechanical ventilation , and intensive care unit stay were compared . RESULTS Aortic cross-clamp and CPB time was similar in both groups . Prednisolone administration reduced postoperative levels of IL-6 ( 611 versus 92.7 pg/mL ; p = 0.003 ) , TNF-alpha ( 24.4 versus 11.0 pg/L , p = 0.02 ) , and E-selectin ( 327 versus 107 ng/mL , p = 0.02 ) . Postoperative recovery did not differ between groups . CONCLUSIONS Preoperative administration of methylprednisolone blunted the increase of IL-6 , TNF-alpha , and E-selectin levels after CPB but had no measurable effect on postoperative recovery BACKGROUND Cytokines regulate inflammation associated with cardiopulmonary bypass ( CPB ) . Pro-inflammatory cytokines may cause myocardial dysfunction and haemodynamic instability after CPB , but the release of anti-inflammatory cytokines is potentially protective . We studied the effects of dexamethasone on pro- and anti-inflammatory cytokine responses during coronary artery bypass grafting surgery . METHODS Seventeen patients were studied : nine patients received dexamethasone 100 mg before induction of anaesthesia ( group 1 ) and eight patients acted as controls ( group 2 ) . Plasma levels of tumour necrosis factor (TNF)-alpha , interleukin (IL)-6 , IL-8 , IL-10 and IL-4 were measured perioperatively . RESULTS TNF-alpha and IL-8 did not increase significantly in group 1 whereas they increased in group 2 to greater than preoperative values ( P<0.05 ) . IL-6 increased in both groups , with lower values in group 1 than in group 2 ( P<0.05 ) . IL-10 increased in both groups , with higher values in group 1 ( P<0.05 ) . IL-4 did not change in group 1 but decreased in group 2 compared with pre-induction values ( P<0.05 ) . After surgery , patients in group 2 had tachycardia , hyperthermia , a greater respiratory rate and higher pulmonary artery pressure , and a longer stay in the intensive care unit . CONCLUSION Dexamethasone given before cardiac surgery changes circulating cytokines in an anti-inflammatory direction . Postoperative outcome may be improved by inhibition of the systemic inflammatory response Introduction Extracorporeal circulation induces hemostatic alterations that lead to inflammatory response ( IR ) and postoperative bleeding . Tranexamic acid ( TA ) reduces fibrinolysis and blood loss after cardiopulmonary bypass ( CPB ) . However , its effects on IR and vasoplegic shock ( VS ) are not well known and elucidating these effects was the main objective of this study . Methods A case control study was carried out to determine factors associated with IR after CPB . Patients undergoing elective CPB surgery were r and omly assigned to receive 2 g of TA or placebo ( 0.9 % saline ) before and after intervention . We performed an intention-to-treat analysis , comparing the incidence of IR and VS . We also analyzed several biological parameters related to inflammation , coagulation , and fibrinolysis systems . We used SPSS version 12.2 for statistical purpose s. Results In the case control study , 165 patients were studied , 20.6 % fulfilled IR criteria , and the use of TA proved to be an independent protective variable ( odds ratio 0.38 , 95 % confidence interval 0.18 to 0.81 ; P < 0.01 ) . The clinical trial was interrupted . Fifty patients were r and omly assigned to receive TA ( 24 ) or placebo ( 26 ) . Incidence of IR was 17 % in the TA group versus 42 % in the placebo group ( P = 0.047 ) . In the TA group , we observed a significant reduction in the incidence of VS ( P = 0.003 ) , the use of norepinephrine ( P = 0.029 ) , and time on mechanical ventilation ( P = 0.018 ) . These patients showed significantly lower D-dimer , plasminogen activator inhibitor 1 , and creatine-kinase levels and a trend toward lower levels of soluble tumor necrosis factor receptor and interleukin-6 within the first 24 hours after CPB . Conclusion The use of TA attenuates the development of IR and VS after CPB.Trial registration numberIS RCT N05718824 OBJECTIVE We sought to determine whether methylprednisolone , when administered to patients undergoing cardiac surgery , is able to ward off the detrimental hemodynamic and pulmonary alterations associated with cardiopulmonary bypass . METHODS After institutional review board approval and informed consent was obtained , 90 patients scheduled for elective cardiac surgery were r and omized to 1 of 3 groups . Group 30MP patients received 30 mg/kg intravenous methylprednisolone during sternotomy and 30 mg/kg during initiation of cardiopulmonary bypass , group 15MP patients received 15 mg/kg methylprednisolone at the same 2 times , and group NS patients received similar volumes of isotonic sodium chloride solution at the same 2 times . Perioperative care was st and ardized , and all caregivers were blinded to treatment group . Various hemodynamic and pulmonary measurements were obtained perioperatively , as well as fluid balance , weight , peak postoperative blood glucose level , and tracheal extubation time . RESULTS Demographic and clinical characteristics of patients and intraoperative data were similar among the 3 groups . Patients receiving methylprednisolone ( either dose ) exhibited significantly increased cardiac index ( P = .0006 ) , significantly decreased systemic vascular resistance ( P = .0005 ) , and significantly increased shunt flow ( P = .0020 ) during the immediate postoperative period . All 3 groups exhibited significant increases in alveolar-arterial oxygen gradient ( P < .0001 ) , significant decreases in dynamic lung compliance ( P < .0001 ) , and significant decreases in static lung compliance ( P < .0001 ) during the immediate postoperative period , with no differences between groups . Perioperative fluid balance and weights were similar between groups . A statistically significant difference in peak postoperative blood glucose level existed ( P = .016 ) among group NS ( 234 + /- 96 mg/dL ) , group 15MP ( 292 + /- 93 mg/dL ) , and group 30MP ( 311 + /- 90 mg/dL ) . In patients extubated within 12 hours of intensive care unit arrival , a statistically significant difference in extubation times existed ( P = .025 ) between group NS ( 5.7 + /- 2.3 hours ) , group 15MP ( 5.9 + /- 2.2 hours ) , and group 30MP ( 7.5 + /- 2.7 hours ) . CONCLUSIONS Methylprednisolone , as used in this investigation , offers no clinical benefits to patients undergoing elective coronary artery bypass grafting with cardiopulmonary bypass and may in fact be detrimental by initiating postoperative hyperglycemia and possibly hindering early postoperative tracheal extubation for undetermined reasons BACKGROUND In cardiac surgery with cardiopulmonary bypass ( CPB ) , corticosteroids are administered to attenuate the physiological changes caused by the systemic inflammatory response . The effects of corticosteroids on CPB-associated renal damage have not been documented . The purpose of this study was to evaluate the effects of dexamethasone on perioperative renal dysfunction in patients undergoing cardiac surgery with CPB . METHODS Renal damage was prospect ively studied in 20 patients without concomitant morbidity undergoing coronary artery surgery with CPB . Patients were r and omized in a double-blind fashion to receive dexamethasone or placebo . Markers of glomerular function ( creatinine clearance ) and damage ( microalbuminuria ) , and markers of tubular function ( fractional excretion of sodium and free water clearance ) and damage ( N-acetyl-beta-D glucosaminidase ( NAG ) ) were evaluated in addition to plasma and urinary glucose levels . Plasma and urinary specimens were obtained at the following time periods : ( 1 ) baseline , during the 12 h before surgery ; ( 2 ) skin incision before heparinization ; ( 3 ) from heparinization until the end of CPB ; ( 4 ) during the 2 h following weaning from CPB ; ( 5 ) in the intensive care unit from 2 to 6 h after weaning of CBP ; ( 6 ) and from 36 to 60 h after weaning of CPB . RESULTS CPB was associated with an increase in markers in the placebo group , which returned to baseline during the second postoperative day , demonstrating a transient impairment of glomerular and tubular renal function . Similar patterns were observed in patients treated with dexamethasone . While postoperative glycosuria was significantly higher in the dexamethasone-treated group , no other differences between groups were observed . CONCLUSION Dexamethasone administration before CPB has no protective effect on perioperative renal dysfunction in low-risk cardiac surgical patients BACKGROUND Cardiopulmonary bypass ( CPB ) initiates inflammation that contributes to multiorgan dysfunction ( SIRS ) . Steroids have been demonstrated to attenuate this response ; however , resistance to use steroids remains because of potential adverse effects of the high doses used . This study examines a lower dose steroid protocol for safety and attenuation of SIRS . METHODS Sixty patients undergoing CPB were r and omized to pulse low doses of methylprednisolone ( 250 mg given twice IV ) or placebo in this RCT . Outcomes pertaining to hemodynamics , ventilator requirement , arrhythmia , and metabolic derangements were recorded . Post-operative glucose control and gastrointestinal prohylaxis was instituted in all patients . RESULTS IL-6 concentrations were lower in the steroid group at 4 and 8 h post-operatively ( P < 0.0001 ) . The steroid group demonstrated more normothermia ( 37.2 degrees C versus 37.6 degrees C , P = 0.002 ) , better hemodynamic stability with less requirement for inotropes or vasopressors ( 0 % versus 27.6 % , P = 0.005 ) , higher SVRIs ( 1840 versus 1340 DSm2/cm5 , P = 0.002 ) , and higher mean arterial pressures ( 79 versus 74 mmHg , P = 0.03 ) . The steroid group had a shorter duration of intubation ( 7.7 versus 10.7 h , P = 0.02 ) , a shorter length of ICU stay ( 1.0 versus 2.0 days , P = 0.03 ) , and less blood loss ( 505 versus 690 ml , P = 0.04 ) with no difference in post-operative blood glucose levels or complications . CONCLUSIONS Patients undergoing cardiopulmonary bypass receiving low pulse dose steroids had better hemodynamics , shorter mechanical ventilation times , less blood loss , and required less time in the ICU compared to those receiving placebo . Therefore , this study demonstrates that prophylactic low dose steroids attenuate the SIRS response to CPB without result ing in any untoward side-effects During cardiac surgery , steroids are frequently administered before the initiation of cardiopulmonary bypass ( CPB ) , termed " pre-treatment , " to reduce " first phase " complement activation during cardiopulmonary bypass ( CPB ) . " Second phase " complement activation also occurs during heparin neutralization with protamine , although the effects of steroid pretreatment on such activation are unknown . This study was performed in patients undergoing coronary artery bypass graft surgery to determine whether high-dose methylprednisolone pretreatment affected complement activation during heparin-protamine interaction after termination of CPB . In eight patients ( group MP ) , methylprednisolone , 30 mg/kg , was administered before CPB commencement , whereas another eight patients received placebo ( group C ) . By using 125I des Arg radioimmunoassay , C3a , C4a , and C5a were measured in the arterial blood sample s drawn before and 10 min after administration of protamine . An increase in C3a and C4a was observed in both groups after protamine , suggesting classic pathway activation ( delta C3a : group C , 4,484 + /- 3,320 ; group MP , 1,394 + /- 1,653 ; delta C4a : group C , 1,810 + /- 731 ; group MP , 717 + /- 580 ) . C3a and C4a levels were significantly lower in group MP patients after protamine compared with controls [ delta C3a , 3,499 + /- 1,826 ( p < 0.05 ) ; delta C4a , 1,241 + /- 232 ( p < 0.05 ) ] . C5a was not detected in any sample s. These results demonstrate that the effect of pretreatment persists beyond the period of CPB and that methylprednisolone inhibits second-phase complement activation during heparin-protamine interaction . These findings have implication for patients with severe anaphylactoid reactions to protamine We studied the circulatory and respiratory effects of methylprednisolone ( MPS ) associated with catecholamine administration of a few hours after cardiopulmonary bypass ( CPB ) . Forty patients undergoing coronary artery bypass grafting were r and omly divided into two groups . Twenty patients in group 1 [ MPS ( - ) group ] did not receive MPS and 20 patients in group 2 [ MPS ( + ) group ] received MPS 15 mg.kg-1 i.v . 60 minutes after CPB . The circulatory and respiratory parameters were measured 60 minutes after CPB , 30 minutes after MPS i.v . and 60 minutes after MPS i.v . The values in MPS ( - ) group were compared with those in MPS ( + ) group . CI and SVI decreased , and SVRI and PQR increased in MPS ( - ) group , but these values were unchanged in MPS ( + ) group . RAP , mPAP , PCWP and PVRI were unchanged in MPS ( - ) group . PCWP increased and the other values were unchanged in MPS ( + ) group . The blood gases and pulmonary alveolar function were not different between the two groups . The oxygen delivery decreased in MPS ( - ) group , but it was unchanged in MPS ( + ) group . The oxygen consumption was unchanged in the two groups . Blood cortisol increased and epinephrine and norepinephrine decreased in MPS ( + ) group . Methylprednisolone had an effect to improve the decreased CI and the increased SVRI , and no respiratory problems were observed in patients for coronary artery bypass grafting with catecholamine administration for a few hours after cardiopulmonary bypass BACKGROUND Traumatic experiences associated with cardiac surgery ( CS ) can result in traumatic memories and posttraumatic stress disorder ( PTSD ) . Because it is known that subjects who develop PTSD often show sustained reductions in circulating cortisol concentrations , we performed a prospect i ve , r and omized study to examine whether exogenously administered stress doses of hydrocortisone during the perioperative period of CS reduces the long-term incidence of chronic stress and PTSD symptoms . METHODS Patients ( n = 91 ) were prospect ively r and omized to receive either stress doses of hydrocortisone or st and ard treatment during the perioperative period of CS . Of 48 available patients at 6 months after CS , 26 had received stress doses of hydrocortisone and 22 st and ard treatment . Traumatic memories and PTSD symptoms were diagnosed with previously vali date d question naires . RESULTS As compared with patients after st and ard therapy , patients from the hydrocortisone group had significantly lower chronic stress symptom scores ( p < .05 ) . There was no significant difference regarding the number or type of traumatic memories between the hydrocortisone and the st and ard treatment groups . CONCLUSIONS Stress doses of hydrocortisone in patients undergoing CS are associated with a lower intensity of chronic stress and PTSD symptoms at 6 months after CS Objective : To determine the plasma concentration of cortisol that is needed for maximal suppression of the systemic inflammatory response to cardiac surgery with cardiopulmonary bypass . Design : Prospect i ve , r and omized , double-blind clinical study of cardiac surgical patients . Setting : Operating room and inpatient care facility of a university medical center . Subjects : Sixty elective cardiac surgical patients scheduled for coronary artery bypass graft , cardiac valve replacement , or both . Interventions : Patients were r and omized to receive one of three different hydrocortisone doses , by intravenous infusion , for 6 hrs before , during , and immediately after surgery while also receiving etomi date to suppress endogenous cortisol production . Measurements and Main Results : Serial determinations of plasma interleukin-6 were studied as a marker of systemic inflammation . Measurements of interleukin-10 were used as a marker of the compensatory antiinflammatory response . Plasma cortisol concentrations in an untreated control group rose from 17 & mgr;g/dL before surgery to a mean of 43 & mgr;g/dL by 4 hrs after surgery . A dose of hydrocortisone ( 4 & mgr;g/kg/min for 6 hrs ) that maintained plasma cortisol between 40 and 50 & mgr;g/dL , starting 60–90 mins before surgery , significantly suppressed plasma interleukin-6 after surgery compared with control while significantly increasing plasma interleukin-10 during surgery . Plasma interleukin-6 after surgery was not suppressed further by increasing the dose of hydrocortisone to 8 & mgr;g/kg/min , although the mean peak plasma interleukin-10 concentration increased further compared with the group that received the 4 & mgr;g/kg/min hydrocortisone dose . Conclusions : At the doses studied , cortisol-induced suppression of plasma interleukin-6 during and after cardiac surgery appears to be a saturable phenomenon at the concentration of plasma cortisol that is normally achieved after surgery in untreated patients The systemic inflammatory response to cardiopulmonary bypass ( CPB ) is associated with increased production of cytokines . This systemic inflammatory response characterized by the activation of interleukin-6 ( IL-6 ) and interleukin-8 ( IL-8 ) during and after CPB is well documented . A prospect i ve , r and omized , double-blind study was performed so as to underst and the effects of low-dose methyl prednisolone sodium succinate ( MPSS ) on the circulating levels of serum cytokines and clinical outcome . Twenty patients were r and omly divided into two groups on the basis of the administration of low-dose ( 1 mg/kg ) MPSS ( n = 10 ) and placebo ( n = 10 ) into the pump prime solution . All patients were scheduled to undergo a primary elective coronary artery bypass grafting operation . Patients receiving concurrent corticosteroids , salicylates , dipyridamol or anticoagulants were excluded from the study . Other exclusion criteria were concurrent chronic obstructive pulmonary disease , chronic renal failure , insulin-dependent diabetes , congestive cardiac failure , peptic ulcer history , prior cardiac operations , recent ( in a one-month period ) myocardial infa rct ion and steroid dependency . Mild systemic hypothermia ( 30 - 32 ° C , rectal ) was assured during the CPB . Four blood sample s were drawn from the radial artery catheter immediately before starting CPB ( T1 ) , following protamine administration ( T2 ) and at 24 ( T3 ) and 48 h ( T4 ) after completion of CPB . In each sample , creatine kinase-myocardial b and ( CK-MB ) , white blood cell ( WBC ) , IL-6 and IL-8 levels were measured . IL-6 and IL-8 concentrations were measured by enzyme immunoassay and enzyme-linked immunoabsorbant assay methods . Serum IL-6 T2 and serum IL-6 T3 levels were significantly higher than IL-6 T1 levels in both groups ( p < 0.001 ) and ( p < 0.01 ) , and there was no significant elevation in serum IL-8 levels in either group . Serum IL-6 levels were significantly higher in the placebo group than in the MPSS group at T3 ( p < 0.009 ) . There was no significant difference in CK-MB T1 levels between the groups . Although there was no significant difference between CK-MB T1 and T2 levels in the MPSS group , the CK-MB T2 and CK-MB T3 levels were significantly higher than T1 levels in the placebo group ( p < 0.001 ) and ( p < 0.05 ) . There was significant elevation of WBC levels at T2 and T3 in both groups without notable difference between the groups ( p < 0.05 ) . This study has shown that low-dose MPSS suppresses CPB-induced inflammatory response . Further clinical studies ( on larger and higher risk groups ) may reveal more information on relations between morbidity and cytokine levels which may have some predictive value on clinical outcome following CPB BACKGROUND Corticosteroids have been recommended to facilitate rapid recovery after cardiac surgery . We previously reported that dexamethasone given after induction of anesthesia decreases the incidence of postoperative shivering . We performed a post hoc analysis of the data obtained during that study , focusing on secondary outcomes . METHODS A total of 235 adult patients undergoing elective coronary or valvular heart surgery were r and omized to receive dexamethasone 0.6 mg/kg or placebo after induction of anesthesia . Patients who had pharmacologically treated diabetes mellitus , had hypersensitivity to dexamethasone , or were receiving treatment with corticosteroids were excluded . RESULTS We found that , compared with placebo , patients receiving dexamethasone were more likely to remain tracheally intubated for 6 hours or less ( 26.4 % vs 10.0 % , p = 0.020 ) and had a lower incidence of early postoperative fever ( 20.2 % vs 36.8 % , p = 0.009 ) and new-onset atrial fibrillation during the first 3 days postoperatively ( 18.9 % vs 32.3 % , p = 0.027 ) . However , we could not demonstrate a statistical difference in the intensive care unit or hospital length of stay , or in overall morbidity and mortality . The dexamethasone-treated patients were also more likely to have a higher blood glucose on admission to the intensive care unit ( 186 mg/dL vs 143 mg/dL , p = 0.012 ) . CONCLUSIONS Dexamethasone facilitates early tracheal extubation and is associated with a lower incidence of early postoperative fever and new-onset atrial fibrillation . Apart from a treatable decreased glucose tolerance , dexamethasone treatment was not shown to affect morbidity or mortality significantly BACKGROUND Proinflammatory cytokines , such as tumor necrosis factor-alpha ( TNF-alpha ) , interleukin (IL)-6 , and IL-8 play a key role in the inflammatory cascade after cardiopulmonary bypass ( CPB ) and may induce cardiac and lung dysfunction . Antiinflammatory cytokines such as IL-10 may also significantly limit these complications . Corticosteroid administration before CPB increases blood IL-10 levels and prevents proinflammatory cytokine release . This study examined the association of increased release of IL-10 , stimulated by steroid pretreatment , with reduced myocardial and lung injury after CPB . METHODS Twenty patients undergoing coronary artery bypass grafting ( CABG ) received either preoperative steroid ( n = 10 , protocol group ) or no steroid ( n = 10 , control group ) . Perioperative care was st and ardized , and all caregivers were blinded to treatment group . Seven intervals of blood sample s were obtained and assayed for TNF-alpha , IL-6 , IL-8 , and IL-10 . Various hemodynamic and pulmonary measurements were obtained perioperatively . Levels of MB isoenzyme creatine kinase ( CK-MB ) were also measured . RESULTS In the protocol group , proinflammatory cytokines were significantly reduced while IL-10 levels were much higher after CPB . The protocol group had a lower alveolar-arterial oxygen gradient and higher ratio of arterial oxygen pressure to fraction of inspired oxygen after CPB . Creatine kinase ( CK ) and CK-MB were reduced in the patients treated with steroid . Correlations were found between plasma cytokines levels and cardiac index , and CK-MB . CONCLUSIONS This study confirms that corticosteroids abolish proinflammatory cytokines release and increase blood IL-10 levels after CPB . Our findings demonstrate a greater release of IL-10 induced by steroid pretreatment , and better heart and lung protection after CPB OBJECTIVES Improvement in health-related quality of life is a major object of cardiac surgery . However , high stress exposure during the perioperative period of cardiac surgery can result in the formation of traumatic memories and symptoms of chronic stress or even posttraumatic stress disorder , which can have negative effects on health-related quality -of-life outcome . In this controlled study we examined whether exogenously administered stress doses of hydrocortisone during cardiac surgery reduce perioperative stress exposure and the long-term incidence of chronic stress symptoms and improve health-related quality of life after cardiac surgery . METHODS Thirty-six high-risk patients undergoing cardiac surgery were prospect ively r and omized to receive either stress doses of hydrocortisone or placebo . Of 28 available patients at 6 months after cardiac surgery , 14 had received hydrocortisone , and 14 had received placebo . Traumatic memories , chronic stress symptoms ( posttraumatic stress disorder scores ) , and health-related quality of life were measured by using vali date d question naires . RESULTS Compared with patients from the placebo group , patients from the hydrocortisone group had a significantly shorter duration of intensive care unit treatment , required lower doses of the stress hormone norepinephrine during cardiac surgery , and had significantly fewer stress symptoms and a better health-related quality of life regarding physical function , chronic pain , general health , vitality , and mental health during follow-up . The groups did not differ with regard to the number or type of intensive care unit-related traumatic memories . CONCLUSIONS The use of stress doses of hydrocortisone in high-risk cardiac surgical patients reduces perioperative stress exposure , decreases chronic stress symptoms , and improves health-related quality of life at 6 months after cardiac surgery BACKGROUND Whether or not methylprednisolone is beneficial during cardiac operation remains controversial . This study examines the effects of the drug on complement activation and hemodynamics in patients undergoing cardiac operation and early extubation . METHODS Patients undergoing cardiac operation were r and omized to receive either intravenous methylprednisolone ( group MP ) or intravenous placebo ( group NS ) . Complement 3a ( C3a ) levels and hemodynamic parameters were obtained perioperatively . Extubation was accomplished at the earliest clinical ly appropriate time . RESULTS Both groups exhibited equivalent increases in C3a levels after exposure to bypass . Group MP exhibited increased cardiac index , decreased systemic vascular resistance , and increased shunt flow when compared to group NS . More group MP patients required hemodynamic support and group MP patients had prolonged extubation times . CONCLUSIONS Methylprednisolone was unable to attenuate complement activation and led to hemodynamic alterations ( primarily vasodilation ) that may hinder early extubation in patients after cardiac operations Neutrophil-endothelial adhesion is the initiating event in neutrophil migration to areas of infection or injury . The binding of neutrophils to endothelium depends upon adhesive glycoproteins , of which the CD11/CD18 glycoproteins are the most important . Because of known upregulation of one of these adhesive glycoproteins ( CD11b ) during cardiopulmonary bypass ( CPB ) in humans , we evaluated CD11a , CD11b , and CD11c surface expression before , during , and after CPB in humans , with or without pre-CPB administration of a glucocorticoid ( methylprednisolone ) . Fourteen patients were r and omized into two groups : Group S received methylprednisolone ( 1 g intravenously ) 5 min prior to CPB ; Group N received no steroid . CD11b was significantly upregulated ( P < 0.01 ) during , and 24 h after , CPB in Group N when compared with controls and Group S at similar time intervals , while in Group S no significant changes were found . Since interleukin-1 , tumor necrosis factor , and endotoxin are known to upregulate neutrophil CD11b surface expression and are released during CPB in humans , while steroids are known to suppress the release of these cytokines , the authors conclude that the blunting effect by steroids on CD11b surface expression upregulation during and after CPB in humans is attributed to suppressed cytokine release Corticosteroids decrease side effects after noncardiac elective surgery . We design ed this r and omized , double-blinded , placebo-controlled study to test the hypothesis that st and ard doses of dexamethasone ( 4 mg ×2 ) would reduce postoperative nausea , vomiting , and pain , decrease the incidence of atrial fibrillation ( AF ) , and improve appetite after cardiac surgery , thereby facilitating the recovery process . A total of 300 patients undergoing coronary revascularization surgery were enrolled in this clinical study . The anesthetic management was st and ardized in all patients . Dexamethasone ( 4 mg/mL ) or saline ( 1 mL ) was administered after the induction of anesthesia and a second dose of the same study drug was given on the morning after surgery . The incidence of AF was determined by analyzing the first 72 h of continuously recorded electrocardiogram records after cardiac surgery . The patients were assessed at 24- and 48-h intervals after surgery , as well as at the time of hospital discharge , to determine the incidence and severity of postoperative side effects ( e.g. , nausea , vomiting , pain ) and patient satisfaction scores . Dexamethasone significantly reduced the need for antiemetic rescue medication on the first postoperative day ( 30 % versus 42 % ) , and the incidences of nausea ( 15 % versus 26 % ) and vomiting ( 5 % versus 16 % ) on the second postoperative day ( P < 0.05 ) . In addition , dexamethasone significantly reduced the percentage of patients with a depressed appetite on the second postoperative day . However , the corticosteroid failed to decrease the incidence of AF ( 27 % versus 32 % ) or the total dosage of opioid analgesic medication administered in the postoperative period . We conclude that dexamethasone ( 8 mg in divided doses ) was beneficial in reducing emetic symptoms and improving appetite after cardiac surgery . However , this dose of the corticosteroid does not seem to have antiarrhythmic or analgesic-sparing properties . IMPLICATION S : Dexamethasone ( 8 mg IV ) was beneficial in reducing emetic symptoms and increasing appetite after cardiac surgery . However , this dose of the corticosteroid failed to decrease postoperative pain or the incidence of new-onset atrial fibrillation Background : Activation of the inflammatory cascade is thought to account for some of the respiratory dysfunction and prolonged mechanical ventilation associated with cardiopulmonary bypass . The objective of this investigation was to identify whether perioperative steroids or hemofiltration during cardiopulmonary bypass , by their attenuation of inflammation , would reduce duration of mechanical ventilation after cardiac surgery . Methods : After Institutional Review Board approval and informed consent , 192 patients scheduled to undergo elective primary coronary artery bypass grafting or valvular replacement or repair were r and omized in a double-blind prospect i ve study into three groups . One group ( Control ) received saline at induction and at 6-h intervals for four doses . Another group ( Hemofil ) received saline and hemofiltration to obtain 27 ml/kg of hemofiltrate . The final group ( Steroid ) received 1 g methylprednisolone before anesthesia induction and then 4 mg of dexamethasone at 6-h intervals for four doses . All patients underwent normothermic cardiopulmonary bypass and received propofol for postoperative sedation . Separate two- sample comparisons were performed to compare each experimental group versus the control group using the Wilcoxon rank sum test for continuous variables and Fisher exact test for categorical variables . In all cases , two-tailed P values ≤ 0.05 were considered statistically significant . Results : The median time until the patient reached an intermittent m and atory ventilation of 4/min ( 258.5 versus 385.0 min , respectively ; P = 0.02 ) and tracheal extubation ( 352.0 versus 518.0 min ; P = 0.03 ) was significantly reduced for group Hemofil but no different for Steroid compared to Control . Conclusions : Hemofiltration and steroids are both previously reported to attenuate the inflammatory response but only hemofiltration reduced time to tracheal extubation for adults after cardiopulmonary bypass in this study AIM To investigate the effects of corticosteroids on the reduction of inflammatory response after cardiopulmonary bypass . METHODS Twenty patients undergoing elective coronary revascularization were r and omized into two groups , which both underwent coronary artery bypass surgery with the aid of normothermic cardiopulmonary bypass . One group received a single dose of methylprednisolone prior to normothermic cardiopulmonary bypass , whereas no steroid treatment was given to other group of patients . The two groups were comparable with respect to preoperative demographic data . Serum sample s from all patients were drawn preoperatively and 3 , 6 , and 24 hours after the surgical procedure . The serum concentrations of tumor necrosis factor alpha ( TNF-alpha ) , interleukin-1beta ( IL-1beta ) , interleukin-6 ( IL-6 ) , interleukin-8 ( IL-8 ) , as well as the white blood cell count were measured . Serum C-reactive protein concentrations ( CRP ) were determined preoperatively and 72 hours postoperatively . St and ard hemodynamic measurements for both groups were collected and analyzed . RESULTS We did not find any increase in the postoperative concentrations of TNF-alpha and IL-1beta in either group . The concentrations of IL-6 and IL-8 increased significantly in both groups , from immeasurable concentrations preoperatively to as high as 496 pg/mL for IL-6 and 128 pg/mL for IL-8 three hours after surgery . However , the observed increase was significantly smaller in the group of patients receiving methylprednisolone . CONCLUSION It seems that the administration of corticosteroids prior to the initiation of cardiopulmonary bypass may alleviate the intensity of the inflammatory response , as evidence d by reduced increase in inflammatory mediators OBJECTIVE To measure the effects of glucocorticoids on the systemic inflammatory response and clinical recovery after cardiac surgery . DESIGN R and omized , prospect i ve , double-blind , placebo-controlled clinical trial with concurrent comparison groups . SETTING University medical center . PARTICIPANTS Patients scheduled for elective coronary artery bypass graft surgery using normothermic cardiopulmonary bypass ( CPB ) and a st and ardized anesthetic . INTERVENTIONS Participants r and omly received either methylprednisolone , 15 mg/kg intravenously 1 hour before surgery and 0.3 mg/kg intravenously every 6 hours x 4 doses , or placebo . Comparison groups included cardiac surgical patients who received etomi date to lower endogenous cortisol during surgery and healthy volunteers who received methylprednisolone only . MEASUREMENTS AND MAIN RESULTS Patients who received methylprednisolone had a significant reduction in circulating interleukin (IL)-6 at 60 minutes after CPB ( p < 0.05 ) and on the morning of the 1st ( p < 0.01 ) and 3rd ( p < 0.05 ) postoperative days and a significant increase in circulating IL-10 at 60 minutes after CPB ( p < 0.01 ) compared with the placebo group . Etomi date , given to lower cortisol during surgery , was associated with significantly decreased IL-6 and IL-10 responses to surgery compared with the placebo group , whereas methylprednisolone alone , given to healthy nonsurgical volunteers , had no effect on these cytokines . After adjusting for age , there were no significant differences in postoperative length of hospital stay between the methylprednisolone-treated ( 4.6 days ) and placebo ( 6.1 days ) groups or in the duration of mechanical ventilation ( 9.9 hours and 15.6 hours ) . No patient treated with methylprednisolone had nausea and vomiting on the 1st postoperative day compared with 33 % of placebo-treated patients ( p = 0.02 ) . Glucose was significantly higher after methylprednisolone treatment at 1 hour after CPB ( 276 mg/dL v 210 mg/dL ; p = 0.001 ) and at 2 hours ( 289 mg/dL v 213 mg/dL ; p = 0.009 ) and 8 hours ( 247 mg/dL v 196 mg/dL ; p = 0.02 ) after surgery . There were no differences in pain scores and no significant intergroup differences in lung peak expiratory flow rate or alveolar-arterial oxygen gradients after surgery . CONCLUSION This study shows significant effects of glucocorticoids on the production of IL-6 and IL-10 in response to cardiac surgery but only minor effects on clinical recovery The aim of this study was to investigate whether steroid administration would increase the risk of postoperative infection . Sixty adults who underwent elective cardiac surgery under cardiopulmonary bypass were prospect ively r and omized into two groups . Thirty-one patients received hydrocortisone ( 50 mg·kg−1 ) before and after cardiopulmonary bypass , the other 29 served as controls . Various hemodynamic and pulmonary measurements were obtained perioperatively , and the white blood cell counts and levels of C-reactive protein were checked up to the 14th postoperative day . Steroid administration did not have any favorable effects during the perioperative period . Re-administration of antibiotics was needed in 7 patients ( 22.6 % ) after the 7th postoperative day in the steroid group , and in 3 ( 10.3 % ) in the control group . The peak white cell counts and C-reactive protein levels after the 7th postoperative day were significantly higher in the steroid group . Steroid administration offered no clinical benefit to patients undergoing cardiac surgery with cardiopulmonary bypass , and it may encourage minor infections in the late postoperative period It has been proposed that a single preoperative dose of a corticosteroid may protect the myocardium from ischemic injury during open heart surgery . To test this hypothesis , a prospect i ve , r and omized , double blind study was carried out in ninety-five patients undergoing coronary bypass surgery using intermittent ischemic arrest with systemic and local hypothermia . Half the patients received 2 gm ( approximately 30 mg/kg ) of methylprednisolone 2 hours prior to the initiation of cardiopulmonary bypass and the other half received a placebo . Postoperative electrocardiograms and blood levels of serum creatine phosphokinase ( CPK ) , lactic dehydrogenase ( LDH ) , and serum glutamic oxalacetic transaminase ( SGOT ) were compared in the two groups . No apparent difference was noted in the number of patients with significantly elevated levels of CPK , LDH , or SGOT or in the number with positive isoenzyme patterns of CPK and LDH . Moreover , there was no significant difference in the mean values of CPK , LDH , or SGOT between the two groups . The number of patients with electrocardiographic evidence of myocardial injury ( 10 per cent ) was the same in both groups and no difference was noted in ( 1 ) the ease with which patients could be weaned from cardiopulmonary bypass , ( 2 ) postoperative arrhythmias , ( 3 ) postoperative bleeding , ( 4 ) postoperative respiratory insufficiency , and ( 5 ) length of hospital stay . It is concluded that a single preoperative dose of 2 gm of methylprednisolone offers no demonstrable protection to the myocardium from the effects of ischemia during coronary artery bypass surgery Numerous clinical studies suggest that methylprednisolone may facilitate early tracheal extubation after cardiac surgery , yet no investigation has rigorously examined the use of the drug in this setting .In this prospect i ve , r and omized , double-blind , placebo-controlled study , we examined the pulmonary effects of methylprednisolone in patients undergoing coronary artery bypass grafting ( CABG ) and early tracheal extubation . Sixty patients undergoing elective CABG and early tracheal extubation were r and omized into two groups . Group MP patients received IV methylprednisolone ( 30 mg/kg during sternotomy and 30 mg/kg during initiation of cardiopulmonary bypass ) and Group NS patients received IV placebo at the same two times . Perioperative management was st and ardized . Alveolar-arterial ( A-a ) oxygen gradient , lung compliance , shunt , and dead space were determined four times perioperatively . Postoperative tracheal extubation was accomplished at the earliest appropriate time . Both groups exhibited significant postoperative increases in A-a oxygen gradient and shunt ( P < 0.000001 for each group ) and significant postoperative decreases in dynamic lung compliance ( P < 0.000001 for each group ) . Patients in Group MP exhibited significantly larger increases in postoperative A-a oxygen gradient ( P = 0.001 ) and shunt ( P = 0.001 ) compared with patients in Group NS . Postoperative alterations in dynamic lung compliance , static lung compliance , and dead space were not statistically significant between the groups . The time to postoperative tracheal extubation was prolonged in Group MP patients compared with Group NS patients ( 769 + /- 294 vs 604 + /- 315 min , respectively ; P = 0.05 ) . Methylprednisolone was associated with larger increases in postoperative A-a oxygen gradient and shunt , was unable to prevent postoperative decreases in lung compliance , and prolonged extubation time , which indicate that use of the drug may hinder early tracheal extubation in patients after cardiac surgery . Implication s : Traditionally , methylprednisolone has been administered to patients undergoing cardiac surgery to decrease postoperative pulmonary dysfunction . This study revealed that the drug is associated with larger increases in postoperative alveolararterial oxygen gradient and shunt and prolonged tracheal extubation time in patients undergoing coronary artery bypass grafting , which indicate that use of the drug may hinder early tracheal extubation . ( Anesth Analg 1998;87:27 - 33 Objective During cardiopulmonary bypass , inflammation and immunosuppression is present . We measured circulating mediators and monocyte-based functions and tested the hypothesis that these variables are influenced by methylprednisolone ( MP ) or tirilazad mesylate ( TM ) treatment . Design R and omized , controlled , double-blind prospect i ve trial . Setting A university hospital . Patients Thirty-nine patients scheduled for conventional coronary surgery with three-vessel disease . Interventions Preoperative application of MP ( 15 mg/kg ) or TM ( 10 mg/kg ) compared with placebo ( PL ) . Measurements and Main Results Circulating proinflammatory markers including interleukin (IL)-6 , IL-8 , monocyte chemoattractant protein 1 , and C-reactive protein were all decreased by MP treatment but not by TM treatment . Whereas rapid increases in circulating anti-inflammatory IL-10 were superinduced by MP but not TM , plasma levels of IL-1RA and transforming growth factor & bgr ; were not altered by either treatment . Decreased ex vivo lipopolysaccharide-stimulated secretion of tumor necrosis factor & agr ; was prolonged after MP treatment but not after TM treatment . Perioperative stimulated secretion of IL-12 and interferon & ggr ; was diminished in all groups , whereas ex vivo IL-1RA secretion tended to increase in all groups . Depression of monocyte surface expression of HLA-DR was significantly greater in patients treated with MP , whereas CD14 expression did not change . Conclusions These data confirm that , during cardiopulmonary bypass , pro- and anti-inflammatory systems are activated at the same time , whereas monocyte-based immune functions are depressed . Treatment with MP abrogates proinflammatory mediators and induces a shift toward anti-inflammation at the cost of further functional monocyte deficits , whereas treatment with TM apparently has neither anti-inflammatory nor immunosuppressive actions in this setting BACKGROUND Steroid use during cardiac operations may reduce the risk of postperfusion lung syndrome , but both cardiopulmonary bypass and steroids are immunosuppressive . The synergistic effects of the bypass and steroids on patients ' immunologic activities , hemodynamics , and metabolisms during and after heart operations have not been clarified systematic ally . METHODS Twenty-four patients undergoing valve replacement were studied in a r and omized , double-blind trial . Twelve of these patients ( S group ) received bolus methylprednisolone , 20 mg/kg body weight , and the remaining 12 patients ( C group ) received a placebo intravenously before and after bypass . Blood cell count , C-reactive protein , lymphocyte surface markers ( CD3 , CD4 , CD8 , CD16 , and CD20 ) , phytohemagglutinin response , interleukin-2 production , and natural killer cell activity were examined on admission through day 7 . Cardiac output , blood gas , electrolyte , lactate , and serum glucose levels were examined perioperatively . RESULTS The peak white blood cell count in the S group was higher than that in the C group ( analysis of variance : p [ group ] = 0.0436 ) . The peak C-reactive protein level was higher in the C group than in the S group ( p [ group ] < 0.0001 ) . From the analysis of the surface markers , the steroid increased the natural killer cells before and soon after bypass ( p [ group ] = 0.0117 ) , and later tended to increase the CD4 + T and B cells during the postoperative recovery period . The phytohemagglutinin response in both groups decreased after bypass ( p [ time ] < 0.0001 ) , but the steroid caused exaggerated decreases before ( p < 0.01 by Student 's t test ) and soon after ( p < 0.001 ) bypass in the S group ( analysis of variance : p [ group ] = 0.0127 ) . The interleukin-2 production was suppressed by bypass alone after the bypass in the C group , but was further suppressed by the steroid before and after bypass in the S group ( p [ group ] = 0.0446 ) . The cardiac index , water balance , electrolytes , arterial oxygen tension , and timing of extubation were not different between the groups . In contrast , the glucose ( p [ group ] = 0.0486 ) and lactate ( p [ group ] = 0.0525 ) levels were higher in the S group than those in the C group . CONCLUSIONS T-cell functions are synergistically suppressed by cardiopulmonary bypass and high-dose methylprednisolone in heart operations . The hemodynamic benefits of the steroid are negligible , whereas glucose tolerance is worsened by the steroid during bypass BACKGROUND It is recognized that the inflammatory mediators complement and cytokines are generated during cardiopulmonary bypass as an endogenous response to extracorporeal circulation . METHODS Nineteen r and omized patients ( 10 steroid/9 nonsteroid ) entered an institutional review board-approved protocol to measure complement and interleukin level generation before and after elective coronary revascularization . The steroid regimen involved 1 g of methylprednisolone sodium succinate intravenously before bypass and 4 mg of dexamethasone every 6 hours for four doses during the first 24 hours of recovery . Complement and interleukin levels were measured before bypass , immediately after bypass , and at 24 , 48 and 72 hours of recovery . RESULTS In the nonsteroid group , there was a significant elevation in all inflammatory mediators relative to the steroid group . The predominant changes occurred at 24 hours after operation . CONCLUSIONS Steroids produced a dramatic reduction in complement and interleukin levels . The number of patients was clearly too small to document a clinical consequence of steroid administration Fifty consecutive adults undergoing elective cardiac surgery with cardiopulmonary bypass received a single dose of methylprednisolone ( 30 mg/kg ) at the time of anesthesia . The results were compared with those in the immediately preceding fifty adult patients who underwent elective cardiac surgery and who did not receive corticosteroids . The age , sex , and weight of the patient , mortality , nature of the lesions treated surgically , bypass time , smoking history , physiologic evidence of preexisting lung disease , preoperative New York Heart Association class , preoperative left ventricular end diastolic pressure , incidence and duration of the postoperative low cardiac output syndrome , postoperative arrhythmias , operative and postoperative blood loss and postoperative hours of respiratory support , dynamic lung-thorax compliance , alveolar arterial oxygen gradient , fraction of wasted ventilation , and incidence of tracheostomy were tabulated and statistically contrasted . The two groups were comparable relative to all preoperative factors , except for a slightly higher end diastolic pressure in the patients who received steroids . Methylprednisolone given at the time of anesthesia was associated with a higher intraoperative blood loss , a higher incidence of low cardiac output syndrome , and an increased requirement for postoperative mechanical ventilation . As bypass time approached three hours , the proportion of patients requiring prolonged support in both groups became similar . It was concluded that pretreatment with methylprednisolone in massive doses had an overall adverse cardiopulmonary effect BACKGROUND Cardiopulmonary bypass ( CPB ) induces a systemic inflammatory response called ' post-pump syndrome ' . As a part of a complex interaction between white cells and vascular endothelium , proinflammatory cytokines IL-6 and IL-8 are part of a phased immune response that is also balanced by anti-inflammatory cytokines such as IL-10 . We compared the influence of heparin-coated circuits , steroids , and aprotinin on these cytokines , looking for ways to reduce the syndrome . METHODS 40 patients with coronary artery disease ( CAD ) undergoing elective CABG were prospect ively studied in four r and omized groups of 10 . Group A received prednisolone pre- and postoperatively ( 2 x 250 mg ) , group B received aprotinin perioperatively ( 6 Mio . KIU ) . In group C , heparin-coated circuits ( ' Bioline ' by Jostra ) were used and in group D no special measures were taken ( controls ) . Plasma levels of cytokines were measured before and during CPB and until 12 h after surgery using an ELISA technique . RESULTS In group A IL-6 was significantly ( p<0.05 ) suppressed in contrast to the control group ( A : peak at 4 h , 155 pg/ml vs. control : peak at 8 h , 565 pg/ml ) . IL-8 was also suppressed ( A : peak at 30 ' , 22 pg/ml vs. control : peak at 30 ' , 55 pg/ml ) . IL-10 level changed first and was markedly upregulated in contrast to the control ( A : peak at 30 ' , 1600 pg/ml vs. control : peak at 30 ' , 130 pg/ml ; p<0.05 ) . In group B ( aprotinin ) the cytokine release was similar to group A. Using heparin-coated circuits ( group C ) also led to a significant ( p<0.05 ) IL-10 upregulation ( C : peak at 2 h , 1380 pg/ml ) and IL-6 suppression ( C : peak at 4 h , 290 pg/ml ) . IL-8 was not influenced significantly . CONCLUSIONS The results show a similar reduction of the inflammatory cytokine release ( IL-6 and IL-8 as markers ) using early steroid application and aprotinin in high dosage . Heparin coating reduces IL-6 and increases IL-10 release , whereas IL-8 is not affected . Further studies should investigate the effects of a combined application for reducing inflammatory cytokine release and the post-pump syndrome Shivering after cardiac surgery is common , and may be a result of intraoperative hypothermia . Another possible etiology is fever and chills secondary to activation of the inflammatory response and release of cytokines by cardiopulmonary bypass . Dexamethasone decreases the gradient between core and skin temperature and modifies the inflammatory response . The goal of this study was to determine whether dexamethasone can reduce the incidence of shivering . Two hundred thirty-six patients scheduled for elective coronary and /or valvular surgery were r and omly assigned to receive either dexamethasone 0.6 mg/kg or placebo after the induction of anesthesia . All patients received st and ard monitoring and anesthetic management . After arrival in the intensive care unit ( ICU ) , nurses unaware of the treatment groups recorded visible shivering , as well as skin and pulmonary artery temperatures . Analysis of shivering rates was performed by using chi squared tests and logistic regression analysis . Compared with placebo , dexamethasone decreased the incidence of shivering ( 33.0 % vs 13.1 % ; P = 0.001 ) . It was an independent predictor of reduced incidence of shivering and was also associated with a higher skin temperature on ICU admission and a lower central temperature in the early postoperative period . Implication s : Dexamethasone is effective in decreasing the incidence of shivering . The effectiveness of dexamethasone is independent of temperature and duration of cardiopulmonary bypass . Shivering after cardiac surgery may be part of the febrile response that occurs after release of cytokines during cardiopulmonary bypass . ( Anesth Analg 1998;87:795 - 9 We examined the plasma ACTH and cortisol responses to surgery in 25 patients with atherosclerotic heart disease undergoing myocardial revascularization . The patients were all premedicated with diazepam , and general anesthesia was induced with thiopental . They were r and omly assigned to one of four groups : I ) no dexamethasone ( DEX ) , enflurane anesthesia , II ) 40 mg DEX , iv , 45 - 60 min before sternotomy , enflurane anesthesia , III ) no DEX , fentanyl [ N-(1-phenethyl-4-piperidyl)propionanilide ] anesthesia ( 50 - 100 micrograms/kg ) , and IV ) DEX , fentanyl anesthesia . Isokalemic hemodilution of significant magnitude occurred during cardiopulmonary bypass . All groups had significant increases in plasma ACTH during surgery , which returned to control levels 22 h after the bypass . Group I ( no DEX , no fentanyl ) and group III ( no DEX , fentanyl ) patients had large similar increases in plasma ACTH , which peaked 2 - 4 h postbypass [ 400 + /- 83 ( + /- SEM ) pg/mL ; 88 + /- 18 pmol/L ] . The group II ( DEX , no fentanyl ) patients also had large increases in ACTH which were similar to those in groups I and III , except 2 - 4 h postbypass ( 183 + /- 91 pg/mL ; 40 + /- 20 pmol/L ) . The group IV ( DEX , fentanyl ) patients had a significantly attenuated ACTH response to surgery ; the mean plasma ACTH level 2 - 4 h postbypass was only 54 + /- 21 pg/mL ( 12 + /- 5 pmol/L ) . Therefore , although DEX or fentanyl alone had a minimal effect on the ACTH response to surgery , a significant attenuation occurred when DEX and fentanyl were used in combination . We conclude that glucocorticoids and morphine agonists exert interactive inhibitory effects on ACTH release in humans , probably by virtue of their suppression of CRH release from the hypothalamus A prospect i ve r and omized trial involving 91 patients undergoing cardiopulmonary bypass compared the effects of bubble oxygenators ( with and without methylprednisolone sodium succinate ) and membrane oxygenators on complement activation and transpulmonary sequestration of leukocytes . Patients were divided as follows : Group I , 30 patients , bubble oxygenator ; Group II , 31 patients , bubble oxygenator and methylprednisolone sodium succinate ( 30 mg/kg ) ; Group III , 30 patients , membrane oxygenator . In Group I , C3a increased from 323 + /- 171 ng/ml during cardiopulmonary bypass to 1,564 + /- 785 ng/ml at 25 minutes after bypass ( p less than 0.0001 ) . A significant decrease in C3a was found in Groups II and III compared to Group I ( p less than 0.0001 ) . C5a did not change significantly during cardiopulmonary bypass in any group . Reestablishment of pulmonary circulation at the end of bypass produced significant transpulmonary leukocyte sequestration in Group I ; the median cell difference was 1,700/microliter . Transpulmonary sequestration was significantly ( p less than 0.0001 ) less in Group II ( median cell difference = 200/microliter ) and in Group III ( median cell difference = 400/microliter ) than in Group I. We conclude that cardiopulmonary bypass with a bubble oxygenator alone initiates significantly ( p less than 0.0001 ) more C3a activation and leukocyte sequestration than when methylprednisolone sodium succinate ( 30 mg/kg ) is given 20 minutes before the start of cardiopulmonary bypass with a bubble oxygenator or when a silicone membrane oxygenator is used An increase in circulating levels of IL-10 is believed to contribute to immunosuppression caused by major surgery . Cortisol and catecholamines have been shown to be important costimulatory factors for IL-10 secretion in humans . As thoracic epidural block ( TEB ) should blunt the perioperative increases in cortisol and catecholamines we investigated whether IL-10 secretion is influenced by TEB . Twenty-six patients undergoing coronary artery bypass graft surgery using cardiopulmonary bypass were r and omized to receive either general anesthesia ( GA ) or GA plus TEB . Sensory and pain levels were measured to demonstrate clinical effectiveness . Plasma concentrations of epinephrine , norepinephrine , cortisol , IL-6 and IL-10 as well as monocyte surface expression of HLA-DR and their ex vivo capacity to release TNF-alpha after LPS stimulation were measured perioperatively . TEB was clinical ly effective and patients receiving TEB showed decreased circulating levels of IL-10 . However , this decrease was independent of decreased levels of cortisol or epinephrine . No influence of TEB on IL-6 levels , monocyte capacity to ex vivo release TNF-alpha upon LPS stimulation or their expression of HLA-DR was found . In conclusion , high TEB reduces antiinflammatory immune suppressing mediators including IL-10 and stress mediators . At least in cardiac surgery patients the monocyte functional depression is not related to systemic release of IL-10 and the influence of cortisol or epinephrine is less important for early monocyte deactivation than what in vitro and animal models have suggested Objective : This study examined the correlation between tumour necrosis factor-alfa ( TNF-α ) , interleukin (IL)-6 and IL-8 , IL-10 and methylprednisolone pretreatment . Methods : This is a prospect i ve , r and omized and double-blinded study . Sixty patients undergoing coronary artery bypass grafting ( CABG ) were r and omized to receive either intravenous methylprednisolone ( n=30 , Group M ) or intravenous placebo ( n=30 , Group S ) . The patients received intravenously either 30 mg/kg methylprednisolone ( Group M ) or placebo ( Group S ) 10 min before and after cardiopulmonary bypass ( CPB ) . In an intensive care unit ( ICU ) , four additional doses were given at 6-hourly intervals . Blood sample s for the measurements of TNF-α , IL-6 , IL-8 and IL-10 were obtained before induction of anaesthesia ( T0=control value ) , after induction ( T1 ) , before starting CPB ( T2 ) , after aortic declamping ( T3 ) , at the end of CPB ( T4 ) and 6 hours ( T5 ) , 12 hours ( T6 ) and 24 hours ( T7 ) after skin closure . Creatine kinase ( CK ) and creatine kinase isoenzyme MB ( CK-MB ) were evaluated at the following intervals : T0 , T5 , T6 and T7 . Results : When compared with the control value , TNF-α , IL-6 and IL-8 significantly increased in Group S and Group M ( p B-0.05 ) , but these values were significantly greater in Group S than in Group M ( p B-0.05 ) . In comparison with the control value , IL-10 increased in both groups ( p B-0.05 ) , but was significantly greater in Group M than in Group S ( p B-0.05 ) . CK and CK-MB were increased in both groups in postoperative values compared to control values . In Group S , CK and CK-MB levels were significantly lower than in Group M ( p B-0.05 ) . Conclusion : In this study , we have found that pre-operative administration of methylprednisolone has decreased TNF-α , IL-6 and IL-8 release , and increased the perfusing IL-10 levels after CPB . Thus , methylpredniso-lone may decrease the inflammatory response during the CPB procedure The influence of 3 different , preoperatively given glucocorticoids ( 30 mg/kg bw methylprednisolone , 3 mg/kg bw dexamethasone , 30 mg/kg hydrocortisone ) on extravascular lung water ( EVLW ) was investigated in a r and omised study consisting of 60 patients undergoing elective aortocoronary bypass surgery and compared to a control group having received 0.9 % NaCl as placebo . EVLW- measurements were performed by using the double indicator dilution technique with indocyanine green and a microprocessed lung water computer . Besides EVLW- measurements haemodynamics and various laboratory data were studied before as well as after ( 15 min , 45 min , 5 h ) extracorporeal circulation ( ECC ) . ECC was followed by an increase in EVLW , which was less pronounced in the dexamethasone-group without being statistically significant ( p = 0.1 ) , however . Pulmonary gas exchange , too , did not differ statistically , in spite of a less pronounced ( p = 0.1 ) deterioration of paO2 in the dexamethasone-group . Haemodynamics and laboratory data in the corticoid-group did not show any significant difference compared to the non-treated control group . It was concluded , that pretreatment with corticoids in pharmacological doses in cardiac surgery had no beneficial effects on extravascular lung water and pulmonary function 1 . The presence of histamine and tryptase in serum during and after coronary artery bypass grafting may be an indication of the induction of inflammation . 2 . One group of patients received no glucocorticoids and a second group received methylprednisolone before extracorporeal circulation . In the steroid group no effects were seen on the basal levels of histamine ( 2.84 + /- 0.12 ng/ml ) and tryptase ( 0.50 + /- 0.05 ng/ml ) during and after surgery . In the other group two peak levels of histamine were observed : one at 10 min after starting extracorporeal circulation ( 4.19 + /- 1.79 ng/ml ) and another at 4 h after surgery ( 8.26 + /- 4.85 ng/ml ) . In this group tryptase was only elevated during the period of extracorporeal circulation ( 1.54 + /- 0.16 ng/ml ) . 3 . There were no differences between the two groups in complement activation . C3a levels rose to 170 + /- 8 % and 180 + /- 10 % of the initial value in the steroid and non-steroid group , respectively . 4 . It was concluded that during surgery mast cells were activated , but since tryptase levels decreased in the post-operative period , the second increase in the histamine level can be explained by activation of basophils or by an unknown mechanism for the release of histamine but not tryptase by mast cells . 5 . In the bronchoalveolar lavage fluid the levels of histamine and tryptase showed no differences between the two groups of patients , but histamine was enhanced compared with normal levels Pulmonary dysfunction caused by pulmonary neutrophil sequestration is a frequent postoperative complication in patients undergoing cardiopulmonary bypass ( CPB ) surgery . It is yet unclear whether treatment with corticosteroids in vivo in these patients can prevent complement-mediated neutrophil activation and sequestration in the lungs . Therefore , we conducted a prospect i ve study in order to investigate whether methylprednisolone ( MP ) pretreatment ( 30 mg/kg ) could influence the appearance of IL-8 ( a recently discovered cytokine with potent neutrophil-chemotactic activity ) in the peripheral circulation . We also studied the effects of MP pretreatment on the inflammatory parameters in the bronchoalveolar lavage ( BAL ) fluid 4 h postoperatively . Although peripheral neutropenia and the rise in IL-8 serum levels was less pronounced in MP-treated than in non-steroid-treated patients , there was no significant difference in albumin , total protein , concentrations of IL-8 and C3a , and the number of neutrophils in the BAL fluid between the two groups . However , when cultured in vitro , alveolar macrophages from patients treated with MP released significantly lower IL-8 , both in basal conditions and after stimulation with lipopolysaccharide . Our results show that MP does not prevent ( IL-8-mediated ) pulmonary neutrophil infiltration after CPB , although it might affect certain aspects of the microvascular lung injury UNLABELLED Whilst elevated urinary transforming growth factor beta-1 ( TGFbeta ) is associated with chronic renal dysfunction its role in acute peri-operative renal dysfunction is unknown . In contrast , peri-operative increases in urinary IL-1 receptor antagonist ( IL-1ra ) and TNF soluble receptor-2 ( TNFsr-2 ) mirror pro-inflammatory activity in the nephron and correlate with renal complications . Steroids modulate some plasma cytokines ( decreasing TNFalpha , IL-8 , IL-6 and increasing IL-10 ) , whereas ability to reduce plasma and urinary TNFsr-2 and IL-1ra and peri-operative renal injury is unknown . Patients undergoing coronary artery bypass grafting with cardiopulmonary bypass ( CPB ) were r and omised to receive methylprednisolone ( n = 18 ) or placebo ( n = 17 ) before induction of anaesthesia . Plasma and urinary pro- and anti-inflammatory cytokine balance was determined along with sub clinical proximal tubular injury and dysfunction , measured by urinary N-acetyl-beta-d-glucosaminidase (NAG)/creatinine and alpha-1-microglobulin/creatinine ratios , respectively . In the control group compared with baseline , plasma IL-8 , TNFalpha , IL-10 , IL-1ra and TNFsr-2 were significantly elevated along with urinary IL-1ra , TNFsr-2 and TGFbeta1 . Urinary NAG/creatinine and alpha-1-microglobulin/creatinine ratios rose from completion of revascularisation until 6 h with recovery at 24 h with a further rise in NAG/creatinine ratio at 48 h. Compared to placebo , the methylprednisolone group showed significantly reduced plasma IL-8 , TNFalpha , IL-1ra and TNFsr-2 whereas plasma IL-10 increased . Compared to placebo , the methylprednisolone group demonstrated significantly reduced urinary NAG/creatinine ratio , TNFsr-2 and TGFbeta1 at 24 h whereas urinary alpha-1-microglobulin/creatinine ratios increased . CONCLUSIONS Methylprednisolone administration during cardiac surgery significantly reduces plasma and urinary TNFsr-2 and IL-1ra , urinary TGFbeta1 and sub clinical renal injury but not dysfunction Glucocorticosteroid , methylprednisolone sodium succinate ( MPSS ) , 30 mg/kg of body weight , or dexamethasone sodium phosphate ( DSP ) , 6 mg/kg of body weight , were given intravenously to 60 patients , divided into two groups of 30 45 minutes prior to cardiopulmonary bypass for coronary artery bypass . These two groups were compared with 30 patients in a control group receiving a placebo and undergoing the same surgery . The study was carried out in a double-lind fashion . Patients receiving MPSS had a significantly higher cardiac index in both the preoperative and postoperative periods . This was accompanied by a decreased peripheral resistance . Patients receiving either MPSS or DSP also showed some evidence for the " washout " phenomenon indicating the possibility of better microcirculatory flow . Gluconeogenesis may have been enhanced in both groups receiving MPSS or DSP , but the evidence was greater in thos patients receiving MPSS . There were no hospital deaths in any of the three groups totaling 90 patients Abstract . Introduction : Cardiopulmonary bypass ( CPB ) induces an inflammatory response believed to contribute to postoperative morbidity . We hypothesized that the magnitude of the inflammatory response following CPB would be associated with adverse clinical outcomes .¶ Methods : Twenty-nine patients had plasma TNF , IL-6 , IL-8 , elastase , histamine , complement C5a , and complement C3a measured by ELISA before , during , and after cardiac operations employing CPB . Inflammatory mediator levels were analyzed with respect to outcomes .¶ Results : Mediator levels peaked at 4 h post-CPB and either returned to baseline or substantially decreased by 24 h. Patients with peak mediator levels above the median for the group as a whole were classified as ' hyper-responders ' ; those with levels below the median were classified as ' normal responders ' . While IL-8 , C3a , and IL-6 levels were independently associated with adverse outcomes , TNF , histamine , and C5a levels were not . Elastase levels trended towards adverse outcomes . IL-8 ' hyper-responders ' experienced significantly greater postoperative weight gain and had higher IL-8 levels at 24 h ( p<0.05 ) , with trends towards renal impairment and protracted supplemental oxygen requirements . C3a ' hyper-responders ' strongly trended towards increased bleeding , delayed extubation , greater postoperative weight gain , and decreased levels of independent functioning at discharge ( p≤0.10 ) . IL-6 ' hyper-responders ' experienced significantly more postoperative bleeding , delayed extubation , and higher IL-6 levels at 24 h compared to ' normal responders ' ( p<0.05 ) . They strongly trended towards greater postoperative weight gain and decreased levels of independent functioning at discharge (p≤0.10).¶ Conclusions : Patients who have an exaggerated inflammatory response to CPB tend to bleed more , require more respiratory support , demonstrate greater capillary leak via weight gain , and display a decline in independent functioning relative to normal responders . Thus , it appears that the magnitude of the inflammatory response to CPB adversely influences clinical outcomes ObjectiveS evere systemic inflammation with a vasodilatory syndrome occurs in about one third of all patients after cardiac surgery with cardiopulmonary bypass . Hydrocortisone has been used successfully to reverse vasodilation in septic patients . We evaluated if stress doses of hydrocortisone attenuate severe systemic inflammatory response syndrome in a predefined risk group of patients after cardiac surgery with cardiopulmonary bypass . Design R and omized , nonblinded , controlled trial . Setting Anesthesiologic intensive care unit for cardiac surgical patients of an university hospital . Patients After a risk analysis , we enrolled 91 patients into a prospect i ve r and omized trial . Patients were included according to the evaluated criteria ( preoperative ejection fraction , duration of cardiopulmonary bypass , type of surgery ) . Interventions The treatment group received stress doses of hydrocortisone perioperatively : 100 mg before induction of anesthesia , then 10 mg/hr for 24 hrs , 5 mg/hr for 24 hrs , 3 × 20 mg/day , and 3 × 10 mg/day . Measurements and Main Results We measured various laboratory ( e.g. , lactate ) and clinical variables ( e.g. , duration of ventilation and length of stay in the intensive care unit ) , characterizing the patients ’ outcome . The two study groups did not differ regarding age , preoperative medication , duration of the cardiopulmonary bypass , and type of surgery . The patients in the treatment group had significantly lower concentrations of IL-6 and lactate , higher antithrombin III concentration , lower need for circulatory and ventilatory support and for transfusions , lower Therapeutic Intervention Scoring System values , and shorter length of stay in the intensive care unit and in the hospital . The mortality rate did not differ significantly between the groups . Conclusions Although we acknowledge the limitations of a nonblinded interventional trial , stress doses of hydrocortisone seem to attenuate systemic inflammation in a predefined risk group of patients after cardiac surgery with cardiopulmonary bypass and improve early outcome Previous reports showed that cardiac surgery with cardiopulmonary bypass ( CPB ) impair cell-mediated immunity by using antigen-non-specific responses . This study eluci date d the effects of cardiac surgery with CPB on antigen-specific immunity . Twenty patients who underwent elective cardiac surgery using CPB were r and omly divided into two groups : group A ( n=10 ) and group B ( n=10 ) with and without steroid administration , respectively . Group C patients underwent off-pump CABG ( n=8 ) . Peripheral blood mononuclear cells ( P BMC s ) were taken before and after surgery . Proliferation responses to pure protein derivative antigen were measured . The effects of CPB and steroid on T cell response and antigen-presentation were assessed by cross-stimulation between the preoperative and the postoperative P BMC s. Antigen-specific T cell responses decreased to about 5 % of the preoperative values immediately after surgery with CPB , regardless of steroid administration . The T cell response in group B on POD 7 was significantly higher than that in group A. CPB impaired mainly T cell responses , and steroid administration enhanced impairment of T cell response and antigen-presentation . Open-heart surgery with CPB severely impaired antigen-specific immunity . Steroid administration enhanced the impairment of antigen-presentation as well as T cell function , and retarded the recovery of antigen-specific immunity Complications of coronary artery surgery were analyzed in a prospect i ve controlled study of 150 patients , one group receiving methylprednisolone before temporary cardiopulmonary bypass . The patient population was comparable in both the groups . The number of deaths were the same in both the groups , myocardial infa rct ion and cardiac arrhythmias were definitely lower in the Solu-Medrol group . Cerebral vascular accidents were higher in the control group and there were none in the drug treated group . Incidences of pulmonary embolism was reduced by the drug . Oxygen consumption by the tissues was higher in the Solu-Medrol treated group . There were no known complications of the drug , such as stress ulcer and infection . One patient did receive prophylactic antibiotics . Solu-Medrol was deliberately given in patients who were known to have uncomplicated duodenal ulcer . Post-operative bleeding in patients with duodenal ulcer was not noted . This could be explained due to the short acting nature of Solu-Medrol . We feel that Solu-Medrol does minimize serious sequelae of heart-lung machine in coronary artery surgery OBJECTIVE To discover the possible effects of methylprednisolone on the systemic inflammatory response during aprotinin treatment . DESIGN R and omized , double-blinded study . SETTING University-affiliated heart center . PARTICIPANTS Fifty-two patients scheduled for elective coronary artery bypass grafting . INTERVENTIONS In the methylprednisolone group ( n = 26 ) , 1 g of methylprednisolone was administered 30 minutes before cardiopulmonary bypass ( CPB ) . The 26 control patients received a placebo instead . High-dose aprotinin was administered to all participants . MEASUREMENTS AND MAIN RESULTS After CPB , the concentration of the proinflammatory cytokines , interleukin-6 and interleukin-8 , was significantly less in the methylprednisolone group . The anti-inflammatory interleukin-10 concentration was , in contrast , greater . After CPB , PaO2 was greater in the methylprednisolone group ( 245+/-17 v 195+/-16 mmHg ) . Dynamic pulmonary compliance was also greater , whereas the alveolar-arterial oxygen difference was less ( 376+/-17 v 428+/-16 mmHg ) . On arrival in the intensive care unit , the oxygen delivery index was greater in the methylprednisolone group ( 62+/-2.7 v 54+/-2.3 mL/min/m2 ) and the oxygen extraction rate was less ( 25%+/-0.02 % v 30%+/-0.02 % ) . After CPB , the cardiac index was significantly greater in the methylprednisolone group ( 4.1+/-0.2 v 3.6+/-0.2 L/min/m2 ) . These patients had less blood loss postoperatively ( 616+/-52 v 833+/-71 mL ; p = 0.017 ) and a greater urine output ( 8,015+/-542 v 6,417+/-423 mL/24 h ; p = 0.024 ) . CONCLUSION The use of methylprednisolone attenuates the systemic inflammatory response during aprotinin treatment and improves clinical outcome parameters BACKGROUND Despite recent rediscovery of beating heart cardiac surgical techniques , extracorporeal circulation remains appropriate for most heart operations . To minimize deleterious effects of cardiopulmonary bypass , antiinflammatory strategies have evolved . METHODS Four state-of-the-art strategies were studied in a prospect i ve , r and omized , preoperatively risk stratified , 400-patient study comprising primary ( n = 358 ) , reoperative ( n = 42 ) , coronary ( n = 307 ) , valve ( n = 27 ) , ascending aortic ( n = 9 ) , and combined operations ( n = 23 ) . Groups were as follows : st and ard , roller pump , membrane oxygenator , methylprednisolone ( n = 112 ) ; aprotinin , st and ard plus aprotinin ( n = 109 ) ; leukocyte depletion , st and ard plus a leukocyte filtration strategy ( n = 112 ) ; and heparin-bonded circuitry , centrifugal pumping with surface modification ( n = 67 ) . RESULTS Analysis of variance , linear and logistic regression , and Pearson correlation were applied . Actual mortality ( 2.3 % ) was less than half the risk stratification predicted mortality ( 5.7 % ) . The treatment strategies effectively attenuated markers of the inflammatory response to extracorporeal circulation . Compared with the other groups the heparin-bonded circuit had highly significantly decreased complement activation ( p = 0.00001 ) , leukocyte filtration blunted postpump leukocytosis ( p = 0.043 ) , and the aprotinin group had less fibrinolysis ( p = 0.011 ) . Primary end points , length of stay , and hospital charges , were positively correlated with operation type , age , pump time , body surface area , stroke , pulmonary sequelae , predicted risk for stroke , predicted risk for mortality , and risk strata/treatment group interaction ( p = 0.0001 ) . In low-risk patients , leukocyte filtration reduced length of stay by 1 day ( p = 0.02 ) and mean charges by $ 2,000 to $ 6,000 ( p = 0.05 ) . For high-risk patients , aprotinin reduced mean length of stay up to 10 fewer days ( p = 0.02 ) and mean charges by $ 6,000 to $ 48,000 ( p = 0.0007 ) . CONCLUSIONS These pharmacologic and mechanical strategies significantly attenuated the inflammatory response to extracorporeal circulation . This translated variably into improved patient outcomes . The increased cost of treatment was offset for selected strategies through the added value of significantly reduced risk Patients undergoing cardiopulmonary bypass were r and omly allocated to receive methylprednisolone 30 mg/kg in a single dose prior to bypass , or to a control group receiving saline . The effect of this treatment on 2,3‐DPG and oxygen delivery to the tissues was determined ABSTRACT Postoperative morbidity after coronary artery bypass grafting ( CABG ) using cardiopulmonary bypass ( CPB ) can be influenced by pro‐ and anti‐inflammatory cytokines like interleukin 6 ( IL‐6 ) and IL‐10 triggering and balancing the acute phase response . The extent of cytokine release can be modulated by different methods . This prospect i ve r and om‐ ized study examines the effect of treatment of patients with steroid ( group 1 , 250 mg of prednisolone)(Solu‐Decortin HTM ) ) , aprotinin ( group 2 , 6 Mio . KIU [ kallikrein inhibitory units ] aprotinin [ TrasylolTM ] ) , and heparine coating of the artificial surface ( group 3 , BiolineTM ) on the systemic release of IL‐6 and IL‐10 in four groups of 40 patients with coronary artery disease ( CAD ) scheduled for CABG . Group 4 ( st and ard medication ) served as control . Twenty hemodynamic and biochemical parameters of the CPB were analyzed regarding correlation to cytokine levels measured by enzyme‐linked immunosor‐ bent assay ( ELISA ) . In group 1 , IL‐6 was suppressed compared to the control ( P < 0.01 ) . IL‐10 was upregulated ( P < 0.01 ) . In group 2 , cytokine release was similar to group 1 . Using heparin‐coated circuits in group 3 led to IL‐10 upregulation ( P < 0.05 ) and IL‐6 suppression ( P < 0.05 ) . We found an exponential relationship between IL‐10 levels ( IL‐6 levels ) and cardiac ischemia time , duration of CPB , and the extent of negative base excess . An inverse relationship was found for IL‐10 ( IL‐6 ) levels and venous O2 saturation ( SvO2 ) , and mean arterial pressure ( MAP ) . Hypothermia ( < 34 ° C ) reduced IL‐10 and IL‐6 release , whereas long duration of hypothermia correlated with higher IL‐10 and IL‐6 release . Cytokine release after extracorporeal circulation ( ECC ) can be modulated pharmacologically and by distinct perfusion regimen Tumor necrosis factor-alpha ( TNF-alpha ) is released in inflammatory lung conditions , raising airway nitric oxide ( NO ) concentrations through the cytokine-mediated induction of nitric oxide synthase ( NOS ) . Cardiopulmonary bypass ( CPB ) creates an inflammatory state , characterized by the release of TNF-alpha , that may result in lung injury following CPB . This study measured plasma levels of TNF-alpha and interleukin-6 ( IL-6 ) as well as airway NO concentrations during CPB , and the effect of methylprednisolone ( MPSS ) on the levels of these inflammatory products . Twenty adult males scheduled for coronary artery bypass grafting ( CABG ) were anesthetized and r and omized to a group given MPSS at 1 gm intravenously 5 min before CPB ( Group S ) or a group not given MPSS ( Group N ) . Plasma levels of TNF-alpha and IL-6 were measured by enzyme-linked immunosorbent assay ( ELISA ) and the airway NO concentration by chemiluminescence . TNF-alpha was significantly ( p < 0.05 ) increased at 30 min after the termination of CPB , while IL-6 was significantly ( p < 0.05 ) increased at 50 min into CPB and 30 min after the end of CPB in Group N as compared with controls in the same group and with Group S at the same time intervals . A group of 10 patients undergoing repair of infrarenal aortic aneurysms , which served as a control group for plasma levels of TNF-alpha , showed no significant changes in TNF-alpha concentrations at any time during aneurysm repair . Airway NO increased significantly ( p < 0.01 ) in Group N as compared with Group S at 5 , 20 , 35 , and 50 min of CPB . ( ABSTRACT TRUNCATED AT 250 WORDS OBJECTIVE Cardiac surgery with cardiopulmonary bypass ( CPB ) is associated with an inflammatory response caused by contact of blood with artificial surfaces of the extracorporeal circuit , ischemia-reperfusion injury , and release of endotoxin . The inflammatory reaction involves activation of complement leucocytes , and endothelial cells with secretion of cytokines , proteases , arachidonic acid metabolites , and generation of oxygen derived free radicals ( OFR ) by polymorphonuclear neutrophils ( PMN ) . Although this inflammatory response to CPB often remains at sub clinical levels , it can also lead to major organ dysfunction . A number of studies have demonstrated that treatment of patients with a high-dose ( 30 mg/kg ) of corticosteroids ( methylprednisolone ) attenuates the CPB-induced SIR and improves the outcome of patients undergoing cardiac surgery . However , large doses of steroids can cause abnormal metabolic responses such as metabolic acidosis and hyperglycemia . In the present study , we examined the efficacy of low doses of methylprednisolone ( 5 and 10 mg/kg ) to attenuate the CPB-induced inflammatory response , during and after heart operations . METHODS Thirty-six adult patients undergoing cardiac surgery , were r and omized into three groups : ( 1 ) control group : group A ; ( 2 ) methylprednisolone , 5 mg/kg body weight : group B ; and ( 3 ) methylprednisolone , 10 mg/kg body weight : group C. Plasma levels of the cytokines interleukin-6 ( IL-6 ) and TNF-alpha were analyzed by enzyme-linked immunosorbent assay , before , during , and after CPB . OFR production was determined by cytofluorometry ( FACS ) at the same end points . RESULTS No significant differences in age , body weight , CPB time , and cross-clamp time were observed among the three groups . CPB induced a marked increased in cytokine release and OFR generation . Low-dose of methylprednisolone ( 5 mg/kg ) effectively reduced the increase in TNF-alpha and IL-6 secretion ( P<0.05 compared to control group ) after release of the cross-clamp . However , OFR generation was significantly reduced with a greater dose of methylprednisolone ( 10 mg/kg ) . CONCLUSIONS The results indicate that a single low-dose of methylprednisolone ( 10 mg/kg ) reduces the inflammatory reaction during and after CPB , by inhibition of proinflammatory cytokine release and OFR generation after release of the aortic cross-clamp Forty four patients undergoing open heart surgery were divided into three groups . Group 1 ( 17 patients ) underwent routine anaesthesia and surgery ; group 2 ( 17 patients ) received two doses of methylprednisolone ( 30 mg/kg ) , one during induction of anaesthesia and the other immediately before induction of cardiopulmonary bypass ; and group 3 ( 10 patients ) received pulsatile flow while undergoing pulsatile perfusion by the heart-lung machine . A modification of the previously described technique was used to detect and measure complement activation in plasma before and during the bypass period using crossed immunoelectrophoresis . About 45 % of all patients showed measurable complement activation ( greater than 4.5 % ) during cardiopulmonary bypass and the mean activation in this group was 6.4 % . There was no significant difference between the three groups in complement activation . In group 2 , however , women showed significantly more complement activation than men ( p less than 0.05 ) . It is suggested that neither corticosteroids nor pulsatile flow affect complement activation , but caution should be exercised in women receiving methylprednisolone BACKGROUND Peripheral vasodilation , a potentially adverse effect of warm heart surgery , may be mediated by the perioperative release of cytokines . Corticosteroids may abolish cytokine production and vasodilation . We investigated cytokine production and its inhibition by steroids in patients undergoing elective coronary bypass surgery . METHODS AND RESULTS Twenty-five patients undergoing coronary bypass surgery with normothermic cardiopulmonary bypass received either preoperative steroid ( Solumedrol 250 mg IV , n = 16 ) or no steroid ( n = 9 , control group ) . Blood sample s were obtained serially for 24 hours and assayed for interleukin-6 ( IL-6 ) , tumor necrosis factor ( TNF ) , and interleukin-8 ( IL-8 ) . In the control patients , the IL-6 , TNF , and IL-8 levels were elevated postoperatively and peaked between 3 and 6 hours after surgery ( IL-6 , 1330 + /- 295 [ mean + /- SEM ] pg/mL ; TNF , 18.4 + /- 9.8 pg/mL ; and IL-8 , 150 + /- 51 pg/mL ) . Cytokine release was abolished in patients receiving preoperative corticosteroid ( IL-6 , 75 + /- 38 pg/mL ; TNF , 2.6 + /- 0.5 pg/mL ; and IL-8 , 33 + /- 6.7 pg/mL ; P < .05 ) . Patients receiving steroid premedication had higher arterial pressure , lower cardiac index , and higher systemic vascular resistance , indicating less vasodilation . CONCLUSIONS Our findings demonstrate that cytokine production occurs after normothermic cardiopulmonary bypass . Preoperative administration of steroids abolishes cytokine release and vasodilation STUDY OBJECTIVES Cardiac surgery with cardiopulmonary bypass ( CPB ) results in perioperative organ damage caused by the systemic inflammatory response syndrome ( SIRS ) and ischemia/reperfusion injury . Administration of corticosteroids before CPB has been demonstrated to inhibit the activation of the systemic inflammatory response . However , the clinical benefits of corticosteroid therapy are controversial . This study was design ed to document the effects of dexamethasone on cytokine release and perioperative myocardial , pulmonary , renal , intestinal , and hepatic damage , as assessed by specific and sensitive biomarkers . DESIGN AND PATIENTS A prospect i ve , double-blind , placebo-controlled , r and omized trial for dexamethasone was conducted in 20 patients receiving either dexamethasone ( 1 mg/kg before anesthesia induction and 0.5 mg/kg after 8 h ; n = 10 ) or placebo ( n = 10 ) . Different markers were used to assess the SIRS : interleukin (IL)-6 , IL-8 , IL-10 , C-reactive protein ( CRP ) , and tryptase ; and organ damage : heart ( plasma heart-type fatty acid binding protein , cardiac troponin I [ cTnI ] , creatine kinase-MB ) , kidneys ( N-acetyl-glucosaminidase [ NAG ] , microalbuminuria ) , intestine ( intestinal-type fatty acid binding protein [I-FABP]/liver-type fatty acid binding protein [ L-FABP ] ) , and liver ( alpha-glutathione S-transferase ) . RESULTS Dexamethasone modulated the SIRS with lower proinflammatory ( IL-6 , IL-8 ) and higher antiinflammatory ( IL-10 ) IL levels . CRP and tryptase were lower in the dexamethasone group . cTnI values were lower in the dexamethasone group at 6 h in the ICU ( p = 0.009 ) . Patients in the dexamethasone group had a longer time to tracheal extubation ( 18.86 + /- 1.13 h vs 15.01 + /- 0.99 h , p = 0.02 [ mean + /- SEM ] ) , with a lower oxygenation index at that time : Pa(O2)/fraction of inspired oxygen ratio , 37.17 + /- 1.8 kPa vs 29.95 + /- 2.1 kPa ( p = 0.009 ) . The postoperative glucose level ( 10.7 + /- 0.6 mmol/L vs 7.4 + /- 0.5 mmol/L , p = 0.005 ) was higher in the dexamethasone group . Serum glucose was independently associated with intestinal injury ( urine I-FABP peak , R2 = 42.5 % , beta = 114.4 + /- 31.4 , significant at p = 0.002 ; urine L-FABP peak , R2 = 47.3 % , beta = 7,714.1 + /- 1,920.9 , significant at p = 0.001 ) and renal injury ( urine NAG , R2 = 32.1 % , beta = 0.21 + /- 0.07 , significant at p = 0.009 ) . Tryptase peaks correlated negatively with peaks of intestinal and renal injury biomarkers . CONCLUSION Even while inhibiting SIRS , dexamethasone treatment offered no protection against transient , sub clinical , perioperative abdominal organ damage . Tryptase release could have a preconditioning effect , offering protection against perioperative intestinal and renal damage . Dexamethasone treatment result ed in more pronounced postoperative pulmonary dysfunction , prolonged time to tracheal extubation , and initiated postoperative hyperglycemia in patients undergoing elective on-pump coronary artery bypass graft surgery BACKGROUND Cardiopulmonary bypass (CPB)-related inflammatory response can be attenuated by glucocorticoid treatment , but its impact on postoperative cardiopulmonary function remains controversial . It was investigated whether the systemic and myocardial antiinflammatory effects of glucocorticoids are associated with improved cardiopulmonary function in cardiac surgery patients . METHODS Eighty patients undergoing elective coronary artery bypass grafting were r and omly assigned to receive a single shot of methylprednisolone ( 15 mg/kg ) or placebo before CPB . Variables of myocardial and pulmonary function and systemic hemodynamics were measured before and 1 , 4 , 10 , and 24 hours after CPB . Blood was sample d for measurement of proinflammatory ( tumor necrosis factor-alpha , interleukin 6 , interleukin 8) and antiinflammatory ( interleukin 10 ) cytokines ( by enzyme-linked immunoassay ) , troponin T , and C-reactive protein . Phosphorylation of inhibitory kappa-B alpha and p38 mitogen-activated protein kinase was determined in right atrial biopsies before and after CPB ( phosphoprotein assay ) . RESULTS Preoperative and intraoperative characteristics of patients were not different between groups . Methylprednisolone attenuated postoperative tumor necrosis factor-alpha , interleukin 6 , interleukin 8 , and C-reactive protein levels while increasing interleukin 10 release . Myocardial inhibitory kappa-B alpha was preserved with methylprednisolone ( p < 0.05 versus placebo ) , but p38 mitogen-activated protein kinase activation occurred in both groups after CPB ( p < 0.05 versus before CPB ) . Methylprednisolone improved postoperative cardiac index and was associated with decreased troponin T when compared with placebo ( p < 0.05 ) . Postoperative blood glucose , oxygen delivery index , and pulmonary shunt flow were increased in the methylprednisolone group ( p < 0.05 ) . There was no difference in postoperative oxygenation index , ventilation time , and clinical outcome between treatment groups . CONCLUSIONS Glucocorticoid treatment before CPB attenuates perioperative release of systemic and myocardial inflammatory mediators and improves myocardial function , suggesting potential cardioprotective effects in patients undergoing cardiac surgery Methylprednisolone was given to patients undergoing open‐heart surgery in a dose of 30 mg/kg administered following induction of anaesthesia and repeated with the start of cardiopulmonary bypass . The effects of this treatment on 2,3‐DPG , P50 and cardiac index were compared with a control group who did not receive steroids . In addition plasma levels of methylprednisolone were assayed throughout the operations and up to 24 hours postoperatively . There was no significant difference between the two groups despite apparently adequate plasma levels of methylprednisolone , and it is concluded that steriods do not affect the P50 or 2,3‐DPG in patients undergoing cardiopulmonary bypass In this study , the authors administered high dose ( 30 mg/kg body weight i.v . ) methylprednisolone before cardiopulmonary bypass to observe the effects on complement , immunoglobulins and pulmonary neutrophil sequestration . Fifty patients undergoing valve replacements were included in this study . Patients were divided into two groups : group I ( 20 patients ) served as control and did not receive methylprednisolone , group II ( 30 patients ) received methylprednisolone . Blood sample s for complements ( C3c and C4 ) were taken , before cardiopulmonary bypass , at 5 , 10 and 30 min intervals from the end of cardiopulmonary bypass , after reversal of heparin with protamine infusion , and after skin closure . Blood sample s for immunoglobulins were taken before cardiopulmonary bypass , 30 min after onset of cardiopulmonary bypass and after skin closure . After onset of cardiopulmonary bypass , all C3c and C4 levels decreased in both groups . There was a significant decrease in C4 levels at end of cardiopulmonary bypass and after protamine infusion in group I compared with group II ( P < 0.05 ) . C3c levels in group I decreased significantly compared with group II after 30 min of cardiopulmonary bypass and after protamine infusion ( P < 0.05 ) . All immunoglobulin ( IgG , IgM , IgA ) levels were decreased in both groups , but the decrease in IgG was statistically significant after skin closure in group I compared with group II ( P < 0.05 ) . Pulmonary neutrophil sequestration was higher in the control group compared with the methyl-prednisolone group ( P < 0.05 ) . In conclusion , methylprednisolone administration before cardiopulmonary bypass may prevent the harmful effects of complement activation , immunoglobulin denaturation and neutrophil sequestration in the pulmonary capillary system Background : During conventional cardiac surgery ischemia and reperfusion may cause excessive production of reactive oxygen species leading to tissue damage including early arrhythmias . We therefore assessed the kinetics of markers of radical stress including oxidized and reduced glutathione ( GSSG/GSH ) , oxidized proteins ( PCG ) and malondialdehyde ( MDA ) , and tested the hypothesis that different steroid treatments inhibit these markers and early reperfusion‐associated supraventricular and ventricular extrasystolic beats It has been reported that interleukin 8 ( IL-8 ) and interleukin 6 ( IL-6 ) are two of the chemical mediators causing myocardial injury . It is not clear whether treatment with corticosteroids in vitro in these patients can prevent the production of interleukin 8 and 6 . This prospect i ve study was conducted to investigate whether methylprednisolone ( MP ) pretreatment ( 30 mg · kg−1 before CPB and before declamping of aorta ) influenced the production of IL-8 and 6 in the peripheral circulation in 27 patients undergoing elective coronary artery bypass surgery . The IL-8 and IL-6 concentrations were measured by ELISA kit . We also studied the effect of MP pretreatment on postoperative cardiac Junction . Serum concentration of IL-8 in non-MP-treated patients ( 37 ± 44 pg · ml−1 preoperatively ) increased to 169 ± 86 pg · ml−1 60 min after declamping of the aorta ( P < 0.001 ) . The increase was greater than the increase from 22 ± 8.9 pg · ml−1 to 52 ± 35 pg · ml−1 in the MP-treated patients ( P < 0.01 ) . Serum IL-6 concentration in non-MP-treated patients increased from the preoperative value of 59 ± 30 pg · ml−1 to 436 ± 143 pg · ml−1 60 min after declamping of the aorta ( P < 0.001 ) . The increase was greater than the increase from 36 ± 15 pg · ml−1 to 135 ± 55 pg · ml−1 in the MP-treated patients ( P < 0.01 ) . Furthermore , postoperative cardiac index in MP-treated patients ( 3.6 ± 1.1 L · min−1 · m−2 ) was higher than 2.3 ± 0.8 L · min−1 · m−2 of non MP-treated patients ( P < 0.05 ) . The levels of IL-8 max during surgery correlated negatively with postoperative cardiac index ( γ = −0.67 ) . These results suggest that methylprednisolone suppresses production of IL-8 and 6.RésuméOn a rapporté que l’interleukine 8 ( IL-8 ) et que l’interleukine 6 ( IL-6 ) étaient deux des médiateurs chimiques de la lésion cardiaque . Toutefois , on ne sait pas encore si le traitement aux corticostéroïdes in vivo prévient la production des interleukines 8 et 6 . Cette étude prospect i ve vise à déterminer si le prétraitement à la méthylprednisolone ( MP ) ( 30 mg · kg−1 avant le CEC et avant le déclampage de l’aorte ) influence la concentration de l’IL-8 de l’IL-6 du sang veineux périphérique de 27 patients soumis à une chirurgie réglée de revascularisation myocardique . Les concentrations de l’IL-8 de l’IL-6 sont mesurée avec une trousse Elisa . Nous étudions aussi les répercussions du traitement à la MP sur la fonction cardiaque postopératoire . La concentration sérique de l’IL-8 des patients non traités ( 37 ± 44 pg · ml−1 en préopératoire ) augmente à 169 ± 86 pg · ml−1 60 minutes après le déclampage de l’aorte ( P < 0,001 ) . Cette augmentation est plus importante que l’augmentation de 22 ± 8,9 pg · ml−1 à 52 ± 55 pg · ml−1 notée chez les patients traité à la MP ( P < 0,01 ) . La concentration serique de l’IL-6 chez les patients non traités à la MP augmente de la valeur préopératoire de 59 ± 30 pg · ml−1 à 436 ± 143 pg · ml−1 60 min après le déclampage de l’aorte ( P < 0,001 ) . Cette augmentation est plus importante que celle de 36 ± 15 pg · ml−1 à 135 ± 55 pg · ml−1 survenue chez les patients traités à la MP ( P < 0,01 ) . De plus , l’index cardiaque postopératoire des patients traités à la MP ( 3,6 ± 1,1 L · ml−1 · m−2 ) est plus élevé que celui des patients non traités 2,3 ± 0,8 L · ml−1 · m− 2 ( P < 0,05 ) . Les niveaux maximaux de 1’IL-8 sont en corrélation négative avec l’index cardiaque postopératoire ( y = 0,67 ) . Ces result ats suggèrent que la méthylprednisolone supprime la production de l’IL-8 et de l’IL-6 Cardiopulmonary bypass induces an inflammatory state characterized by tumor necrosis factor-alpha release . Integrin CD11b is a neutrophil surface adhesive glycoprotein integrin that is rapidly and permanently unregulated by tumor necrosis factor-alpha exposure . The CD11b integrin is known to be the primary neutrophil integrin responsible for neutrophil lung and myocardial entrapment after cardiopulmonary bypass and subsequent reperfusion injury . Twenty-four adults admitted to the hospital for myocardial revascularization were equally r and omized to one of three groups : group A ( control ) , group B ( methylprednisolone before cardiopulmonary bypass ) , and group C ( low-dose aprotinin protocol ) . Blood was collected at three times : ( 1 ) baseline , ( 2 ) 50 minutes of cardiopulmonary bypass duration , and ( 3 ) 30 minutes after cardiopulmonary bypass termination . Neutrophil CD11b integrin expression was measured by fluorescence-activated cell sorter analysis and plasma tumor necrosis factor-alpha levels measured by enzyme-linked immunosorbent assay . Group A demonstrated significant ( p < 0.05 ) increases in CD11b expression at times 2 and 3 when results were compared with those of the same group baseline and with those of groups B and C at similar times . No significant changes were noted between groups B and C at any time . Group A demonstrated a significant ( p < 0.05 ) increase in levels of tumor necrosis factor-alpha at time 3 when results were compared with those of the same group baseline and of groups B and C at the same time . No significant changes were noted between B and C at any time . These results demonstrate low-dose aprotinin has a similar antiinflammatory effect to that of methylprednisolone in blunting cardiopulmonary bypass-induced systemic tumor necrosis factor-alpha release and neutrophil integrin CD11b upregulation |
13,616 | 21,248,514 | In this meta- analysis , the use of albumin-containing solutions for the resuscitation of patients with sepsis was associated with lower mortality compared with other fluid resuscitation regimens . | OBJECTIVE To assess whether resuscitation with albumin-containing solutions , compared with other fluids , is associated with lower mortality in patients with sepsis . | Objective To determine whether outcomes of resuscitation with albumin or saline in the intensive care unit depend on patients ' baseline serum albumin concentration . Design Analysis of data from a double blind , r and omised controlled trial . Setting Intensive care units of 16 hospitals in Australia and New Zeal and . Participants 6045 participants in the saline versus albumin fluid evaluation ( SAFE ) study . Interventions Fluid resuscitation with 4 % albumin or saline in patients with a baseline serum albumin concentration of 25 g/l or less or more than 25 g/l . Main outcome measures Primary outcome was all cause mortality at 28 days . Secondary outcomes were length of stay in the intensive care unit , length of stay in hospital , duration of renal replacement therapy , and duration of mechanical ventilation . Main results The odds ratios for death for albumin compared with saline for patients with a baseline serum albumin concentration of 25 g/l or less and more than 25 g/l were 0.87 and 1.09 , respectively ( ratio of odds ratios 0.80 , 95 % confidence interval 0.63 to 1.02 ) ; P=0.08 for heterogeneity . No significant interaction was found between baseline serum albumin concentration as a continuous variable and the effect of albumin and saline on mortality . No consistent interaction was found between baseline serum albumin concentration and treatment effects on length of stay in the intensive care unit , length of hospital stay , duration of renal replacement therapy , or duration of mechanical ventilation . Conclusion The outcomes of resuscitation with albumin and saline are similar irrespective of patients ' baseline serum albumin concentration . Trial registration IS RCT N76588266 Objective Both albumin and synthetic colloids such as hydroxyethyl starch ( HES ) solution are used to optimize hemodynamics in the critically ill . The influence of different long-term infusion regimes on platelet function was studied . Design Prospect i ve , r and omized study . Setting Clinical investigation on a university hospital surgical intensive care unit . Patients Twenty-eight consecutive trauma patients ( injury severity score>15 points ) and 28 consecutive nontraumatized surgical patients with sepsis . Interventions The patients received either 20 % human albumin ( HA trauma , n=14 ; HA sepsis , n=14 ) or 10 % low-molecular-weight HES solution HES 200/0.5 ( HES trauma , n=14 ; HES sepsis;n=14 ) for 5 days to maintain central venous pressure and /or pulmonary capillary wedge pressure between 12 and 16 mmHg . Measurements and results Platelet function was assessed by aggregometry ( = turbidimetric technique ) using adenosine diphosphate 2.0 μmol/l , collagen 4 μl/ml , and epinephrine 25 μmol/l as inductors . Arterial blood was sample d on the day of admission or the day of diagnosis of sepsis ( = baseline value ) and over the next 5 days . St and ard coagulation parameters ( antithrombin III , fibrinogen , partial thromboplastin time ) were also measured . Total use of HES by the 5th day totalled 4870±990 ml in the trauma and 3260±790 ml in the sepsis patients ( HA trauma : 1850±380 ml ; HA sepsis : 1790±400 ml ) . Maximum platelet aggregation decreased significantly during the first 2–3 days after baseline in all groups . At the end of the investigation period , platelet aggregation variables had recovered and reached ( or even exceeded ) baseline values . Within the entire investigation period , the course of platelet aggregation variables did not differ significantly between HA and HES-treated patients irrespective of whether they were trauma or sepsis patients . Conclusions Alterations in hemostasis may occur for several reasons in the critically ill . Human albumin is the preferred first-line volume therapy in patients at risk for coagulation disorders . With respect to platelet function , volume replacement with ( lower-priced ) low-molecular-weight HES solutions can be recommended in this situation without any risk BACKGROUND It remains uncertain whether the choice of resuscitation fluid for patients in intensive care units ( ICUs ) affects survival . We conducted a multicenter , r and omized , double-blind trial to compare the effect of fluid resuscitation with albumin or saline on mortality in a heterogeneous population of patients in the ICU . METHODS We r and omly assigned patients who had been admitted to the ICU to receive either 4 percent albumin or normal saline for intravascular-fluid resuscitation during the next 28 days . The primary outcome measure was death from any cause during the 28-day period after r and omization . RESULTS Of the 6997 patients who underwent r and omization , 3497 were assigned to receive albumin and 3500 to receive saline ; the two groups had similar baseline characteristics . There were 726 deaths in the albumin group , as compared with 729 deaths in the saline group ( relative risk of death , 0.99 ; 95 percent confidence interval , 0.91 to 1.09 ; P=0.87 ) . The proportion of patients with new single-organ and multiple-organ failure was similar in the two groups ( P=0.85 ) . There were no significant differences between the groups in the mean ( + /-SD ) numbers of days spent in the ICU ( 6.5+/-6.6 in the albumin group and 6.2+/-6.2 in the saline group , P=0.44 ) , days spent in the hospital ( 15.3+/-9.6 and 15.6+/-9.6 , respectively ; P=0.30 ) , days of mechanical ventilation ( 4.5+/-6.1 and 4.3+/-5.7 , respectively ; P=0.74 ) , or days of renal-replacement therapy ( 0.5+/-2.3 and 0.4+/-2.0 , respectively ; P=0.41 ) . CONCLUSIONS In patients in the ICU , use of either 4 percent albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days BACKGROUND Baseline data collected on each patient at r and omisation in controlled clinical trials can be used to describe the population of patients , to assess comparability of treatment groups , to achieve balanced r and omisation , to adjust treatment comparisons for prognostic factors , and to undertake subgroup analyses . We assessed the extent and quality of such practice s in major clinical trial reports . METHODS A sample of 50 consecutive clinical -trial reports was obtained from four major medical journals during July to September , 1997 . We tabulated the detailed information on uses of baseline data by use of a st and ard form . FINDINGS Most trials presented baseline comparability in a table . These tables were often unduly large , and about half the trials inappropriately used significance tests for baseline comparison . Methods of r and omisation , including possible stratification , were often poorly described . There was little consistency over whether to use covariate adjustment and the criteria for selecting baseline factors for which to adjust were often unclear . Most trials emphasised the simple unadjusted results and covariate adjustment usually made negligible difference . Two-thirds of the reports presented subgroup findings , but mostly without appropriate statistical tests for interaction . Many reports put too much emphasis on subgroup analyses that commonly lacked statistical power . INTERPRETATION Clinical trials need a predefined statistical analysis plan for uses of baseline data , especially covariate-adjusted analyses and subgroup analyses . Investigators and journals need to adopt improved st and ards of statistical reporting , and exercise caution when drawing conclusions from subgroup findings Symptomatic severe malarial anaemia ( SMA ) has a high fatality rate of 30–40 % ; most deaths occur in children awaiting blood transfusion . Blood transfusion services in most of Africa are not capable of delivering adequate supplies of safe blood in a timely manner to critically ill children with SMA . Contrary to widely held belief , hypovolaemia , rather than heart failure , has emerged as a common complication in such children . We examined the safety of pre‐transfusion management ( PTM ) by volume expansion , aim ed at stabilizing children and obviating the urgency for blood transfusion . Kenyan children with severe falciparum anaemia ( haemoglobin < 5 g/dl ) and respiratory distress were r and omly assigned to 20 ml/kg of 4·5 % albumin or 0·9 % saline or maintenance only ( control ) while awaiting blood transfusion . PTM was apparently safe since it did not lead to the development of pulmonary oedema or other adverse events . There was no significant difference in the primary outcome [ mean percentage reduction in base excess between admission and 8 h ( 95 % confidence interval ) ] between the control group 42 % ( 19–66 % ) albumin group 44 % ( 32–57 % ) and saline group 36 % ( 16–57 % ) ; adjusted analysis of variance F = 0·31 , P = 0·7 . However , the number of children requiring emergency interventions was significantly greater in the control group , four of 18 ( 22 % ) than the saline group 0 of 20 ( P = 0·03 ) . We have established the safety of this PTM in children with SMA whilst awaiting blood transfusion at a hospital with an adequate blood‐banking program . The impact on mortality should be assessed where blood transfusion services are unable to supply emergency transfusions BACKGROUND / AIMS Recent studies demonstrated that extravascular lung water ( EVLW ) is a reliable and independent marker for outcome . The primary therapeutically goal in critically ill patients is to resuscitate and retain adequate organ perfusion by fluid administration , where is necessary to achieve adequate intravascular filling , but avoid initiation of pulmonary edema . METHODOLOGY Patients with severe sepsis were r and omly allocated to a group treated with 20 % Albumin 100 ml every 12 hours ( ALB ; n = 30 ) or with 6 % hydroxyethylstarch 130/0 , 4 250 ml every 6 hours ( HES ; n = 26 ) . Both treatments were completed by crystalloids or norephinephrin as necessary . We analyzed amount of developed EVLW , and relation with mortality , PaO2/FiO2 and alveolo-arterial oxygen difference . RESULTS We observed significantly greater decrease of EVLW when compared with baseline during whole monitored period of 72 hours in ALB group in contrast to HES patients ( p < 0.05 ) . Despite no significant changes of EVLW in HES group , we noted improve of PaO2/FiO2 and AaDO2 in both groups . We did not observed significant difference in mortality . CONCLUSION The present study results show can summarize that albumin reduces in a higher amount and earlier the extravascular lung water than HES , but this reduction was not associated with improvement of oxygenation functions , which was better in HES group BACKGROUND Metabolic acidosis is the best predictor of death in children with severe falciparum malaria ; however , its treatment presents a therapeutic dilemma , because acidosis and hypovolemia may coexist with coma , which can be associated with elevated intracranial pressure . We postulated that volume resuscitation with albumin might correct acidosis and hypovolemia with a lower risk of precipitating cerebral edema than crystalloid . In an open-label , r and omized , controlled trial , we compared the safety of resuscitation with albumin to saline in Kenyan children with severe malaria . METHODS We r and omly assigned children with severe malaria and metabolic acidosis ( base deficit , > 8 mmol/L ) to receive fluid resuscitation with either 4.5 % albumin or normal saline . A control ( maintenance only ) group was only included for patients with a base deficit of < 15 mmol/L. The primary outcome measure was the percentage reduction in base deficit at 8 h. Secondary end points included death , the requirement for rescue therapies , and neurological sequelae in survivors . RESULTS Of 150 children recruited for the trial , 61 received saline , 56 received albumin , and 33 served as control subjects . There was no significant difference in the resolution of acidosis between the groups ; however , the mortality rate was significantly lower among patients who received albumin ( 3.6 % [ 2 of 56 patients ] ) than among those who received saline ( 18 % [ 11 of 61 ] ; relative risk , 5.5 ; 95 % confidence interval , 1.2 - 24.8 ; P=.013 ) . CONCLUSIONS In high-risk children with severe malaria and acidosis , fluid resuscitation with albumin may reduce mortality . Our study design did not enable us to determine whether saline administration is preferable to fluid restriction or whether saline administration is actually hazardous . Further studies are needed to confirm our findings before definitive treatment recommendations can be made Various vasoactive substances are involved in the regulation of the macro- and microcirculation . We have investigated if these regulators change during long-term volume therapy with human albumin ( HA ) or hydroxyethylstarch solution ( HES ) in trauma and sepsis patients . To maintain pulmonary capillary wedge pressure ( PCWP ) at 10 - 15 mm Hg , either 20 % HA ( HA-trauma , n = 14 ; HA-sepsis , n = 14 ) or 10 % low-molecular weight HES solution ( HES-trauma , n = 14 ; HES-sepsis , n = 14 ) were infused for 5 days , otherwise patient management did not differ between the two groups ( trauma/sepsis ) . Mean arterial pressure ( MAP ) , heart rate ( HR ) , PCWP and cardiac index ( CI ) were monitored in all patients . Liver function was assessed using the monoethylglycinexylidide ( MEGX ) test , and gastric intramucosal pH ( pHi ) was monitored by tonometry to assess splanchnic perfusion . Plasma concentrations of vasopressin , endothelin-1 , adrenaline , noradrenaline , atrial natriuretic peptide and 6-keto-prostagl and in F1 alpha were measured from arterial blood sample s. All measurements were carried out on the day of admission to the intensive care unit ( trauma patients ) or on diagnosis of sepsis , and daily over the next 5 days at 12:00 . MAP , HR and PCWP did not differ between the corresponding subgroups ( trauma/sepsis ) . Cl increased significantly more in the HES than in the HA groups . pHi and MEGX plasma concentrations did not differ in the trauma patients throughout the study . Both were lower than normal in the sepsis groups and increased more markedly in the HES than in the albumin-treated patients ( P < 0.05 ) . In the trauma patients , concentrations of all vasoactive regulators were very similar in both groups . In both sepsis groups , vasopressors ( vasopressin , endothelin-1 , noradrenaline and adrenaline ) were significantly increased above normal at baseline and decreased more markedly in HES than in HA patients . Concentrations of atrial natriuretic peptide increased only in the HA patients ( from 159 ( SD 31 ) to 215 ( 38 ) pg ml-1 on day 2 ) . Plasma concentrations of 6-keto-prostagl and in F1 alpha decreased significantly only in the HES sepsis patients ( from 112 ( 25 ) to 47 ( 15 ) pg ml-1 ) Summary Objective To determine whether intravenous infusion of either human albumin or hydroxyethylstarch ( HES ) in hypo-albuminemic critically ill may lead to an increase in colloid osmotic pressure and to a better clinical outcome , i.e. lower mortality and fewer complications , compared to fluid replacement with normal saline Design Prospect i ve , r and omized controlled clinical trial during 72 hours in 61 consecutively admitted severely ill patients . R and omisation took place by sealed envelope , kept outside of the hospital . Setting Intensive care unit of the Twenteborg Hospital , Almelo , The Netherl and s . SubjectsSixty-three severely ill , hypo-albuminemic patients were selected ; 27 patients had severe sepsis and 36 were post-surgical patients with SIRS . Two patients died shortly after r and omization , 15 patients received human albumin , 15 HES 500 and 15 HES 1000 ml , and 16 saline . Interventions The patients were r and omized to receive 300 ml human albumin ( 20 % ) per day , or 1000 ml normal saline per day , or 500 ml or 1000 ml HES per day , all for 72 hours . Main outcome measures The primary outcome was plasma colloid osmotic pressure ( COP ) . Secondary end-points were fluid balance and the development of pulmonary edema . Results Administration of human albumin was effective in raising COP ( P<0.001 on day 2 and day 3 , compared to saline and HES ) . Neither fluid balances nor the development of peripheral or pulmonary edema were different between the groups . Mortality as well as length of stay at ICU were slightly higher in the group receiving human albumin although not statistically significant . Conclusion Raising colloid osmotic pressure with human albumin in hypoalbuminemic patients is not associated with improvement of the clinical STUDY OBJECTIVE To compare the hemodynamic effects of two different concentrations of pentastarch hydroxyethyl starch ( HES ; 200/0.5 ) solutions with a 4 % human albumin solution for fluid resuscitation . DESIGN Open-label , r and omized , controlled study . SETTING Medical-surgical intensive care unit . PATIENTS 34 consecutive , hemodynamically stable , adult patients with sepsis and suspected hypovolemia . INTERVENTIONS Patients received a 400 mL infusion of either 10 % HES ( n = 11 ) , 6 % HES ( n = 10 ) , or 4 % albumin ( n = 13 ) over 40 minutes . MEASUREMENTS Hemodynamic and blood data were collected 40 , 70 , 100 , and 160 minutes after the start of the fluid challenge . MAIN RESULTS Cardiac index , stroke volume index , and left ventricular stroke work index increased more in the 10 % HES group than the 6 % HES or albumin groups ( P < 0.05 ) . Oxygen delivery increased only in the 10 % HES group . A decrease in hemoglobin concentration occurred in all three groups but was greatest in the 10 % HES group . CONCLUSIONS HES is as effective as albumin for volume resuscitation in septic patients Forty-six patients with severe pulmonary insufficiency were prospect ively studied to compare the effects of resuscitation with either crystalloid or colloid . By r and om number , 26 patients received RL and 20 patients received 5 per cent ALB to maintain hemodynamic stability . Groups were comparable with respect to the cause of pulmonary insufficiency , age and sex . For the duration of the study and at 48 hours , there was no statistically significant difference between groups with respect to the following : cardiac index , colloid osmotic pressure ( COP ) , pulmonary capillary wedge pressure ( PCWP ) , COP-PCWP gradient , right and left ventricular stroke work indices , and amount of constant positive airway pressure required for treatment . Both groups had a significant improvement in intrapulmonary shunt ( Qs/Qt ) after 24 hours of treatment . The Qs/Qt in the ALB group was significantly lower than the RL group at the termination of the study , but this did not affect outcome . The RL group required more fluid than the ALB group , but the difference was not statistically significant . No clinical advantage was found for either solution in this study OBJECTIVE The ability to accurately identify articles about therapy in large bibliographic data bases such as EMBASE is important for research ers and clinicians . Our study aim ed to develop optimal search strategies for detecting sound treatment studies in EMBASE in the year 2000 . METHODS H and search es of journals were compared with retrievals from EMBASE for c and i date search strategies . Six trained research assistants review ed fifty-five journals indexed in EMBASE and rated articles using purpose and quality indicators . C and i date search strategies were developed for identifying treatment articles and then tested , and the retrievals were compared with the h and - search data . The operating characteristics of the strategies were calculated . RESULTS Three thous and eight hundred fifty articles were original studies on treatment , of which 1,256 ( 32.6 % ) were method ologically sound . Combining search terms revealed a top performing strategy ( r and om:.tw . OR clinical trial:.mp . OR exp health care quality ) with sensitivity of 98.9 % and specificity of 72.0 % . Maximizing specificity , a top performing strategy ( double-blind:.mp . OR placebo:.tw . OR blind : .tw . ) achieved a value over 96.0 % , but with compromised sensitivity at 51.7 % . A 3-term strategy achieved the best optimization of sensitivity and specificity ( r and om:.tw . OR placebo:.mp . OR double-blind:.tw . ) , with both these values over 92.0 % . CONCLUSION Search strategies can achieve high performance for retrieving sound treatment studies in EMBASE Sufficient intravascular fluid therapy is of major importance in the treatment of the critically ill patient . The present study assessed whether the cardiorespiratory response of long-term volume replacement with low-molecular weight ( LMW ) hydroxyethyl starch solution ( HES ) differs from that of human albumin ( HA ) . According to a r and omized sequence , 30 trauma patients ( injury severity score [ ISS ] between 15 and 30 ) and 30 sepsis patients ( secondary to major general surgery ) received either 10 % HES ( mean molecular weight 200,000 daltons ; HES trauma [ n = 15 ] , HES sepsis [ n = 15 ] ) or human albumin 20 % ( HA trauma [ n = 15 ] , HA sepsis [ n = 15 ] ) over 5 days to keep pulmonary capillary wedge pressure ( PCWP ) between 12 and 18 mm Hg . Cardiorespiratory variables were measured by a pulmonary artery catheter on the day of inclusion into the study and daily during the next 5 days . Gastric intramucosal pH ( pHi ) was measured by tonometry . Central venous pressure and PCWP were comparable within the subgroups ( trauma/sepsis ) throughout the entire study period . In the trauma patients , cardiac index ( CI ) , oxygen consumption index ( VO2 I ) , and oxygen delivery index ( DO ( 2 ) I ) , significantly increased only in the HES-treated patients . In the sepsis patients , CI , VO2 I , and DO2 I increased and remained higher than baseline only in the HES group ( P < 0.01 ) . Right ventricular ejection fraction ( RVEF ) was reduced ( < 40 % ) in the HA patients and increased only in the HES patients ( from 34 % + /- 4 % to 42 % + /- 3 % ; P < 0.05 ) . pHi remained normal ( > 7.35 ) in both trauma groups and in the HES-treated sepsis patients . In the HA sepsis group , pHi decreased ( < 7.20 ) within the study period ( 7.15 + /- 0.12 on Day 4 ) , indicating deteriorated splanchnic perfusion . We conclude that long-term intravascular fluid therapy with HA in traumatized and sepsis patients has no advantages in comparison to LMW-HES . In both groups , volume replacement with HES even result ed in improved systemic hemodynamics . Decrease in pHi in the sepsis patients was blunted by HES infusion indicating improved splanchnic perfusion by this regimen of volume therapy . ( Anesth Analg 1996;83:254 - 61 Twenty consecutive patients with severe sepsis were r and omized to fluid challenge with 5 % albumin or 10 % low MW hydroxyethyl starch ( pentastarch ) solutions . Fluid challenge was administered iv as 250 ml of test colloid every 15 min until the pulmonary artery wedge pressure ( WP ) was greater than or equal to 15 mm Hg or a maximum dose of 2000 ml was infused . Hemodynamic , respiratory , and coagulation profiles were measured before and after fluid infusion . The amount of colloid required to achieve a WP of 15 mm Hg was comparable between groups . Both colloid infusions result ed in similar increases in cardiac output , stroke output , and stroke work . The effect of fluid infusion with pentastarch on coagulation was not significantly different from albumin , although pentastarch was associated with a 45 % decrease in factor VIII : c . We conclude that pentastarch is equivalent to albumin for fluid resuscitation of patients with severe sepsis The endothelium plays an important role in the regulation of haemostasis by producing substances such as thrombomodulin ( TM ) . The influence of long-term volume replacement with different types of fluid on the TM-protein C-protein S system was investigated in a prospect i ve , r and omized study . Thirty trauma patients and 30 patients suffering from sepsis after major surgery received either 10 % low-molecular weight ( LMW ) hydroxyethylstarch solution ( HES-trauma , n = 15 ; HES-sepsis , n = 15 ) or 20 % human albumin ( HA-trauma , n = 15 ; HA-sepsis , n = 15 ) for 5 days to maintain central venous pressure ( CVP ) between 12 and 16 mm Hg . Plasma concentrations of TM , protein C , ( free ) protein S and thrombin-antithrombin ( TAT ) were measured in arterial blood sample s obtained on the day of admission to the intensive care unit or on the day of diagnosis of sepsis and over the next 5 days . There were no differences between HA- and HES-treated trauma patients . Protein C and protein S also did not differ between HA- and HES-treatments . At baseline , TM plasma concentrations were increased to > 40 micrograms litre-1 in both sepsis groups only . In the HA-sepsis group , TM increased significantly ( from 48.1 ( SD 13.9 ) to 68.4 ( 13.0 ) micrograms litre-1 ) , whereas it remained almost unchanged in the HES-sepsis group . In HES-sepsis patients , protein C ( from 51.0 ( 10.1 ) to 71.9 (8.9)% ) and protein S ( from 19.0 ( 6.0 ) to 40.8 (11.4)% ) increased significantly during the study , whereas both remained reduced in HA- patients . TAT ( indicating intravascular coagulation ) did not differ between the two fluid groups . We conclude that in trauma patients , the type of volume therapy had no influence on the TM-protein C-protein S system . In sepsis patients , volume therapy with HES was beneficial , whereas infusion of HA had no substantial positive effect on endothelial-associated coagulation Twenty-six consecutive patients in hypovolemic shock were r and omized to fluid challenge with 5 % albumin ( A ) , 6 % hetastarch ( H ) , or 0.9 % saline ( S ) solutions . Fluid challenge consisted of 250 ml of test fluid every 15 min until the pulmonary artery wedge pressure ( WP ) reached 15 mm Hg . Thereafter , WP was maintained at 15 mm Hg for an additional 24 h with infusions of the same test fluid . Vital signs , hemodynamic and respiratory variables , as well as arterial lactate and colloid osmotic pressure ( COP ) were monitored according to protocol . Chest x-rays were performed by st and ardized technique before fluid challenge and at 12 and 24 h of maintenance fluid therapy and were evaluated for evidence of pulmonary edema . Cardiac function and hemodynamic stability were restored by fluid challenge with A , H , and S. Two to 4 times the volume of S as A or H was required to achieve similar hemodynamic endpoints . COP was increased by fluid challenge with A or H but was markedly reduced by fluid challenge with S and throughout the 24-h maintenance period . Fluid challenge result ed in reductions in COP-WP gradient of 62 % in the A , 43 % in the H , and 125 % in the S groups . Resuscitation with S result ed in a significantly higher incidence of pulmonary edema ( 87.5 % ) than did resuscitation with A ( 22 % ) or H ( 22 % ) . Urine output was not different among the groups at any time during the study . We conclude that 6 % H performs as well as 5 % A as a resuscitative fluid and that resuscitation with either of these colloids is associated with a lower incidence of pulmonary edema than is resuscitation with 0.9 % The influence of four different kinds of intravascular volume replacement on platelet function was investigated in 60 patients undergoing elective aortocoronary bypass grafting using cardiopulmonary bypass ( CPB ) . In a r and omized sequence , high-molecular weight hydroxyethyl starch solution ( HMW-HES , mean molecular weight [ Mw ] 450,000 d ) , low-molecular weight HES ( LMW-HES , Mw 200,000 d ) , 3.5 % gelatin or 5 % albumin were infused preoperatively to double reduced filling pressure ( pulmonary capillary wedge pressure [ PCWP ] < 5 mm Hg ) . Fifteen untreated patients served as a control . Platelet function was assessed by aggregometry using turbidometric technique ( inductors : ADP , epinephrine , collagen ) . Maximum aggregation , maximum gradient of aggregation , and platelet volume were measured before , during , and after CPB until the first postoperative day . HMW-HES 840 + /- 90 mL , LMW 850 + /- 100 mL , gelatin 950 + /- 110 mL , and albumin 810 + /- 100 mL were given preoperatively . Maximum platelet aggregation ( ranging from -23 % to -44 % relative from baseline value ) and maximum gradient of platelet aggregation ( ranging from -26 % to -45 % relative from baseline values ) were reduced only in the HMW-HES patients . After CPB , aggregometry also was impaired most markedly in these patients . The other volume groups showed less reduction in platelet aggregation and were similar to the untreated control . On the first postoperative day , aggregation variables had returned almost to baseline in all patients . Platelet volume was the same among the groups within the investigation period . Postbypass blood loss was highest in the HMW-HES group ( 890 + /- 180 mL ) . There was significant ( P < 0.04 ) correlation in this group between blood loss and change in platelet aggregation . ( ABSTRACT TRUNCATED AT 250 WORDS Objective : There are still several concerns about the extensive and prolonged use of hydroxyethylstarch solution ( HES ) in critically ill patients . The effects of volume replacement with HES over 5 days on hemodynamics , laboratory data , and organ function were compared with volume therapy using human albumin ( HA ) . Design : Prospect i ve , r and omized study . Setting : Clinical investigations on a surgical intensive care unit ( ICU ) of a university hospital . Patients : 150 traumatized patients ( injury severity score > 15 ) and 150 postoperative patients with sepsis were analyzed . Interventions : Either 10 % low-molecular weight HES ( HES-trauma , n = 75 ; HES-sepsis , n = 75 ) or 20 % HA ( HA-trauma , n = 75 ; HA-sepsis , n = 75 ) was given for 5 days to maintain the pulmonary capillary wedge pressure ( PCWP ) between 12 and 15 torr . The entire management of therapy of the patients was performed by physicians who were not involved in the study and blinded to the infusion regimen . Measurements and results : In addition to extensive cardiorespiratory monitoring , several routine laboratory parameters for assessing pulmonary , renal , hepatic , and coagulation function were analyzed from arterial blood sample s on the day of admission to the ICU and on the day of sepsis diagnosis , respectively ( “ baseline ” value ) and daily over the following 5 days . Mortality during and after the study did not differ significantly between the infusion groups . There were also no differences between the incidence of pulmonary , renal , or hepatic failure in the two subgroups . Mean arterial pressure , heart rate , and PCWP were similar in both subgroups , whereas cardiac index , oxygen delivery index , oxygen consumption index , and the ratio between the partial pressure of oxygen in arterial blood and fractional inspired oxygen were higher in the HES- than in the HA-treated groups . St and ard coagulation parameters did not differ , albumin concentration increased significantly in both HA groups , and lactate concentrations decreased only in the HES-sepsis patients ( from 2.8 ± 0.5 to 1.5 ± 0.4 mg/dl ) . Volume replacement using albumin was significantly ( p < 0.001 ) more costly than therapy with HES . Conclusions : Volume therapy with 10 % HES for 5 days in the ICU patient showed no disadvantages compared with an infusion regimen using 20 % albumin . Volume replacement using HES may even be associated with improved hemodynamics . HES appears to be a valuable and significantly cheaper alternative to albumin – even for prolonged volume therapy in the critically ill patient Objective : To compare crystalloid and colloid fluids in their effect on pulmonary edema in hypovolemic septic and nonseptic patients with or at risk for acute lung injury/acute respiratory distress syndrome . We hypothesized that 1 ) crystalloid loading results in more edema formation than colloid loading and 2 ) the differences among the types of fluid decreases at high permeability . Design , Setting , and Patients : Prospect i ve r and omized clinical trial on the effect of fluids in 24 septic and 24 nonseptic mechanically ventilated patients with clinical hypovolemia . Interventions : Patients were assigned to NaCl 0.9 % , gelatin 4 % , hydroxyethyl starch 6 % , or albumin 5 % loading for 90 minutes according to changes in filling pressures . Measurements and Main Results : Twenty-three septic and 10 nonseptic patients had acute lung injury/acute respiratory distress syndrome ( p < 0.001 ) . Septic patients had greater pulmonary capillary permeability , edema , and severity of lung injury than nonseptic patients ( p < 0.01 ) , as measured by the pulmonary leak index ( PLI ) for 67Gallium-labeled transferrin , extravascular lung water ( EVLW ) , and lung injury score ( LIS ) , respectively . Colloids increased plasma volume , cardiac index , and central venous pressure ( CVP ) more than crystalloids ( p < 0.05 ) , although more crystalloids were infused ( p < 0.05 ) . Colloid osmotic pressure ( COP ) increased in colloid and decreased in crystalloid groups ( p < 0.001 ) . Irrespective of fluid type or underlying disease , the pulmonary leak index increased by median 5 % ( p < 0.05 ) . Regardless of fluid type or underlying disease , EVLW and LIS did not change during fluid loading and EVLW related to COP-CVP ( rs = −.40 , p < 0.01 ) . Conclusions : Pulmonary edema and LIS are not affected by the type of fluid loading in the steep part of the cardiac function curve in both septic and nonseptic patients . Then , pulmonary capillary permeability may be a smaller determinant of pulmonary edema than COP and CVP . Safety factors may have prevented edema during a small filtration pressure-induced rise in pulmonary protein and thus fluid transport |
13,617 | 17,443,536 | In 11 RCTs amongst 1389 people , there was no significant difference in need for recatheterisation , although recatheterisation after removal at night was more likely to be during working hours .
AUTHORS ' CONCLUSIONS There is suggestive but inconclusive evidence of a benefit from midnight removal of the indwelling urethral catheter .
The evidence also suggests shorter hospital stay after early rather than delayed catheter removal but the effects on other outcomes are unclear .
There is little evidence on which to judge other aspects of management , such as catheter clamping | BACKGROUND Approximately 15 % to 25 % of all hospitalised patients have indwelling urethral catheters , mainly to assist clinicians to accurately monitor urine output during acute illness or following surgery , to treat urinary retention , and for investigative purpose s. OBJECTIVES The objective of this review was to determine the best strategies for the removal of catheters from patients with a short-term indwelling urethral catheter .
The main outcome of interest was the number of patients who required recatheterisation following removal of indwelling urethral catheter . | OBJECTIVE To investigate whether early catheter removal following transurethral prostatectomy ( TURP ) is safe and whether it has any effect on the length of hospital stay . PATIENTS AND METHODS Following transurethral prostatectomy 59 patients were r and omized into one of two groups : those whose catheter was removed on day 1 after surgery and those whose catheter was removed on day 2 . The incidence of complications and the duration of post-operative hospital stay were assessed . RESULTS Catheter removal on day 1 led to a significantly shorter post-operative hospital stay ( 2.3 days versus 3.3 days ) and did not incur a higher incidence of complications . CONCLUSIONS Removal of the catheter on the first day following TURP is safe in selected patients and leads to a shorter post-operative hospital stay In the fields of both nursing and medicine there is a dearth of published literature on the optimum time to remove indwelling urinary catheters ( IDCs ) following urological surgery . Tradition seems to be in favour of removing IDCs at 0600 hours despite a lack of evidence to support this practice . This study was undertaken to determine whether midnight removal of IDCs result ed in patients ' resuming normal voiding patterns . A prospect i ve clinical trial was conducted to determine the impact midnight removal of urinary catheters would have on the patients ' voiding pattern , and subsequent discharge from hospital . One hundred and sixty patients were entered into the study . The patients were allocated at r and om to have their urinary catheter removed either at midnight or at 0600 hours . Patients who had their catheters removed at midnight passed a greater volume of urine with both their first ( 268 ml compared with 177 ml ; P<0.0001 ) and second voids ( 322 ml compared with 195 ml ; P<0.0001 ) than their counterparts in the 0600 group . This permitted earlier discharge from hospital . The results reported in this study support the findings of earlier research that midnight removal of IDC leads to an earlier resumption of normal voiding patterns , permits earlier discharge from hospital and appears to reduce patients ' anxiety . The recommendation from this study is that there should be a change in hospital policy so that the majority of IDCs are removed at midnight Patients who had undergone bladder neck surgery were r and omized to having their urethral catheters removed either early in the morning or late at night . There was no difference in the incidence of urinary retention between these two groups of patients . However , patients who presented with acute urinary retention had a higher incidence of postoperative urinary retention . This study suggests that a urethral catheter may be safely removed in the evening without increasing the risk of urinary retention . There also seems to be no greater chance of the patient having to be recatheterized at an unsocial hour OBJECTIVE In-dwelling catheters for 24 hours after operation are used routinely in gynecologic surgery . This study assesses whether the immediate removal of an in-dwelling catheter after the operation affects the rate of recatheterization , febrile morbidity , symptomatic urinary tract infections , or subjective pain assessment s. STUDY DESIGN This study was a prospect i ve r and omized controlled trial comprised of 250 women who underwent hysterectomy and who did not require bladder suspension or strict fluid treatment . The in-dwelling catheter was removed either immediately after the operation or on the first day after the operation . The association between clinical variables and the length of catheterization were assessed by chi-squared analysis . RESULTS Patients were assigned r and omly into 2 groups , with no significant differences in the outcomes , only in the perception of pain . Clinical events included fever ( > /=38.5 degrees C ) that occurred in 6 patients in the in-dwelling catheter group compared with 5 patients in the early removal group ( P=.01 ) , symptomatic urinary tract infections in 3 patients in both groups ( P=.99 ) , and recatheterization in 3 patients in the in-dwelling catheter group compared with 5 patients in the early removal group ( P=.17 ) . Subjectively , patients in the early removal group reported significantly less pain than did the in-dwelling group ( P<.001 ) . CONCLUSION The early removal of in-dwelling catheters after operation was not associated with an increased rate of febrile events , urinary tract infections , or need for recatheterization . In addition , subjective pain assessment was significantly less in the early removal group . Early removal of an in-dwelling catheter immediately after operation is not associated with adverse events OBJECTIVES Postoperative urethral catheter drainage after radical prostatectomy is bothersome to patients . A pilot study was initiated to determine if urethral catheter removal prior to hospital discharge is feasible . METHODS Thirty-three consecutive men undergoing radical retropubic prostatectomy were prospect ively studied and followed for a minimum of 6 months ( mean , 8.5 ) . Postoperative cystography was utilized to direct early catheter removal . RESULTS Of 33 patients , 27 ( 82 % ) underwent successful catheter removal at a mean of 4.2 postoperative days . No patient experienced urinary retention , urinoma development , pelvic abscess , or anastomotic stricture . Urinary continence is excellent ( no pads required ) in 70 % and good ( stress incontinence requiring 1 to 2 pads/24 hours ) in 18 % of patients at last follow-up . CONCLUSIONS Following radical prostatectomy , early catheter removal prior to hospital discharge is feasible . Early results suggest no deleterious consequences . Prospect i ve monitoring of more patients is needed to determine if this practice is widely applicable The interval before removal of the catheter used in prostatic transurethral surgery depends to a great extent on the surgeon , with a frequently empirical orientation . We conducted a prospect i ve , r and omized and controlled study of 213 patients who underwent transurethral surgery for benign prostatic hyperplasia . The catheter was removed systematic ally 24 hours after transurethral incision and 48 hours after transurethral resection of the prostate ( group 1 - 52 and 54 patients , respectively ) or the catheterization interval was determined by each surgeon in accordance with the usual criteria ( group 2 - 52 and 55 patients , respectively ) . No statistically significant differences were noted between these 2 groups in regard to complications . We conclude that systematic removal of the catheter at the aforementioned periods is cost-effective , safe and comfortable for the patient A total of 60 patients with acute urinary retention were studied to establish whether a trial without a catheter was justified and to identify subgroups of patients most likely to benefit from this practice . The patients were r and omly allocated to 3 groups ; the catheters were removed either immediately after the bladder was emptied , or 24 or 48 h later ; 17 patients urinated satisfactorily after removal of the catheter . Re-establishment of micturition was not associated with the length of history or severity of symptoms of prostatism , with age or the presence of urinary tract infection . The mean retained volume of urine in patients with a satisfactory result was 786 ml and 1069 ml in the failures . Of the 34 patients with retained volumes of less than 900 ml , 15 were successful in re-establishing micturition compared with 2 of 26 of those with retained volumes greater than 900 ml . The time of catheter removal was not important . The 17 successful patients were review ed 6 months later . None reported further urinary retention ; 6 had required prostatectomy for severe symptoms , 6 had minor symptoms and 5 were symptomless . It was concluded that a trial without a catheter is worthwhile , since 11 of 60 patients had not required surgery , but it should be avoided in patients with a residual volume exceeding 900 ml This study shows that removal of urinary catheters at midnight has several advantages over removal at 6 AM . The midnight group had a significantly greater initial voided volume and a longer time to first void than the equivalent 6 AM group . Advantages to midnight catheter removal also exist for nursing staff . Midnight tends to be less busy on the nursing unit compared with 6 AM , thus making it a preferable time for performance of routine tasks . Catheter removal at midnight also allows for convenient observation of patient voiding and assessment earlier in the day . This means that any necessary intervention can take place during working hours when more staff are on duty . There is also the potential for earlier discharge , with economic benefits related to shorter bed stay and more efficient discharge planning . We believe midnight catheter removal offers considerable benefits over the traditional 6 AM time on both general and urology units BACKGROUND Voiding dysfunction is frequently observed after rectal resection and justifies urinary drainage . However , there is no agreement about the optimal duration of this postoperative drainage . The aim of this controlled trial was to compare 1 versus 5 days of transurethral catheterization after rectal resection , with special reference to urinary tract infection and bladder retention . METHODS One hundred twenty-six patients undergoing rectal resection were included in a prospect i ve r and omized study design ed to compare the results for patients undergoing 1 day of transurethral catheterization after rectal resection ( 1-day group ) with those for patients undergoing 5 days ' catheterization ( 5-day group ) . RESULTS Patients were r and omly assigned to the 1-day and 5-day groups ( n = 64 and 62 , respectively ) . Clinical findings and surgical procedures were comparable in both groups . Acute urinary retention occurred in 16 patients ( 25 % ) in the 1-day group versus 6 ( 10 % ) in the 5-day group ( P < .05 ) . Urinary tract infection was observed in 13 of 64 patients ( 20 % ) in the 1-day group versus 26 of 62 ( 42 % ) in the 5-day group ( P < .01 ) . Multivariate analysis revealed that after 1 day of catheterization carcinoma of the low rectum and lymph node metastasis were significant risk factors for acute urinary retention ( P < .05 for both factors ) . After selection of patients without low rectum carcinoma , the acute urinary retention rate was comparable in both groups ( 14 % in the 1-day group versus 7 % in the 5-day group ) , but the urinary tract infection rate was significantly lower in the 1-day group versus the 5-day group ( 14 % vs 40 , P < .01 ) . CONCLUSIONS Our controlled study showed that after rectal resection 1 day of urinary drainage can be recommended for most patients . Five-day drainage should be reserved for patients with low rectal carcinoma OBJECTIVES Shortening hospital stay yet not compromising quality of care can result in significant cost savings for children undergoing surgical correction of vesicoureteral reflux . METHODS We review ed the medical records of pediatric patients who underwent ureteroneocystostomy between July 1995 and July 1997 . A total of 43 patients , aged 0.2 to 18 years ( mean 5.2 ) who all received identical postoperative care , except for their pain management and the time of bladder catheter removal , were included in the study . Twenty-three were treated with intravenous ketorolac tromethamine ( Toradol ) ; the remaining 20 received narcotics in the immediate postoperative period . The bladder catheter was removed in less than 24 hours in 22 children , and greater than 24 hours in 21 . RESULTS Patients who received ketorolac tromethamine for postoperative analgesia had on average shorter hospital length of stays than those treated with narcotics ( 1.4 versus 2.5 days , respectively ; P < 0.001 ) . The average stay for children whose bladder catheter was removed within 24 hours postoperatively was significantly shorter than those whose catheter was removed after a 24-hour period ( 1.4 versus 2.4 days , respectively ; P < 0.001 ) . There were no reimplantation failures . One child presented 2 days postoperatively with anemia , which did not require transfusion . CONCLUSIONS Our review demonstrates that ketorolac tromethamine can be used safely and effectively in children for immediate postoperative analgesia , and that its proper use combined with early catheter removal can reduce the length of hospital stay for pediatric patients undergoing ureteroneocystostomy PURPOSE We prospect ively tested the safety of routine removal of the catheter as early as 2 to 4 days after laparoscopic radical prostatectomy . MATERIAL S AND METHODS Between March 1998 and March 2001 , 228 patients underwent laparoscopic radical prostatectomy for clinical ly organ confined prostate cancer . The last 113 consecutive patients were included in a prospect i ve study according to gravitational cystography performed 2 to 4 days postoperatively . If no leak was seen the catheter was removed . If a leak was apparent the catheter was left indwelling for another 6 days and cystography was repeated . RESULTS Cystography 2 to 4 days postoperatively showed an anastomosis without a leak in 96 ( 84.9 % ) patients who subsequently had the catheters removed . There were 28 patients who had the catheter removed on postoperative day 2 , 28 day 3 and 40 day 4 . In 17 ( 15.1 % ) patients an anastomotic leak was observed , and the catheter was not removed at that time . Of the 96 patients in whom the catheter was removed early 10 ( 10.4 % ) had urinary retention that necessitated re-catheterization . This procedure was performed without the need for cystoscopy . After the catheter was removed all patients were able to void 24 hours later . Median followup was 7 months ( range 1 to 15 ) and showed continence rates greater than 93 % . No anastomotic stricture , pelvic abscess or urinoma developed in any patient . CONCLUSIONS Patients who undergo laparoscopic radical prostatectomy can have the catheter safely removed 2 to 4 days postoperatively without a higher risk of incontinence , stricture or leak related problems OBJECTIVE To compare three methods for a trial of micturition ( TOM ) ( the midnight removal of the catheter , dawn removal , and a new infusion method ) in a r and omized prospect i ve study . PATIENTS AND METHODS A total of 118 consecutive patients who had undergone transurethral resection of the prostate ( TURP ) or bladder neck incision ( BNI ) underwent TOM by one of the three methods . In the infusion method , the bladder was filled at a fast-drip rate via the catheter from a bag of normal saline connected by an intravenous supply set . The catheter was then removed , the patient voided and the volume was measured . From the volume of saline remaining , it was possible to calculate the residual volume in the patient . RESULTS The infusion TOM took a mean 13 h less than the other two methods , which were statistically indistinguishable . CONCLUSION The infusion TOM is safe and simple , is quick to carry out and can be performed at any time . It establishes the completeness of bladder emptying , which helps in the assessment of voiding Objective To examine the effect of bladder infusion before catheter removal on patients ' readiness for discharge and the day of discharge after transurethral resection of the prostate ( TURP ) Catheterization is considered to be a m and atory procedure for adequate bladder drainage following an anti-incontinence operation until the recovery of normal voiding function occurs . We conducted this prospect i ve study to challenge this practice . A total of 86 patients with genuine stress incontinence who underwent a modified Burch coplosuspension were r and omized into two groups based on the day of operation . The study group consisted of 42 patients who had the transurethral Foley catheter removed postoperatively the next morning ( Group A ) . The control group was composed of 43 patients who had the transurethral indwelling catheter left in place until the fifth postoperative day ( Group B ) . The percentages of immediate voiding difficulties in Groups A and B were 7.1 % and 0 % , respectively ( P > 0.05 ) . The postoperative urinary tract infection rates of Groups A and B were 16.6 % and 23.3 % , respectively ( P > 0.05 ) . The success rates of our patients were not compromised after our modified operative procedures ( 78.6 % with dry results and 19.0 % with improved symptoms in Group A vs. 74.4 % with dry results and 20.9 % with improved symptoms in Group B , P > 0.05 ) . Our results imply that it is not necessary that an indwelling catheter , for bladder drainage , be left in place until the fifth postoperative day to prevent immediate voiding difficulties PURPOSE We tested the hypothesis that early catheter removal may be accomplished safely after radical prostatectomy . MATERIAL S AND METHODS Cystography on postoperative day 4 or 5 in 42 of 67 consecutive patients who underwent radical retropubic prostatectomy revealed no extravasation in 30 and the urethral catheter was removed ( group 1 ) . The control group included 25 patients who did not undergo cystography , and the catheter was removed 14 days postoperatively ( group 2 ) . RESULTS Immediate and late continence was achieved in 14 ( 46.7 % ) and 25 ( 83.3 % ) cases in group 1 , and in 8 ( 32 % ) and 22 ( 88 % ) cases in group 2 , respectively ( p>0.05 ) . Catheterization was performed easily without any endoscopic or surgical procedure in 2 patients ( 6.7 % ) in group 1 who presented in urinary retention after catheter removal . Wound infection and pelvic abscess developed in 1 case ( 3.3 % ) . There were no late complications . In group 2 urinary retention developed in 1 patient ( 4 % ) , wound infection in 1 ( 4 % ) and hematuria in 1 ( 4 % ) . Two patients ( 8 % ) had late vesical neck contracture at 4 and 10 months , respectively , which required urethrotomy in 1 . In 1 patient ( 4 % ) a stricture in the anterior urethra was dilated . CONCLUSIONS Our study shows that early catheter removal may be accomplished safely in most patients after radical retropubic prostatectomy , and was not associated with a higher complication rate This prospect i ve study was done to see if reducing transurethral Foley catheterization from 3 days to 1 would lead to fewer urinary tract infections without an increase in voiding problems . Ninety-one women undergoing retropubic surgery for stress urinary incontinence ( Burch or Marshall-Marchetti-Krantz ) were r and omized to either 1 or 3 days ' catheterization . Antibiotics were not used . Infection was diagnosed in 9 ( 20.0 % ) patients in the 1-day group and in 16 ( 34.8 % ) in the 3-day group . Delayed voiding occurred in 13 ( 28.9 % ) and 10 ( 21.7 % ) patients , respectively , and 5 ( 11.1 % ) and 3 ( 6.5 % ) , respectively , received a new catheter . The differences do not reach statistical significance . Therefore , catheter time may safely be reduced to 1 day . This may lead to fewer infections but also somewhat more voiding problems . If a transurethral catheter is to be used , on balance the two regimens are equivalent The post surgical urinary retention syndrome is a frequent problem after vaginal surgery . In many medical centers it is used a transurethral vesical drainage for three to five days with or without vesical reeducation to prevent it . In order to determine the importance of the time of drainage and vesical reeducation in the presence of this syndrome 106 patients su bmi tted to vaginal surgery were studied at r and om and prospect ively , in our service . Patients were distributed in three groups : the first one , with 37 women in which the drainage was withdrawn at 24 hours ; in the second group it was retired at 72 hours and in the third group the drainage was removed at 72 hours with previous vesical reeducation . The results show that those patients who were less time under vesical drainage presented a minor frequency of urinary retention after surgery ( 24.3 % vs 30.7 % and 43.7 % ) AIM The aim of the present study was to compare the effectiveness of a cholinergic drug , an alpha-blocker and combinations of the two for the treatment of underactive detrusor . METHODS One hundred and nineteen patients with underactive bladder were assigned to three groups : the cholinergic group , consisting of 40 patients taking bethanechol chloride ( 60 mg/day ) or distigmine bromide ( 15 mg/day ) ; the alpha-blocker group , consisting of 38 patients taking urapidil ( 60 mg/day ) ; and the combination group , consisting of 41 patients taking both a cholinergic drug and an alpha-blocker . The effectiveness of each therapy was assessed 4 weeks after initialization of the therapy . RESULTS Total urinary symptom scores ( International Prostate Symptom Score , IPSS ) remained unchanged after the cholinergic therapy , but were significantly lower after the alpha-blocker treatment ( P = 0.0001 ) and the combination therapy ( P = 0.0001 ) . With regard to the total IPSS , there were significant differences between the cholinergic and the alpha-blocker groups ( P = 0.0008 ) , and also between the cholinergic and combination groups ( P = 0.0033 ) , in favor of the latter . The average and maximum flow rates did not increase significantly after monotherapy with either the cholinergic drug or the alpha-blocker , but they significantly increased after combination therapy compared to baseline values ( P = 0.0033 and P= 0.0004 , respectively ) . Postvoid residual volume did not decrease significantly after the cholinergic drug therapy , but decreased significantly after the alpha-blocker ( P = 0.0043 ) and the combination therapies ( P = 0.0008 ) . The percentage of residual urine decreased significantly after therapy in all groups ( P = 0.0005 , P= 0.0176 and P= 0.0001 , respectively ) . CONCLUSION Combination therapy with a cholinergic drug and an alpha-blocker appears to be more useful than monotherapy for the treatment of underactive detrusor Objective To determine whether prolonged urinary bladder catheterisation after vaginal prolapse surgery is advantageous Background : With an increasing role of the patient as a partner in making a combined decision in care plan goals , it is important to identify the patient ’s perspective of the experience of removal of catheter ( ROC ) . Methods : A non-consecutive prospect i ve r and omized study was performed in 84 patients who underwent a transurethral resection of the prostate to determine the impact of midnight versus early-morning ROC on sleep deprivation , over all discomfort to the patient . Results : There was no difference in the patient experience in both groups . We found a reduced frequency during the first 6 h of ROC at midnight . However , there was an increased incidence of sleep disturbances in this group . This may in part be due to an anxiety of urge incontinence and may be allayed by appropriate counselling . There was no delay in discharge of the patients in both groups . Conclusion : The patients must , therefore , be given the choice of ROC either at midnight or early morning , as the advantages of a reduced frequency must be correlated with an increased incidence of sleep disturbances OBJECTIVE Literature indicates that removing urinary catheters at midnight facilitates earlier discharge among urology patients , but the effect of evening removal on the general patient population is unknown . The objective of this study was to investigate whether removing a urinary catheter at 22.00 hours compared to 06.00 hours among a general hospital population would lead to earlier hospital discharge . DESIGN R and omized controlled trial . SETTING AND SUBJECTS The study was conducted in a large tertiary hospital in Brisbane , Australia . Two hundred and ten general surgical and medical patients who had an indwelling catheter as part of their routine care were included . RESULTS Length of hospital stay after catheter removal was not significantly affected by the timing of its removal among general hospital patients : mean hours morning 186.1 ; mean evening 209.3 , ( P = .309 ) . In a cohort of surgical patients , the hospital stay was shorter in the evening removal group ( mean hours morning 186.1 ; mean evening 209.3 ) , but this result was not statistically significant ( P = .127 ) . Patients in the evening group were more likely to have a longer time period between catheter removal and the first postcatheter void , mean hours morning , 3.76 vs evening , 4.89 ( t = −2.59 , CI − 1.99 to −0.27 ) . Timing of removal of the urinary catheter had no effect on the volume of the first void , mean volume morning , 214.7 mL vs evening , 221.4 mL. Twenty-five ( 12.1 % ) patients were recatheterized , but the rate of recatheterization between groups was similar . There were no differences in postdischarge problems between groups . CONCLUSION Among general hospital patients , removing an indwelling urinary catheter at 22:00 hours does not shorten the length of stay and is effective in increasing the time to first void A r and omised controlled trial was undertaken to determine the effects of midnight removal of urinary catheters on patients ' voiding patterns and subsequent discharge from hospital . Patients whose urinary catheters were removed at midnight showed a greater volume of initial void than those whose catheters were removed at the usual time of 0600 . Removal of urinary catheters routinely at midnight permits earlier assessment of patients ' voiding , which may allow for earlier discharge from hospital Radical perineal prostatectomy allows for a watertight closure of the urethrovesical anastomosis . This trial determined that early catheter removal may be feasible and desirable in patients undergoing radical perineal prostatectomy . Early catheter removal can lead to improved patient comfort and well-being Background : There has been no consensus on the best catheterization strategy for the management of postoperative urinary retention . A prospect i ve r and omized trial was undertaken to establish the best practice guidelines for the management of postoperative urinary retention . The authors also evaluated the contemporary incidence of urinary retention following different categories of general surgery and examined risk factors associated with its occurrence In a r and omized trial , treatment of urethral stricture by direct visual internal urethrotomy with 3 days of postoperative catheterisation was found to be sufficient , given minimal complications , and had a cure rate of 85 % after 6 months and 80 % after 1 year follow-up . The postoperative follow-up should not include urethrography , but patient 's statement and maximal urinary flow rate might be adequate This study was design ed to compare the effectiveness of two approaches to urinary catheter management in controlling postoperative urinary dysfunction in 110 patients following abdominoperineal resection or low anterior bowel resection . Patients , stratified by sex and surgical procedure , were r and omly assigned to either straight gravity drainage or a 6-day progressive catheter clamping program . The bladder training program following abdominoperineal resection reduced significantly the urinary dysfunction rate in women but not in men . Marked differences in dysfunction rates were related to type of surgery , gender , and surgeon . Etiology of postoperative voiding dysfunction in various groups is discussed |
13,618 | 15,674,930 | Review suggested a modest to moderate benefit for psychological interventions , particularly those using a cognitive-behavioural framework , which was largely restricted to the first three months after the intervention .
The evidence for brief interventions was less clear . | BACKGROUND Recurrent chest pain in the absence of coronary artery disease is a common problem that sometimes leads to excess use of medical care .
Although many studies examine the causes of pain in these patients , few clinical trails have evaluated treatment .
The studies review ed in this paper provide an insight into the effectiveness of psychological interventions for this group of patients .
OBJECTIVES To investigate psychological treatments for non-specific chest pain ( NSCP ) with normal coronary anatomy . | Abstract Objective : To examine the additional effect of cognitive behavioural therapy for patients with medically unexplained physical symptoms in comparison with optimised medical care . Design : R and omised controlled trial with follow up assessment s six and 12 months after the baseline evaluation . Setting : General medical outpatient clinic in a university hospital . Subjects : An intervention group of 39 patients and a control group of 40 patients . Interventions : The intervention group received between six and 16 sessions of cognitive behavioural therapy . Therapeutic techniques used included identification and modification of dysfunctional automatic thoughts and behavioural experiments aim ed at breaking the vicious cycles of the symptoms and their consequences . The control group received optimised medical care . Main outcome measures : The degree of change , frequency and intensity of the presenting symptoms , psychological distress , functional impairment , hypochondriacal beliefs and attitudes , and ( at 12 months of follow up ) number of visits to the general practitioner . Results : At six months of follow up the intervention group reported a higher recovery rate ( odds ratio 0.40 ; 95 % confidence interval 0.16 to 1.00 ) , a lower mean intensity of the physical symptoms ( difference −1.2 ; −2.0 to −0.3 ) , and less impairment of sleep ( odds ratio 0.38 ; 0.15 to 0.94 ) than the controls . After adjustment for coincidental baseline differences the intervention and control groups also differed with regard to frequency of the symptoms ( 0.32 ; 0.13 to 0.77 ) , limitations in social ( 0.35 ; 0.14 to 0.85 ) and leisure ( 0.36 ; 0.14 to 0.93 ) activities , and illness behaviour ( difference −2.5 ; −4.6 to −0.5 ) . At 12 months of follow up the differences between the groups were largely maintained . Conclusion : Cognitive behavioural therapy seems to be a feasible and effective treatment in general medical patients with unexplained physical symptoms We performed a prospect i ve study to describe the broad spectrum of causes of chest pain in patients presenting to the emergency department and to compare the diagnoses in referred patients , self-referred patients and patients rushed in by ambulance . The final diagnosis in a consecutive case series of 578 chest pain patients was established after discharge from the hospital . The underlying disorders were grouped into cardiac , respiratory , gastro-oesophageal disorders , musculoskeletal pathology , somatization disorders , other diseases and unknown . For comparison of the frequencies of the disease categories the Chi-squared test was used . Out of 578 patients , 161 ( 27.9 % ) were self-referred , 369 ( 63.8 % ) were referred by the general practitioner and 48 ( 8.3 % ) were rushed in by ambulance . Cardiac diseases represented 51.7 % of the cases , myocardial infa rct ion and unstable angina 19 % and 12.8 % respectively . Cardiac diseases were statistically significantly less common in self-referred patients ( p < 0.0005 ) . Pulmonary diseases encompassed 14.2 % of the population , followed by somatization disorders ( 9.2 % ) , musculoskeletal pathology ( 7.1 % ) and other causes ( 4.3 % ) . In 11.1 % of the cases no definite final diagnosis could be established . Somatization disorders were significantly more frequent in self-referred and ambulance patients . Cardiac and pulmonary problems are the most frequent underlying disorders in acute chest pain patients in the emergency department . Somatization disorders and musculoskeletal pathology represented respectively 19.1 % and 14.8 % of the non-cardiac causes . The referral pattern influenced significantly the distribution of the disease categories with more cardiac and less psychiatric disorders in referred patients Three methods of breathing retraining ( guided breathing retraining , guided breathing retraining with physiologic monitoring of thoracic and abdominal movement plus peripheral temperature , and guided breathing retraining with physiologic monitoring of thoracic and abdominal movement , peripheral temperature and end-tidal carbon dioxide ) were compared with a no-treatment control group to determine the effectiveness of breathing retraining on modifying respiratory physiology and reducing functional cardiac symptoms in subjects with signs associated with hyperventilation syndrome . Of 41 subjects studied , 16 were diagnosed with mitral valve prolapse . Results demonstrated that all 3 methods of breathing retraining were equally effective in modifying respiratory physiology and reducing the frequency of functional cardiac symptoms . Results determined that respiratory rate and subject 's perception that training had generalized were the best predictors of treatment success . Furthermore , it was found that subjects with mitral valve prolapse responded as well to treatment as did those without prolapse Personality and life events were measured in 69 consecutive patients ( 36 men and 33 women ) below age 40 attending the emergency care unit because of chest pain without obvious organic cause ( 91 % participation rate ) . The results were compared with 32 r and omly sample d healthy subjects matched with regard to age and sex ( 86 % participation rate ) . The patient group had significantly higher scores for " neuroticism ' , ' Type A behaviour ' and ' vital exhaustion ' . Further more the patients had experienced significantly more life events , in particular uncontrollable ones , during the last year . We conclude that ' Type A behaviour ' , ' neuroticism ' , ' vital exhaustion ' and critical recent life events are linked with emergency consultation for chest pain of non-cardiac origin . Possible explanations of the link between the psychological reaction and the chest pain are enhanced tension in the thoracic muscles producing chest pain and oesophageal disorders . This study stresses the importance of careful medical and psychosocial examination of each case of unexplained chest pain at the emergency care unit One hundred four clients completed a mailed follow-up 1 year after completing 8 of 16 sessions of treatment , either cognitive-behavioral ( CB ) or psychodynamic-interpersonal ( PI ) psychotherapy . Although mean scores on outcome measures at 1 year suggested that gains were , in general , well maintained , only 29 % of clients were asymptomatic on all 3 occasions of testing ( end of treatment , 3 months and 1 year later ) without recourse to further treatment . However , only 11 % of those asymptomatic at end of treatment experienced relapse or recurrence of depression , albeit on the limited evidence of just two follow-up assessment s. The results of comparisons among treatment conditions at 1 year differed substantially from those obtained earlier : Eight-session PI treatment now appeared less efficacious than the other 3 treatment conditions , and there was now no measurable benefit of 16-session over 8-session CB , irrespective of initial severity of depression . These findings confirm the importance of follow-up in evaluation of psychotherapies for depression |
13,619 | 29,331,953 | Meta-analyses showed no significant differences between controlled-release ( CR ) and immediate-release oxycodone in pain intensity or adverse events but did show significantly better pain relief after treatment with CR morphine compared with CR oxycodone .
Meta-analyses of the adverse events showed a significantly lower risk of hallucinations after treatment with CR oxycodone compared with CR morphine , but no other differences .
None found any clear superiority or inferiority of oxycodone in pain relief or adverse events .
Conclusions Oxycodone offers similar levels of pain relief and adverse events to other strong opioids .
Our conclusions are consistent with other review s and suggest that oxycodone can be used first line as an alternative to morphine .
However , because it is cheaper , morphine generally remains the first-line opioid of choice | null | null |
13,620 | 27,609,070 | Current evidence fails to show that WHP programs improve the work ability , productivity or job retention of older workers .
In addition , there is limited evidence that WHP programs are effective in improving lifestyles and concur to maintain the health and well-being of older workers . | Background Aging of the workforce is a growing problem .
As workers age , their physical , physiological and psychosocial capabilities change .
Keeping older workers healthy and productive is a key goal of European labor policy and health promotion is a key to achieve this result .
Previous studies about workplace health promotion ( WHP ) programs are usually focused on the entire workforce or to a specific topic .
Within the framework of the EU-CHAFEA ProHealth65 + project , this paper aims to systematic ally review the literature on WHP interventions specifically targeted to older workers ( OWs ) . | Objective : We sought to assess whether either a low-cost educational intervention or small monetary incentive is more effective than usual care in lowering low-density lipoprotein ( LDL ) cholesterol among employees . Methods : Employees with an LDL-C > 130 mg/dL were eligible . After receiving on-line educational material s , subjects were assigned to three groups : group 1 received $ 100 if they reduced their LDL-C by 15 % within 6 months , group 2 participated in a multi-disciplinary educational program , and group 3 received no further intervention . Results : In total , 171 employees participated . Baseline mean LDL-C was 156 mg/dL. Approximately 6 months after r and omization , mean LDL-C was reduced 17.9 mg/dL ( 11.3 % ) in group 1 , 17.9 mg/dL ( 11.5 % ) in group 2 , and 5.5 mg/dL ( 3.5 % ) in group 3 . Reductions in groups 1 and 2 were statistically superior to group 3 ( P = 0.02 ) . Conclusions : Both an employer directed low-cost educational program and small monetary incentives similarly lowered LDL-C compared with usual care Objective To evaluate the effectiveness of a worksite vitality intervention on vigorous physical activity ( VPA ) , fruit intake , aerobic capacity , mental health and need for recovery after work among older hospital workers ( ie , 45 years and older ) . Methods The 6-month intervention was evaluated using a r and omised controlled trial design . Workers who were r and omised to the intervention group ( n=367 ; control : n=363 ) received the Vital@Work intervention containing ( 1 ) a Vitality Exercise Program ( VEP ) combined with ( 2 ) three visits to Personal Vitality Coach . The VEP consisted of a weekly yoga session , a weekly workout session and weekly unsupervised aerobic exercising . Free fruit was provided at the VEP . Data on the outcome measures were collected ( ie , year 2009–2010 ) at baseline ( n=730 ) and 6 months of follow-up after baseline ( n=575 ) using question naires , accelerometers and 2 km walk tests . Effects were analysed according to the intention-to-treat principle with complete cases ( n=575 ) and imputed data ( n=730 ) using linear regression analyses . Additional analyses were performed for high yoga and workout compliance ( ie , > mean number of sessions ) . Results Effects were found for sports activities ( β=40.4 min/week , 95 % CI 13.0 to 67.7 ) and fruit intake ( β=2.7 pieces/week , 95 % CI 0.07 to 4.7 ) and were stronger for workers with high compliance to yoga ( sport : β=49.6 min/week , 95 % CI 13.9 to 85.2 ; fruit : β=3.8 pieces/week , 95 % CI 1.1 to 6.4 ) and workout sessions ( sport : β=72.9 min/week , 95 % CI 36.1 to 109.8 ; fruit : β=4.0 pieces/week , 95 % CI 1.1 to 6.4 ) . The intervention group lowered their need for recovery , when compared to controls ( β=−3.5 , 95 % CI −6.4 to −0.54 ) , with stronger effects for high workout compliance ( β=−5.3 , 95 % CI −9.3 to −1.3 ) . No effects were found on VPA , aerobic capacity or mental health . Conclusions Implementation of worksite yoga and workout facilities and minimal fruit interventions should be considered by employers to promote transitions into healthier lifestyles and thereby health Objective : To conduct a cost-effectiveness and return-on-investment analysis comparing a worksite vitality intervention with usual care . Methods : A total of 730 older hospital workers were r and omized to the intervention or control group . The 6-month intervention consisted of yoga and aerobic exercising , coaching , and fruit . At baseline , and 6 and 12 months , general vitality , work-related vitality , and need for recovery were determined . Cost data were collected on a 3-monthly basis . The cost-effectiveness analysis was performed from the societal perspective and the return-on-investment analysis from the employer 's perspective using bootstrapping techniques . Results : No significant differences in costs and effects were observed . Incremental cost-effectiveness ratios in terms of general vitality ( range , 0 to 100 ) , work-related vitality ( range , 0 to 6 ) , and need for recovery ( range , 0 to 100 ) were , respectively , & OV0556;280 , & OV0556;7506 , and & OV0556;258 per point improvement . Per euro invested , & OV0556;2.21 was lost . Conclusions : The intervention was neither cost-effective nor cost-saving OBJECTIVES We examined the effects of 2 worksite health-promotion interventions ( compared with a health-education control ) on older workers ' healthy behaviors and health outcomes . METHODS We conducted a prospect i ve , r and omized controlled trial with 423 participants aged 40 years and older . Participants were categorized into 3 study arms : the COACH intervention combined Web-based risk assessment s with personal coaching support , the RealAge intervention used a Web-based risk assessment and behavior-specific modules , and a control group received printed health-promotion material s. Participants were assessed at baseline , 6 months , and 12 months . R and om-effects modeling controlled for baseline stage of change for all behaviors of interest in all groups . RESULTS At 6 and 12 months , COACH participants showed significantly increased fruit and vegetable consumption ( P = .026 ; P < .001 ) and participation in physical activity ( P = .05 ; P = .013 ) , and at 12 months they showed decreased percentage of energy from fat ( P = .027 ) . RealAge participants showed significantly decreased waist circumference at 6 and 12 months ( P = .05 ; P = .018 ) . CONCLUSIONS COACH participants were twice as likely to use the COACH intervention as RealAge participants were to use the RealAge intervention . COACH participants experienced twice the number of positive outcomes that control participants experienced OBJECTIVES A worksite lifestyle intervention aim ing to improve lifestyle behaviors could be an effective tool to keep older workers vital , and thereby prolong their labor participation . Therefore , this study evaluates the effectiveness of such an intervention on vitality , work engagement , productivity and sick leave . METHODS In a r and omized controlled trial design , 367 workers ( control group : N=363 ) received a 6-month intervention , which included two weekly guided group sessions : one yoga and one workout , as well as one weekly session of aerobic exercising , without face-to-face instruction , and three individual coach visits aim ed at changing workers ' lifestyle behavior by goal setting , feedback , and problem-solving strategies . Furthermore , free fruit was provided at the guided sessions . Data on work-related vitality ( UWES vitality scale ) , general vitality ( R AND -36 vitality scale ) , work engagement ( UWES ) , productivity ( single item scoring 0 - 10 ) , and sick leave ( yes/no past 3 months ) were collected using question naires at baseline ( N=730 ) , and at 6- ( N=575 ) and 12-months ( N=500 ) follow-up . Effects were analyzed according to the intention-to-treat principle with complete cases ( N=500 ) and imputed data ( N=730 ) . RESULTS There were no significant differences in vitality , work engagement , productivity , and sick leave between the intervention and control group workers after either 6- and 12-months follow-up . Yoga and workout subgroup analyses showed a 12-month favorable effect on work-related vitality [ β=0.14 , 95 % confidence interval ( 95 % CI ) 0.04 - 0.28 ] and general vitality ( β=2.9 , 95 % CI 0.02 - 5.9 ) among high yoga compliers . For high workout compliers , this positive trend was also seen , but it was not statistically significant . CONCLUSIONS Implementation of worksite yoga facilities could be a useful strategy to promote vitality-related work outcomes , but only if high compliance can be maximized . Therefore , impeding factors for participation should be investigated in more detail in future research Aims : To evaluate an occupational health intervention programme for workers at risk for early retirement . Methods : Between April 1997 and May 1998 , 116 employees of a large company who were older than 50 years indicated that they would not be able to work up to their retirement . They were r and omly assigned to an intervention ( n = 61 ) or control group ( n = 55 ) . The intervention programme lasted six months and was executed by an occupational physician . Job position and number of sick leave days after two years were collected from the company ’s computer data base . A question naire was sent to the employees at baseline , after six months , and after two years ; it included the Work Ability Index , the Utrecht Burn Out Scale , and the Nottingham Health Profile measuring quality of life . Results : Fewer employees ( 11 % ) in the intervention group retired early than in the control group ( 28 % ) . The total average number of sick leave days in two years was 82.3 for the intervention group and 107.8 for the control group . Six months after baseline , employees in the intervention group had better work ability , less burnout , and better quality of life than employees in the control group . Two years after r and omisation no differences between the two groups were found . Conclusions : This occupational health intervention programme proved to be a promising intervention in the prevention of early retirement BACKGROUND Menopause related symptoms modify quality of life and may also have an impact on work ability . OBJECTIVE The aim of this study was to investigate the effects of physical exercise on work ability and daily strain among women with menopausal symptoms . METHODS Occupationally active symptomatic menopausal women ( n=123 ) were r and omized into 24-week aerobic exercise intervention and control groups . Mobile phone question naires were used to collect daily data on perceived physical and mental strain in a r and omised and controlled setting . Work ability was measured with the Work Ability Index ( WAI ) and with questions about work strain . PARTICIPANTS In all 123 women aged 44 - 62 ( mean age 53.8 ± 3.4 ) years who worked full- or part-time participated in the study . Women were r and omized into a control ( n=60 ) and intervention group ( n=63 ) . The subjects were mostly working in mentally dem and ing jobs ( e.g. , office worker ) , but also in physical ( e.g. , cleaner ) and mixed ( physical and mental ) jobs ( e.g. , nurse ) . RESULTS The increase in mental re sources and decrease in physical strain from baseline to end were statistically significantly greater among the intervention group than among the control group . Between-group differences in the change in WAI were , however , statistically non-significant . CONCLUSION A 6-month physical exercise intervention among symptomatic menopausal women seems not to be enough to increase perceived work ability but the physical exercise may increase perceived mental re sources and decrease perceived daily physical strain . This study evaluates the effects of the American Heart Association ’s Heart At Work program on cardiovascular disease risk factor awareness , self-efficacy , and health behaviors . A prospect i ve , quasi-experimental research design was used to assess the impact of the program at two factory sites ( one intervention and one control ) . A total of 633 employees participated . Intervention site respondents significantly improved their knowledge of blood pressure management , the relationship between nutrition and cardiovascular disease , and heart attack risk factors . They also were more likely to begin treatment for hypertension , to report fewer sick days , and to have plans to improve their diet and lose weight . These findings suggest that the Heart At Work program had a favorable overall impact PURPOSE The purpose of this pilot study was to assess the feasibility of a Tai Chi workplace wellness program as a cost effective way of improving physical and mental health , reducing work related stress , and improving work productivity among older nurses in a hospital setting Design A r and omized control trial of two groups ( control and Tai Chi group ) . DESIGN A r and omized control trial of two groups ( control and Tai Chi group ) . SETTING S Northeastern academic medical center . SUBJECTS A convenience sample of eleven female nurses ( mean age 54.4 years ) . INTERVENTION The Tai Chi group ( n = 6 ) was asked to attend Tai Chi classes once a week offered at their worksite and to practice on their own for 10 minutes each day at least 4 days per week for 15 weeks . Controls ( n = 5 ) received no intervention . MEASURES SF-36 Health Survey , Nursing Stress Scale ( NSS ) , Perceived Stress Scale ( PSS ) , Sit- and -Reach test , Functional Reach test , the Work Limitations Question naire , workplace injury and unscheduled time off . ANALYSIS The two study groups were compared descriptively and changes across time in the intervention versus control were compared . RESULTS The Tai Chi group took no unscheduled time-off hours , whereas , the control group was absent 49 hours during the study period . There was also a 3 % increase in work productivity and significant improvement in functional reach ( p=0.03 ) compared to the control group . Other outcomes were not statistically significant . CONCLUSION This pilot study demonstrates the feasibility of Tai Chi with older female workers as a cost effective wellness option in the workplace ; thus encouraging replication with a larger sample . Method ological implication s were also addressed BACKGROUND Older workers are less physically active and have a higher rate and cost of injury than younger workers and so have reduced work-ability . Concurrently , sedentary behaviour in the workplace , in transport and in the home is increasing and has harmful health effects . Walking is a familiar , convenient , and free form of health-enhancing physical activity that can be integrated into working life and sustained into older age however workplace walking programs targeted at older workers have not been evaluated . PURPOSE We design ed a r and omised-controlled trial to evaluate the impact of a phased individually-tailored 10-week walking program on work-day steps , health status and work-ability of employees at an Australian university with an ageing sedentary workforce . METHODS A convenience sample of 154 academic and administrative employees aged 45 - 70 years will be recruited and r and omly allocated to either an experimental ( walking ) group or control ( maintain usual activity ) group . Participants will be provided with a pedometer and complete measures for step count , % body fat , waist circumference , blood pressure , self-reported physical activity , psychological wellbeing and work-ability , at baseline and end-intervention . ' Walkers ' will select approaches tailored to their individual preference , psychological characteristics or life circumstances . Two distinct intervention phases will target adoption ( weeks 2 - 5 ) and adherence ( weeks 7 - 12 ) using ' Stages of Behaviour Change ' principles . An ANOVA will test for effect of treatment on outcome with the baseline value entered as a covariate . DISCUSSION This study will test whether tailoring worksite walking is an effective means of promoting health-enhancing physical activity in ageing sedentary workers Background Recent evidence supports the efficacy of programs that promote improvements in the health practice s of workers 50 years and older who are at higher risk for chronic diseases than younger workers are . Internet-based programs that promote healthy practice s have also shown promise and , therefore , should be especially appropriate for workers aged 50 years and older . Objective The purpose of the research was to evaluate the effectiveness of HealthyPast50 , a fully automated Web-based health promotion program based on social cognitive theory and aim ed specifically at workers 50 years and older . Methods The r and omized controlled trial was conducted across multiple US offices of a large global information technology company . The sample included 278 employees aged 50 to 68 who were recruited online and r and omly assigned to the Web-based HealthyPast50 program or to a wait-list control condition . Self-report measures of diet , physical activity , stress , and tobacco use were collected online before and 3 months after the program group was given access to the program . Use data included number of log-ins and number of pages accessed . The primary analysis was multiple linear regression , following intent-to-treat principles with multiple imputation using the Markov chain Monte Carlo ( MCMC ) approach for nonmonotone missing data . Potential moderators from demographic characteristics and program dosage effects were assessed using multiple linear regression models . Additional analyses were conducted on complete ( nonimputed ) cases , excluding program participants who used the program for less than 30 minutes . Results Retention rates were good for both groups : 80.4 % ( 111/138 ) for the program group and 94.3 % ( 132/140 ) for the control group . Program group participants spent a mean of 102.26 minutes in the program ( SD 148.32 ) , logged in a mean of 4.33 times ( SD 4.28 ) , and viewed a mean of 11.04 pages ( SD 20.08 ) . In the analysis of the imputed data set , the program group performed significantly better than the control group on diet behavioral change self-efficacy ( estimated adjusted difference [Δ]=0.16 , P=.048 ) , planning healthy eating ( Δ=0.17 , P=.03 ) , and mild exercise ( Δ=1.03 , P=.01 ) . Moderator and dosage analyses of the data set found no significant program effects . Analyses of the nonimputed data set comparing program users with controls found additional significant program effects on eating practice s ( Δ=0.09 , P=.03 ) , exercise self-efficacy ( Δ=0.12 , P=.03 ) , exercise planning ( Δ=0.18 , P=.03 ) , and aging beliefs ( Δ=0.17 , P=.01 ) . Moderator analysis of this data set also found significant moderator effects of gender on multiple measures of exercise . Conclusions A Web-based health promotion program showed promise for making a significant contribution to the short-term dietary and exercise practice s of older working adults . Gender effects suggest that the program effects on exercise are due mainly to improvements among women |
13,621 | 29,761,060 | In both anticipation and loss outcome phases , participants showed large and robust activations in the bilateral striatum , ( anterior ) insula , and anterior cingulate gyrus relatively to Loss > Neutral contrast .
Although relatively similar activation patterns were observed during the two event types , they differed in the pattern of prefrontal activations : ventro-lateral prefrontal activations were observed during loss anticipation , while medial prefrontal activations were observed during loss receipt .
Discussion Considering that previous meta-analyses highlighted activations in the medial prefrontal cortex/anterior cingulate cortex , the anterior insula and the ventral striatum , the current meta- analysis highlighted the potential specificity of the ventro-lateral prefrontal regions , the median cingulate cortex and the amygdala in the loss events . | Background Reward seeking and avoidance of punishment are key motivational processes .
Brain-imaging studies often use the Monetary Incentive Delay Task ( MIDT ) to evaluate motivational processes involved in maladaptive behavior .
Although the bulk of research has been done on the MIDT reward events , little is known about the neural basis of avoidance of punishment .
Therefore , we conducted a meta- analysis of brain activations during anticipation and receipt of monetary losses in healthy controls . | BACKGROUND Negative symptoms may be associated with dysfunction of the brain reward system in schizophrenia . We used functional magnetic resonance imaging ( fMRI ) to assess the BOLD response in the ventral striatum of unmedicated schizophrenics during presentation of reward-indicating and loss-indicating stimuli . METHODS A total of 10 schizophrenic men ( 7 never medicated , 3 unmedicated for at least 2 years ) and 10 age-matched healthy male volunteers participated in an incentive monetary delay task , in which visual cues predicted that a rapid response to a subsequent target stimulus would result either in monetary gain or loss or would have no consequence . RESULTS Compared to healthy controls , unmedicated schizophrenics showed reduced ventral striatal activation during the presentation of reward-indicating cues . Decreased activation of the left ventral striatum was inversely correlated with the severity of negative ( and trendwise positive ) symptoms . DISCUSSION Reduced activation in one of the central areas of the brain reward system , the ventral striatum , was correlated with the severity of negative symptoms in medication-free schizophrenics . In unmedicated schizophrenic patients , a high striatal dopamine turnover may increase the " noise " in the reward system , thus interfering with the neuronal processing of reward-predicting cues by phasic dopamine release . This , in turn , may contribute to negative symptoms as such as anhedonia , apathy , and loss of drive and motivation Comparative studies have implicated the nucleus accumbens ( NAcc ) in the anticipation of incentives , but the relative responsiveness of this neural substrate during anticipation of rewards versus punishments remains unclear . Using event-related functional magnetic resonance imaging , we investigated whether the anticipation of increasing monetary rewards and punishments would increase NAcc blood oxygen level-dependent contrast ( hereafter , " activation " ) in eight healthy volunteers . Whereas anticipation of increasing rewards elicited both increasing self-reported happiness and NAcc activation , anticipation of increasing punishment elicited neither . However , anticipation of both rewards and punishments activated a different striatal region ( the medial cau date ) . At the highest reward level ( $ 5.00 ) , NAcc activation was correlated with individual differences in self-reported happiness elicited by the reward cues . These findings suggest that whereas other striatal areas may code for expected incentive magnitude , a region in the NAcc codes for expected positive incentive value Rationale Dysfunctional reward processing has been proposed as a main deficit in attention-deficit/hyperactivity disorder ( ADHD ) , which could be modulated by treatment with methylpheni date ( MPH ) . Objectives We examined differences in reward processing in adulthood ( independent of actual ADHD ) depending on MPH treatment during childhood . Methods Eleven males with childhood ADHD treated with MPH , 12 drug-naïve males with childhood ADHD , and 12 controls matched by age , h and edness , and smoking behavior were studied drug-free using functional magnetic resonance imaging . BOLD-responses were compared during a monetary incentive delay task using an ANOVA design focusing on the ventral striatum during anticipation and the orbitofrontal cortex during outcome . Results Controls , drug-naïve , and treated subjects did not differ significantly in their activations in the ventral striatum and orbitofrontal cortex . Explorative analyses revealed decreased insula activation during outcome of loss avoidance in drug-naïve subjects in comparison to both groups , while treated subjects did not differ from controls . Insula activation correlated significantly positive with harm avoidance in the treated group . Furthermore , comparing subjects with actual ADHD symptoms , remitters and controls we observed decreased putamen activition in ADHD persisters . Conclusions Basal ganglia reward processing seemed to be unrelated to MPH pretreatment , but was related to remission . On the other h and , the revealed differences between treated and drug-naïve subjects with childhood ADHD , i.e. , in the insula , give evidence for more pronounced abnormal activation in reward-associated brain regions in untreated subjects with childhood ADHD and underpin the need of prospect i ve studies on long-term effects of psychostimulant treatment Certain classes of stimuli , such as food and drugs , are highly effective in activating reward regions . We show in humans that activity in these regions can be modulated by the predictability of the sequenced delivery of two mildly pleasurable stimuli , orally delivered fruit juice and water . Using functional magnetic resonance imaging , the activity for rewarding stimuli in both the nucleus accumbens and medial orbitofrontal cortex was greatest when the stimuli were unpredictable . Moreover , the subjects ' stated preference for either juice or water was not directly correlated with activity in reward regions but instead was correlated with activity in sensorimotor cortex . For pleasurable stimuli , these findings suggest that predictability modulates the response of human reward regions , and subjective preference can be dissociated from this response |
13,622 | 18,652,730 | Current prediction rules for ACS have substantial method ological limitations and have not been successfully implemented in the clinical setting . | OBJECTIVE We sought to determine the diagnostic accuracy of clinical prediction rules to exclude acute coronary syndrome ( ACS ) in the emergency department ( ED ) setting . | STUDY OBJECTIVE Current risk stratification tools do not identify very-low-risk patients who can be safely discharged without prolonged emergency department ( ED ) observation , expensive rule-out protocol s , or provocative testing . We seek to develop a clinical prediction rule applicable within 2 hours of ED arrival that would miss fewer than 2 % of acute coronary syndrome patients and allow discharge within 2 to 3 hours for at least 30 % of patients without acute coronary syndrome . METHODS This prospect i ve , cohort study enrolled consenting eligible subjects at least 25 years old at a single site . At 30 days , investigators assigned a diagnosis of acute coronary syndrome or no acute coronary syndrome according to predefined explicit definitions . A recursive partitioning model included risk factors , pain characteristics , physical and ECG findings , and cardiac marker results . RESULTS Of 769 patients studied , 77 ( 10.0 % ) had acute myocardial infa rct ion and 88 ( 11.4 % ) definite unstable angina . We derived a clinical prediction rule that was 98.8 % sensitive and 32.5 % specific . Patients have very low risk of acute coronary syndrome if they have a normal initial ECG , no previous ischemic chest pain , and age younger than 40 years . In addition , patients at least 40 years old and with a normal ECG result , no previous ischemic chest pain , and low-risk pain characteristics have very low risk if they have an initial creatine kinase-MB ( CK-MB ) less than 3.0 microg/L or an initial CK-MB greater than or equal to 3.0 microg/L but no ECG or serum-marker increase at 2 hours . CONCLUSION The Vancouver Chest Pain Rule for early discharge defines a group of patients who can be safely discharged after a brief evaluation in the ED . Prospect i ve validation is needed INTRODUCTION We use clinical , ECG , and biochemical data to stratify risk in patients with chest pain without ST segment elevation . However , the prognostic performance of these studies in relation to time from onset of symptoms is unknown . PATIENTS AND METHOD In a single-center , prospect i ve study , 321 consecutive patients who had been admitted in the emergency room with a suspected acute coronary syndrome without ST segment elevation were included in the study . Blood sample s were collected for CK , CK-MB mass , myoglobin , and cardiac troponin T analysis 6 , 12 and 18 hours after the onset of pain and other clinical and ECG data were recorded . Univariate and multivariate analysis was used to identify independent prognostic predictors 6 and 12 hours after the onset of chest pain . RESULTS Five variables were independent predictors of the recurrence of ischemia . The model correctly classified 82 % of the patients . Age , history of coronary artery disease , prolonged chest pain at rest in the preceding 15 days , pain , ST-segment changes with pain , and cardiac troponin T in excess of 0.1 ng/m 12 hours after the onset of chest pain were identified by logistic regression . A similar model was analyzed at 6 hours , after changing the cutoff point for cardiac troponin T. Cardiac troponin T was considered positive with values of 0.04 ng/ml 6 hours after the onset of chest pain . CONCLUSIONS More than 80 % of the patients admitted to the emergency room with chest pain without ST segment elevation can be correctly classified for new ischemic recurrences using clinical , ECG , and biochemical parameters 6 hours after the onset of pain STUDY OBJECTIVE Accurate identification of the presence of acute myocardial infa rct ion in adult patients who present to the emergency department with anterior chest pain remains elusive . The artificial neural network is a powerful nonlinear statistical paradigm for the recognition of complex patterns , with the ability to maintain accuracy when some data required for network function are missing . Earlier studies revealed that the artificial neural network is able to accurately identify acute myocardial infa rct ion in patients experiencing chest pain . However , these studies did not measure network performance in real time , when a significant amount of data required for network function may not be available . They also did not use chemical cardiac marker data . METHODS Two thous and two hundred four adult patients presenting to the ED with anterior chest pain were used to train an artificial neural network to recognize the presence of acute myocardial infa rct ion . Only data available at the time of initial patient evaluation were used to replicate the conditions of real-time patient evaluation . Forty variables from patient histories , physical examinations , ECG results , and chemical cardiac marker determinations were used to train and then test the network . RESULTS The network correctly identified 121 of the 128 patients ( sensitivity 94.5 % ; 95 % confidence interval 90.6 % to 97.9 % ) with myocardial infa rct ion at a specificity of 95.9 % ( 95 % confidence interval 93.0 % to 98.5 % ) , despite the fact that an average of 5 % ( individual range 0 % to 35 % ) of the input data required by the network were missing on all patients . CONCLUSION Network accuracy and the maintenance of that accuracy when some data required for function are unavailable suggest that the artificial neural network may be a potential real time aid to the diagnosis of acute myocardial infa rct ion during initial patient evaluation BACKGROUND Appropriate treatment policies should include an accurate estimate of a patient 's baseline risk . Risk modeling to date has been underutilized in patients with acute coronary syndromes without persistent ST-segment elevation . METHODS AND RESULTS We analyzed the relation between baseline characteristics and the 30-day incidence of death and the composite of death or myocardial (re)infa rct ion in 9461 patients with acute coronary syndromes without persistent ST-segment elevation enrolled in the PURSUIT trial [ Platelet glycoprotein IIb/IIIa in Unstable angina : Receptor Suppression Using Integrilin ( eptifibatide ) Therapy ] . Variables examined included demographics , history , hemodynamic condition , and symptom duration . Risk models were created with multivariable logistic regression and vali date d by bootstrapping techniques . There was a 3.6 % mortality rate and 11.4 % infa rct ion rate by 30 days . More than 20 significant predictors for mortality and for the composite end point were identified . The most important baseline determinants of death were age ( adjusted chi(2)=95 ) , heart rate ( chi(2)=32 ) , systolic blood pressure ( chi(2)=20 ) , ST-segment depression ( chi(2)=20 ) , signs of heart failure ( chi(2)=18 ) , and cardiac enzymes ( chi(2)=15 ) . Determinants of mortality were generally also predictive of death or myocardial (re)infa rct ion . Differences were observed , however , in the relative prognostic importance of predictive variables for mortality alone or the composite end point ; for example , sex was a more important determinant of the composite end point ( chi(2)=21 ) than of death alone ( chi(2)=10 ) . The accuracy of the prediction of the composite end point was less than that of mortality ( C-index 0.67 versus 0.81 ) . CONCLUSIONS The occurrence of adverse events after presentation with acute coronary syndromes is affected by multiple factors . These factors should be considered in the clinical decision-making process Background : Most Canadian emergency departments use an unstructured , individualized approach to patients with chest pain , without data to support the safety and efficiency of this practice . We sought to determine the proportions of patients with chest discomfort in emergency departments who either had acute coronary syndrome ( ACS ) and were inappropriately discharged from the emergency department or did not have ACS and were held for investigation . Methods : Consecutive consenting patients aged 25 years or older presenting with chest discomfort to 2 urban tertiary care emergency departments between June 2000 and April 2001 were prospect ively enrolled unless they had a terminal illness , an obvious traumatic cause , a radiographically identifiable cause , severe communication problems or no fixed address in British Columbia or they would not be available for follow-up by telephone . At 30 days we assigned predefined explicit outcome diagnoses : definite ACS ( acute myocardial infa rct ion [ AMI ] or definite unstable angina ) or no ACS . Results : Of 1819 patients , 241 ( 13.2 % ) were assigned a 30-day diagnosis of AMI and 157 ( 8.6 % ) , definite unstable angina . Of these 398 patients , 21 ( 5.3 % ) were discharged from the emergency department without a diagnosis of ACS and without plans for further investigation . The clinical sensitivity for detecting ACS was 94.7 % ( 95 % confidence interval [ CI ] 92.5%– 96.9 % ) and the specificity 73.8 % ( 95 % CI 71.5%– 76.0 % ) . Of the patients without ACS or an adverse event , 71.1 % were admitted to hospital or held in the emergency department for more than 3 hours . Interpretation : The current individualized approach to evaluation and disposition of patients with chest discomfort in 2 Canadian tertiary care emergency departments misses 5.3 % of cases of ACS while consuming considerable health care re sources for patients without coronary disease . Opportunities exist to improve both safety and efficiency Identifying acute coronary syndrome is a difficult task in the emergency department because symptoms may be atypical and the electrocardiogram has low sensitivity . In this prospect i ve cohort study done in a tertiary community emergency hospital , we developed and tested a neural diagnostic tree in 566 consecutive patients with chest pain and no ST-segment elevation for the diagnosis of acute coronary syndrome . Multivariate regression and recursive partitioning analysis allowed the construction of decision rules and of a neural tree for the diagnosis of acute myocardial infa rct ion and acute coronary syndrome . Predictive variables of acute coronary syndrome were : age > or = 60 years ( odds ratio [ OR ] = 2.3 ; P = 0.0016 ) , previous history of coronary artery disease ( OR = 2.9 ; P = 0.0008 ) , diabetes ( OR = 2.8 ; P = 0.0240 ) , definite/probable angina-type chest pain ( OR = 17.3 ; P = 0.0000 ) and ischemic electrocardiogram ( ECG ) changes on admission ( OR = 3.5 ; P = 0.0002 ) . The receiver operating characteristic curve of possible diagnostic decision rules of the regression model disclosed a C-index of 0.904 ( 95 % confidence interval = 0.878 to 0.930 ) for acute coronary syndrome and 0.803 ( 95 % confidence interval 0.757 to 0.849 ) for acute myocardial infa rct ion . For both disorders , sensitivities of the neural tree were 99 % and 93 % , respectively , and negative predictive values were both 98 % . Negative likelihood ratios were 0.02 and 0.1 , respectively . It is concluded that this simple and easy-to-use neural diagnostic tree was very accurate in the identification of non-ST segment elevation chest pain patients without acute coronary syndrome . Patients identified as low probability of disease could receive immediate stress testing and be discharged if the test is negative STUDY OBJECTIVE The Thrombolysis in Myocardial Infa rct ion ( TIMI ) risk score is a 7-item tool derived from trials of patients with unstable angina/non-ST segment elevation myocardial infa rct ion for risk stratification with respect to outcomes . It has been retrospectively evaluated in emergency department ( ED ) patients with potential acute coronary syndrome but has not been prospect ively vali date d in this patient population . To vali date the use of the TIMI risk score in the ED , we prospect ively assess its potential utility in a broad ED chest pain patient population . METHODS This was a prospect i ve observational cohort study of consecutive ED chest pain patients enrolled from July 2003 until October 2004 . Data included demographics , medical and cardiac history , and components of the TIMI risk score . Investigators followed the hospital course daily for admitted patients , and 30-day follow-up was performed on hospitalized and discharged patients . The main outcome was death , acute myocardial infa rct ion , or revascularization as stratified by TIMI risk score at 30 days . RESULTS There were 1,481 eligible patient visits ; 30-day follow-up was completed on 1,458 ( 98.4 % ) patients . Patients had mean age of 53.2+/-14 years and were 40 % men , 66 % black , and 30 % white . Myocardial infa rct ion occurred in 95 patients . The incidence of each TIMI risk factor was age greater than 65 years 21 % , known coronary stenosis 18 % , 3 or more risk factors 26 % , ST-segment deviation 6 % , 2 or more anginal events in the previous 24 hours 33 % , aspirin use in the previous 7 days 35 % , and elevated markers 6 % . The incidence of 30-day death , acute myocardial infa rct ion , and revascularization according to TIMI score is as follows : TIMI 0 , 1.7 % ( 95 % confidence interval [ CI ] 0.42 to 2.95 ) ; TIMI 1 , 8.2 % ( 95 % CI 5.27 to 11.04 ) ; TIMI 2 , 8.6 % ( 95 % CI 5.02 to 12.08 ) ; TIMI 3 , 16.8 % ( 95 % CI 10.91 to 22.62 ) ; TIMI 4 , 24.6 % ( 95 % CI 16.38 to 32.77 ) ; TIMI 5 , 37.5 % ( 95 % CI 21.25 to 53.75 ) ; and TIMI 6 , 33.3 % ( 95 % CI 0 to 100 ) . This relationship was highly significant . CONCLUSION Among ED patients with chest pain , the TIMI risk score does correlate with outcome . However , in our study the TIMI risk score failed to stratify these patients into discrete groups according to risk score . Also , patients with the lowest risk as defined by a TIMI score of zero had a 1.7 % incidence of adverse events . Therefore , the TIMI risk score should not be used in isolation to determine disposition of ED chest pain patients BACKGROUND Artificial neural networks apply non-linear statistics to pattern recognition problems . One such problem is acute myocardial infa rct ion ( AMI ) , a diagnosis which , in a patient presenting as an emergency , can be difficult to confirm . We report here a prospect i ve comparison of the diagnostic accuracy of a network and that of physicians , on the same patients with suspected AMI . METHODS Emergency department physicians who evaluated 1070 patients 18 years or older presenting to the emergency department of a teaching hospital in California , USA with anterior chest pain indicated whether they thought these patients had sustained a myocardial infa rct ion . The network analysed the patient data collected by the physicians during their evaluations and also generated a diagnosis . FINDINGS The physicians had a diagnostic sensitivity and specificity for myocardial infa rct ion of 73.3 % ( 95 % confidence interval 63.3 - 83.3 % ) and 81.1 % ( 78.7 - 83.5 % ) , respectively , while the network had a diagnostic sensitivity and specificity of 96.0 % ( 91.2 - 100 % ) and 96.0 % ( 94.8 - 97.2 % ) , respectively . Only 7 % of patients had had an AMI , a low frequency but typical for anterior chest pain . INTERPRETATION The application of non-linear neural computational analysis via an artificial neural network to the clinical diagnosis of myocardial infa rct ion appears to have significant potential OBJECTIVES The authors sought to vali date a clinical decision rule that young adult ( younger than 40 years ) chest pain patients without known cardiac disease who had either no cardiac risk factors and /or a normal electrocardiogram ( ECG ) are at low risk ( < 1 % ) for acute coronary syndromes ( ACS ) and 30-day adverse cardiovascular ( CV ) events . METHODS A prospect i ve cohort study of patients 24 - 39 years old who received an ECG for chest pain from July 1999 to March 2002 were included . Cocaine users were excluded . Data collection was structured at presentation , hospital course was followed daily , and 30-day follow-up was obtained by telephone . The main outcome was 30-day adverse CV events ( death , acute myocardial infa rct ion , percutaneous intervention , and coronary artery bypass graft ) . Descriptive statistics were used . RESULTS Of 4,492 visits for chest pain , 1,023 met criteria . Patients were most often female ( 61 % ) and African American ( 73 % ) . Ninety-eight percent were available for 30-day follow-up . The overall risks of ACS and 30-day adverse CV events were 5.4 % and 2.2 % , respectively , in our entire cohort . For patients with no cardiac history and no cardiac risk factors , the risk of ACS and 30-day adverse CV events was 1.8 % . The risk in patients with no cardiac history and a normal ECG was 1.3 % . Patients with no cardiac history , no cardiac risk factors , and a normal ECG had a risk of 1.0 % . A modified clinical decision rule found that in young adult patients without a known cardiac history , either no classic cardiac risk factors or a normal ECG , and initially normal cardiac marker studies , the risk of ACS was also extremely low ( 0.14 % ) and there were no adverse CV events at 30-day follow-up ( 95 % confidence interval = 0.1 % to 0.2 % ) . CONCLUSIONS A modified clinical decision rule described a group of patients with a 0.14 % risk of ACS that was free from 30-day adverse CV events BACKGROUND Accurate identification of low-risk emergency department ( ED ) chest pain patients who may be safe for discharge has not been well defined . Goldman criteria have reliably risk-stratified patients but have not identified any subset safe for ED release . Cardiac troponin I ( cTnI ) values have also been shown to risk-stratify patients but have not identified a subset safe for ED release . OBJECTIVE To test the hypothesis that ED chest pain patients with a Goldman risk of < or = 4 % and a single negative cTnI ( < or = 0.3 ng/mL ) at the time of ED presentation would be safe for discharge [ < 1 % risk for death , acute myocardial infa rct ion ( AMI ) , revascularization ] . METHODS A prospect i ve cohort study was performed in which consecutive ED chest pain patients were enrolled from July 1999 to November 2000 . Data collected included patient demographics , medical and cardiac history , electrocardiogram , and creatine kinase-MB and cTnI. Goldman risk stratification score was calculated while patients were still in the ED . Hospital course was followed daily . Telephone follow-up occurred at 30 days . The main outcome was death , AMI , or revascularization ( percutaneous transluminal coronary angioplasty/stents/coronary artery bypass grafting ) within 30 days . RESULTS Of 2,322 patients evaluated , 998 had both a Goldman risk < or = 4 % and a cTnI < or = 0.3 ng/mL. During the initial hospitalization , 37 patients met the composite endpoint ( 3.7 % ) : 6 deaths ( 0.7 % ) , 17 AMIs ( 1.7 % ) , 18 revascularizations ( 1.8 % ) . Between the time of hospital discharge and 30-day follow-up , 15 patients met the composite endpoint : 4 deaths ( 0.4 % ) , 6 AMIs ( 0.6 % ) , and 5 revascularizations ( 0.5 % ) . Overall , 49 patients met the composite endpoint ( 4.9 % ; 95 % CI = 3.6 % to 6.2 % ) : 10 deaths ( 1.0 % ; 95 % CI = 0.4 % to 1.6 % ) ; 23 AMIs ( 2.3 % ; 95 % CI = 1.4 % to 3.2 % ) , and 23 revascularizations ( 2.3 % ; 95 % CI = 1.4 % to 3.2 % ) within 30 days of presentation . CONCLUSIONS The combination of two risk stratification modalities for ED chest pain patients ( Goldman risk < or = 4 % and cTnI < or = 0.3 ng/mL ) did not identify a subgroup of chest pain patients at < 1 % risk for death , AMI , or revascularization within 30 days BACKGROUND It has been nearly a decade since Goldman 's computer-driven algorithm to predict myocardial infa rct ion was vali date d. Despite the potential to avoid admission of patients without acute myocardial infa rct ion ( AMI ) to the coronary care unit ( CCU ) , the routine use of computer-generated protocol s has not been widely adopted . METHODS Two hundred consecutive patients admitted to a university-affiliated community hospital with the suspected diagnosis of AMI as determined by physicians without the aid of the Goldman protocol underwent a blinded prospect i ve evaluation to assess the performance of the Goldman algorithm in predicting the presence of AMI . Over the same time period , the Goldman algorithm was applied by retrospective chart review in 762 patients with non-AMI admitting diagnoses . Prospect i ve history , physical examination , and electrocardiographic data were obtained within 24 hours of admission to the CCU by a physician blinded to each patient 's clinical course . Retrospective chart review s were conducted for 762 patients with chest pain given with non-AMI diagnoses . RESULTS The diagnosis of AMI was confirmed in 68.5 % ( 137/200 ) of patients with suspected AMI admitted to the CCU . In prospect i ve parallel evaluations the Goldman algorithm predicted the presence of AMI in 167 ( 83.5 % ) of these 200 patients . All 137 confirmed patients with AMI were correctly identified by the Goldman algorithm . All major in-hospital complications occurred in the 137 patients who were diagnosed as having AMI . Of the 762 patients with chest pain with non-AMI diagnoses , only 27 ( 3.5 % ) sustained an AMI . The Goldman algorithm predicted the presence of AMI in 85 % ( 23/27 ) of these patients . Adherence to the use of Goldman 's algorithm in the triage of chest pain could have prevented 16.5 % of CCU admissions for AMI . CONCLUSIONS Routine adherence to the Goldman algorithm for the evaluation of patients with acute chest pain could have decreased the number of CCU admissions for suspected AMI by 16 . 5 % . Because major in-hospital complications occurred only in patients with AMI , this strategy would result in significant cost savings to our health care system without jeopardizing patient safety To achieve more appropriate triage to the coronary care unit of patients presenting with acute chest pain , we used clinical data on 1379 patients at two hospitals to construct a simple computer protocol to predict the presence of myocardial infa rct ion . When we tested this protocol prospect ively in 4770 patients at two university hospitals and four community hospitals , the computer-derived protocol had a significantly higher specificity ( 74 vs. 71 percent ) in predicting the absence of infa rct ion than physicians deciding whether to admit patients to the coronary care unit , and it had a similar sensitivity in detecting the presence of infa rct ion ( 88.0 vs. 87.8 percent ) . Decisions based solely on the computer protocol would have reduced the admission of patients without infa rct ion to the coronary care unit by 11.5 percent without adversely affecting the admission of patients in whom emergent complications developed that required intensive care . Although this protocol should not be used to override careful clinical judgment in individual cases , the computer protocol for the most part yields accurate estimates of the probability of myocardial infa rct ion . Decisions about admission to the coronary care unit based on the protocol would have been as effective as those actually made by the unaided physicians who cared for the patients , and less costly . Whether physicians who are aided by the protocol perform better than unaided physicians can not be determined without further study STUDY OBJECTIVE We compare the diagnostic accuracy of 3 methods --attribute matching , physician 's written unstructured estimate , and a logistic regression formula ( Acute Coronary Insufficiency-Time Insensitive Predictive Instrument , ACI-TIPI)--of estimating a very low pretest probability ( < or = 2 % ) for acute coronary syndromes in emergency department ( ED ) patients evaluated in chest pain units . METHODS We prospect ively studied 1,114 consecutive patients from 3 academic EDs , evaluated for acute coronary syndrome . Physicians collected data required for pretest probability assessment before protocol -driven chest pain unit testing . A pretest probability greater than 2 % was considered " test positive . " The criterion st and ard was the outcome of acute coronary syndrome ( death , myocardial infa rct ion , revascularization , or > 60 % stenosis prompting new treatment ) within 45 days , adjudicated by 3 independent review ers . RESULTS Fifty-one of 1,114 enrolled patients ( 4.5 % ; 95 % confidence interval [ CI ] 3.4 % to 6.0 % ) developed acute coronary syndrome within 45 days , including 4 of 991 ( 0.4 % ; 95 % CI 0.1 % to 1.0 % ) patients , discharged after a negative chest pain unit evaluation result , who developed acute coronary syndrome . Unstructured estimate identified 293 patients with pretest probability less than or equal to 2 % , 2 had acute coronary syndrome , yielding sensitivity of 96.1 % ( 95 % CI 86.5 % to 99.5 % ) and specificity of 27.4 % ( 95 % CI 24.7 % to 30.2 % ) . Attribute matching identified 304 patients with pretest probability less than or equal to 2 % ; 1 had acute coronary syndrome , yielding a sensitivity of 98.0 % ( 95 % CI 89.6 % to 99.9 % ) and a specificity of 26.1 % ( 95 % CI 23.6 % to 28.7 % ) . ACI-TIPI identified 56 patients ; none had acute coronary syndrome , yielding sensitivity of 100 % ( 95 % CI 93.0 % to 100 % ) and specificity of 6.1 % ( 95 % CI 4.7 % to 7.9 % ) . CONCLUSION In a low-risk ED population with symptoms suggestive of acute coronary syndrome , patients with a quantitative pretest probability less than or equal to 2 % , determined by attribute matching , unstructured estimate , or logistic regression , may not require additional diagnostic testing BACKGROUND Discharging patients with acute myocardial infa rct ion or unstable angina from the emergency department because of missed diagnoses can have dire consequences . We studied the incidence of , factors related to , and clinical outcomes of failure to hospitalize patients with acute cardiac ischemia . METHODS We analyzed clinical data from a multicenter , prospect i ve clinical trial of all patients with chest pain or other symptoms suggesting acute cardiac ischemia who presented to the emergency departments of 10 U.S. hospitals . RESULTS Of 10,689 patients , 17 percent ultimately met the criteria for acute cardiac ischemia ( 8 percent had acute myocardial infa rct ion and 9 percent had unstable angina ) , 6 percent had stable angina , 21 percent had other cardiac problems , and 55 percent had noncardiac problems . Among the 889 patients with acute myocardial infa rct ion , 19 ( 2.1 percent ) were mistakenly discharged from the emergency department ( 95 percent confidence interval , 1.1 to 3.1 percent ) ; among the 966 patients with unstable angina , 22 ( 2.3 percent ) were mistakenly discharged ( 95 percent confidence interval , 1.3 to 3.2 percent ) . Multivariable analysis showed that patients who presented to the emergency department with acute cardiac ischemia were more likely not to be hospitalized if they were women less than 55 years old ( odds ratio for discharge , 6.7 ; 95 percent confidence interval , 1.4 to 32.5 ) , were nonwhite ( odds ratio , 2.2 ; 1.1 to 4.3 ) , reported shortness of breath as their chief symptom ( odds ratio , 2.7 ; 1.1 to 6.5 ) , or had a normal or nondiagnostic electrocardiogram ( odds ratio , 3.3 ; 1.7 to 6.3 ) . Patients with acute infa rct ion were more likely not to be hospitalized if they were nonwhite ( odds ratio for discharge , 4.5 ; 95 percent confidence interval , 1.8 to 11.8 ) or had a normal or nondiagnostic electrocardiogram ( odds ratio , 7.7 ; 95 percent confidence interval , 2.9 to 20.2 ) . For the patients with acute infa rct ion , the risk-adjusted mortality ratio for those who were not hospitalized , as compared with those who were , was 1.9 ( 95 percent confidence interval , 0.7 to 5.2 ) , and for the patients with unstable angina , it was 1.7 ( 95 percent confidence interval , 0.2 to 17.0 ) . CONCLUSIONS The percentage of patients who present to the emergency department with acute myocardial infa rct ion or unstable angina who are not hospitalized is low , but the discharge of such patients is associated with increased mortality . Failure to hospitalize is related to race , sex , and the absence of typical features of cardiac ischemia . Continued efforts to reduce the number of missed diagnoses are warranted More than half of emergency department diagnoses of acute cardiac ischemia ( acute myocardial infa rct ion or unstable angina pectoris ) prove to be incorrect [ 1 ] , leading to approximately 2 million unnecessary hospitalizations associated with $ 8 billion in costs annually in the United States [ 2 ] . Underdiagnosis of acute ischemia also occurs : Approximately 2 % of emergency department patients with acute infa rct ion are sent home [ 3 , 4 ] . Unnecessary hospitalization for patients incorrectly presumed to have acute ischemia must be reduced without increasing inadvertent discharges of those with acute ischemia [ 5 , 6 ] . To address this problem , we developed an acute cardiac ischemia predictive instrument to provide real-time guidance for triage decisions in the emergency department [ 1 ] . Programmed initially into a h and -held calculator , a logistic regression formula computed a patient 's probability ( 0 % to 100 % ) of having acute ischemia on the basis of seven yes/no questions , including the presence of chest pain , chest pain as the chief symptom , a history of heart attack or nitroglycerine use , and electrocardiogram ST-segment or T-wave abnormalities . In a 2300-patient controlled clinical trial done in urban and rural hospitals in 1980 - 1981 , providing patients ' probability values of acute ischemia to emergency department physicians improved triage decisions : Admissions to the coronary care unit ( CCU ) for patients without acute ischemia were reduced by 30 % and missed cases of acute ischemia did not increase [ 1 ] . Unfortunately , the calculator-based instrument was not user-friendly for busy emergency department physicians and found limited use . In addition , it required physician interpretation of the ST segment and T waves , which may be incorrect 25 % of the time [ 7 ] , introducing error into predictions . To address these issues , a new version of the instrument was developed for incorporation into conventional computerized electrocardiograph [ 8 - 12 ] . It was design ed to compute the probability value either by using data obtained during real-time emergency department care or retrospective review ; thus , we called it an acute cardiac ischemia time-insensitive predictive instrument ( ACI-TIPI ) [ 8 , 13 ] . This was accomplished primarily by replacing the variables from the medical history with age , sex , and the presence of Q waves on electrocardiography . More detailed data on ST and T waves were also added . Diagnostic performance was equivalent to that of the original version , and no further variables were needed . Of note , classic long-term coronary risk factors , such as hypercholesterolemia and smoking , were not important predictors of acute ischemia in the emergency department compared with the variables used in ACI-TIPI [ 8 , 14 ] . To acquire the ACI-TIPI probability in clinical use , the user enters the patient 's age and sex and indicates whether chest or left arm pain is the primary symptom ; the electrocardiograph then directly measures the waveforms and computes and prints the probability of acute ischemia on the electrocardiogram header for the physician 's immediate use ( Figure 1 ) . Figure 1 . Example of an acute cardiac ischemia time-insensitive predictive instrument ( ACI-TIPI ) electrocardiogram printed by conventional electrocardiograph for the trial . We report the results of a clinical trial to test the effect of electrocardiogram-based ACI-TIPI on emergency department triage of patients with chest pain or other symptoms suggestive of acute cardiac ischemia . We sought to determine whether its use would reduce unnecessary hospital and CCU admission for emergency department patients without cardiac ischemic disease or with stable angina pectoris while not reducing hospitalization of emergency department patients with acute ischemia ( unstable angina or acute infa rct ion ) . Because our previous work showed that the bed capacity of the hospital CCU influences emergency department triage [ 15 ] and that the effects of ACI-TIPI vary with the training level of residents [ 9 ] , we hypothesized that the effect of ACI-TIPI would differ according to the bed capacities of CCUs and physician training status . Thus , we included hospitals with a wide range of CCU bed capacities and emergency department training programs . Methods Sites The study was conducted at 10 hospitals , including public , private , community , and tertiary hospitals with urban , suburban , and semi-rural catchment areas ( Baystate Medical Center [ Springfield , Massachusetts ] ; Boston City Hospital , Boston University Medical Center , and New Engl and Medical Center [ Boston , Massachusetts ] ; Medical College of Virginia [ Richmond , Virginia ] ; Medical College of Wisconsin [ Milwaukee , Wisconsin ] ; Newton-Wellesley Hospital [ Newton , Massachusetts ] ; Rhode Isl and Hospital [ Providence , Rhode Isl and ] ; University of Cincinnati Medical Center [ Cincinnati , Ohio ] ; and University of North Carolina Hospitals [ Chapel Hill , North Carolina ] ) . All emergency departments had internal medicine residents ; four had emergency medicine residents . Patients We included all consenting emergency department patients who 1 ) were at least 30 years of age or at least 18 years of age if they were suspected of using or were reported to have used cocaine recently and 2 ) had a chief symptom of chest , left arm , jaw , or epigastric pain or discomfort ; shortness of breath ; dizziness ; palpitations ; or other symptoms suggestive of acute ischemia . Intervention The ACI-TIPI was installed in each emergency department 's native br and electrocardiographs by using software and necessary equipment up grade s provided by the manufacturer . Both br and s used ( Hewlett-Packard [ Palo Alto , California ] and Marquette [ Milwaukee , Wisconsin ] ) generated equivalent predictions in the same format ( Figure 1 ) . Manufacturers had no input in the design or conduct of the study , data analysis , or reporting of results . The trial was carried out over 7 alternating months of control and intervention periods starting in May 1993 . On presentation to the emergency department , each patient 's ACI-TIPI probability of acute ischemia was automatically computed by the electrocardiograph . During intervention periods , the probability was automatically printed on the electrocardiogram header , with an indication that it was to supplement , not replace physician judgment , along with the st and ard electrocardiogram interpretive header text . During control periods , only the st and ard header text was printed . Data Collection Sociodemographic information , initial and follow-up clinical features , electrocardiographic information , creatine kinase-MB test results , training level and supervision of the triaging physician , and hospital bed capacities were recorded at presentation to the emergency department , during hospitalization , and at the 30-day follow-up . The follow-up rate for data needed to assign confirmed true diagnoses , including those for patients who were not hospitalized , was 99 % . The ACI-TIPI electrocardiograph allowed real-time acquisition of the following variables : age , sex , presence of chest or left arm pain , a chief symptom of chest or left arm pain , pathologic Q waves , and the presence and degree of ST-segment elevation or depression and T-wave elevation or inversion [ 9 , 10 ] . Data Analysis Confirmed diagnoses were assigned by site physicians ( who were blinded to study group assignment ) on the basis of presentation and clinical course , initial and follow-up electrocardiograms , and creatine kinase-MB test results by using World Health Organization criteria [ 16 ] . Angina severity was classified by Canadian Cardiovascular Society classification criteria [ 17 ] and time since angina onset or pattern change . By using an iterative modified Delphi process based on the practice s and opinions of study site emergency physicians , cardiologists , and other experts , we defined the following diagnostic groups for analysis a priori : 1 ) patients with acute cardiac ischemia [ acute infa rct ion or unstable angina ] , who , it was agreed , should be admitted to cardiac telemetry units or CCUs ; 2 ) patients with stable angina pectoris [ Canadian Cardiovascular Society classes 1 or 2 or class 3 without a new or changed anginal pattern in at least 4 days ] who , clinicians felt , could be safely triaged home for outpatient follow-up ; and 3 ) patients without cardiac ischemia , who did not require hospitalization . For analysis , study hospitals were divided into groups according to the pattern of relative CCU bed capacities . Five hospitals with low-capacity telemetry units ( comparatively high-capacity CCUs ) had cardiac telemetry unit-to-CCU bed ratios of 2 to 1 or less . Five hospitals with high-capacity telemetry units ( low-capacity CCUs ) had telemetry-to-CCU bed ratios at least double the ratios of hospitals with low-capacity telemetry units . A priori , we elected to consider physicians who signed the official medical record as the responsible physicians . Thus , each patient was classified as having been triaged by an attending physician ( single signature ) , a resident supervised by an attending ( both signatures ) , or an unsupervised resident ( single signature ) . Statistical Analysis Baseline comparisons of patient characteristics between control and intervention months were done by using t-tests for continuous variables and chi-square tests for categorical variables , including emergency department triage dispositions . Using Cochran-Mantel-Haenszel adjustments for individual hospitals did not change significance levels . When few patients were sent to wards ( 3 % ) , emergency department dispositions to ward and telemetry units were combined for statistical testing in the tables ( but were kept separate for presentation in the text ) . Apparent discrepancies between emergency department triage disposition rates and computer disposition-specific changes are due to the effects of rounding . The possibility of changes over the course of the trial in differences between control and intervention periods ( learning ) was checked by testing OBJECTIVE To vali date prospect ively the use of an artificial neural network to identify myocardial infa rct ion in patients presenting to an emergency department with anterior chest pain . DESIGN Prospect i ve , blinded testing . SETTING Tertiary university teaching center . PATIENTS A total of 331 consecutive adult patients presenting with anterior chest pain . MEASUREMENTS Diagnostic sensitivity and specificity with regard to the diagnosis of acute myocardial infa rct ion . MAIN RESULTS An artificial neural network was trained on clinical pattern sets retrospectively derived from the cases of 351 patients hospitalized with a high likelihood of having myocardial infa rct ion . It was prospect ively tested on 331 consecutive patients presenting to an emergency department with anterior chest pain . The ability of the network to distinguish patients with from those without acute myocardial infa rct ion was compared with that of physicians caring for the same patients . The physicians had a diagnostic sensitivity of 77.7 % ( 95 % CI , 77.0 % to 82.9 % ) and a diagnostic specificity of 84.7 % ( CI , 84.0 % to 86.4 % ) . The artificial neural network had a sensitivity of 97.2 % ( CI , 97.2 % to 97.5 % ; P = 0.033 ) and a specificity of 96.2 % ( CI , 96.2 % to 96.4 % ; P less than 0.001 ) . CONCLUSION An artificial neural network trained to identify myocardial infa rct ion in adult patients presenting to an emergency department may be a valuable aid to the clinical diagnosis of myocardial infa rct ion ; however , this possibility must be confirmed through prospect i ve testing on a larger patient sample OBJECTIVES To determine Canadian emergency physicians ' estimates regarding the safety and efficiency of chest discomfort management in their emergency department ( ED ) , and their attitudes toward and perception of the need for a chest discomfort clinical prediction rule that identifies very low risk patients who are safe to discharge after a brief ED assessment . METHODS 300 members of the Canadian Association of Emergency Physicians ( CAEP ) were r and omly selected to receive a confidential mail survey , which invited them to provide information on current disposition of patients with chest discomfort and their opinions regarding the value of a clinical prediction rule to identify patients with chest discomfort who are safe to discharge after a brief ( approximately 2 hour ) assessment . RESULTS Of the 300 physicians selected , 288 were eligible for the survey and 235 ( 82 % ) responded . Only 5 % follow discharged patients to measure safe practice . Overall , 165 ( 70 % ) felt the proposed prediction rule would be very useful and 43 ( 18 % ) felt it would be useful . Almost all ( 94 % ) believed a prediction rule would be useful if it identified patients safe for discharge without increasing the current rate of missed acute myocardial infa rct ion ( estimated at 2 % ) . Most respondents ( 59 % ) believed that a clinical prediction rule should suggest a course of action , while 30 % felt it should convey a probability of disease . CONCLUSIONS Canadian emergency physicians support the concept of a clinical prediction rule for the early discharge of patients with chest discomfort . Most believe that such a rule would be useful if it identified patients who are safe for discharge after a brief assessment , while maintaining current levels of safety . Future research should be aim ed at deriving a clinical prediction rule to identify low risk patients who can be safely discharged after a limited emergency department evaluation Each year 1.5 million patients are admitted to coronary-care units ( CCUs ) for suspected acute ischemic heart disease ; for half of these , the diagnosis is ultimately " ruled out . " In this study , conducted in the emergency rooms of six New Engl and hospitals ranging in type from urban teaching centers to rural nonteaching hospitals , we sought to develop a diagnostic aid to help emergency room physicians reduce the number of their CCU admissions of patients without acute cardiac ischemia . From data on 2801 patients , we developed a predictive instrument for use in a h and -held programmable calculator , which requires only 20 seconds to compute a patient 's probability of having acute cardiac ischemia . In a prospect i ve trial that included 2320 patients in the six hospitals , physicians ' diagnostic specificity for acute ischemia increased when the probability value determined by the instrument was made available to them . Rates of false-positive diagnosis decreased without any increase in rates of false-negative diagnosis . Among study patients with a final diagnosis of " not acute ischemia , " the number of CCU admissions decreased 30 per cent , without any increase in missed diagnoses of ischemia . The proportion of CCU admissions that represented patients without acute ischemia dropped from 44 to 33 per cent . Widespread use of this predictive instrument could reduce the number of CCU admissions in this country by more than 250,000 per year STUDY OBJECTIVE Clinical and ECG data from presentation are highly discriminatory for diagnosis of acute coronary syndromes , whereas definitive diagnosis from serial ECG and cardiac marker protein measurements is usually not available for several hours . Artificial neural networks are computer programs adept at pattern recognition tasks and have been used to analyze data from chest pain patients with a view to developing diagnostic algorithms that might improve triage practice s in the emergency department . The aim of this study is to develop and optimize artificial neural network models for diagnosis of acute coronary syndrome , to test these models on data collected prospect ively from different centers , and to establish whether the performance of these models was superior to that of models derived using a st and ard statistical technique , logistic regression . METHODS The study used data from 3,147 patients presenting to 3 hospitals with acute chest pain . Data from hospital 1 were used to train the models , which were then tested on independent data from the other 2 hospitals . From 40 potential factors , variables were selected according to the logarithm of their likelihood ratios to produce models using 8 , 13 , 20 , and 40 factors . Identical data were used for logistic regression and artificial neural network models . Calibration and performance were assessed , the latter using receiver operating characteristic ( ROC ) curve analysis . RESULTS Although the performance of artificial neural network models generally increased with increasing numbers of factors , this was insignificant . The 13-factor model was therefore used for the rest of the study owing to its marginally improved calibration over the smallest model . Area under the ROC curve ( with st and ard error ) was 0.97 ( 0.006 ) . The overall sensitivity and specificity of this model for acute coronary syndrome diagnosis using the training data was 0.93 . ROC curves for logistic regression and artificial neural network models applied to data from the 3 hospitals were identical . For the 13-factor artificial neural network model tested on data from hospitals 2 and 3 , area under the ROC curves ( st and ard error ) were 0.93 ( 0.006 ) and 0.95 ( 0.009 ) , respectively . Investigation of the performance of the artificial neural network models throughout the range of predicted probabilities showed that they were well calibrated . CONCLUSION This study confirms that artificial neural networks can offer a useful approach for developing diagnostic algorithms for chest pain patients ; however , the exceptional performance and simplicity of the logistic model militates in favor of logistic regression for the present task . Our artificial neural network models were well calibrated and performed well on unseen data from different centers . These issues have not been addressed in previous studies . However , and unlike in previous studies , we did not find the performance of artificial neural network models to be significantly different from that of suitably optimized logistic regression models |
13,623 | 19,485,897 | Oral naftidrofuryl and cilostazol have an acceptable safety profile as well as sustained evidence ( documented by Cochrane analyses ) of increased walking capacity .
In contrast , buflomedil and pentoxifylline have limited and /or doubtful evidence to increase walking capacity .
Moreover , there were safety concerns about the narrow therapeutic range of buflomedil .
Most other " vasoactive " drugs were either inappropriately or insufficiently tested or showed no significant if not negative effects on IC . "
Vasoactive " drugs are no substitutes for lifestyle or exercise therapy but are adjuvant treatment to the well-appreciated triad of cardiovascular prevention ( antiplatelet agents , statins and ACE-inhibitors ) , of which statins in their own right have documented cl aims to significantly increase walking capacity . | Several oral " vasoactive " drugs cl aim to increase walking capacity in patients with intermittent claudication ( IC ) .
Naftidrofuryl , cilostazol , buflomedil , and pentoxifylline are the most studied molecules .
Although spanning several decades , several studies underlying these cl aims were not properly design ed , underpowered or showed clinical ly doubtful outcomes .
The evidence for these " vasoactive " drugs has always been received with scepticism , creating the need for systematic review s and meta-analyses .
This brief review discusses the benefit-risk assessment of vasoactive drugs , by applying a systematic review to evaluate r and omized , placebo-controlled trials .
Subsequently , these drugs entered recommendations for peripheral arterial disease ( PAD ) . | Intermittent claudication is the primary symptom of peripheral arterial disease , affecting between 1 and 3 million Americans . Symptomatic improvement can be achieved by endovascular revascularization , but such procedures are invasive , expensive , and may be associated with procedural adverse events . Medical treatment options , including claudication medications and supervised exercise training , are also known to be effective , albeit also with associated limitations . The CLEVER ( Claudication : Exercise Vs . Endoluminal Revascularization ) study , funded by the Heart , Lung , and Blood Institute of the National Institutes of Health , is a prospect i ve , multicenter , r and omized , controlled clinical trial evaluating the relative efficacy , safety , and health economic impact of four treatment strategies for people with aortoiliac peripheral arterial disease and claudication . The treatment arms are : ( 1 ) optimal medical care ( claudication pharmacotherapy ) ; ( 2 ) primary stent placement ; ( 3 ) supervised exercise rehabilitation ; and ( 4 ) combined stenting with supervised exercise rehabilitation . The CLEVER study is a 5-year r and omized , controlled clinical trial to be conducted at approximately 25 centers in the United States that will monitor 252 patients and their responses to treatment during an 18-month follow-up period . The primary end point is change in maximum walking duration on a grade d treadmill test . Secondary end points include the change at 18 months in maximum walking duration from baseline , comparisons of free-living daily activity levels assessed by pedometer , health-related quality of life , and cost-effectiveness . Other analyses include the effect of these treatment strategies on anthropomorphic and physiologic variables , including body mass index , waist circumference , blood pressure , pulse pressure , and resting pulse as well as biochemical markers of cardiovascular health , including fasting lipids , fibrinogen , C-reactive protein , and hemoglobin A 1c values Background —We determined whether statin use ( versus nonuse ) is associated with superior lower-extremity functioning independently of cholesterol levels and other confounders in patients with and without peripheral arterial disease . Methods and Results — Participants included 392 men and women with an ankle brachial index ( ABI ) < 0.90 and 249 with ABI 0.90 to 1.50 . Functional outcomes included 6-minute walk distance and 4-meter walking velocity . A summary performance score combined performance in walking speed , st and ing balance , and time for 5 repeated chair rises into an ordinal score ranging from 0 to 12 ( 12=best ) . Adjusting for age , sex , ABI , comorbidities , education level , medical insurance status , cholesterol , and other confounders , participants taking statins had better 6-minute walk performance ( 1276 versus 1218 feet , P = 0.045 ) , faster walking velocity ( 0.93 versus 0.89 m/s , P = 0.006 ) , and a higher summary performance score ( 10.2 versus 9.4 , P < 0.001 ) than participants not taking statins . Positive associations were attenuated slightly after additional adjustment for C-reactive protein level but remained statistically significant for walking velocity and the summary performance score . We did not find significant associations between lower-extremity functioning and aspirin , ACE inhibitors , vasodilators , or & bgr;-blockers . Conclusions —Statin use is associated with superior leg functioning compared with no statin use , independent of cholesterol levels and other potential confounders . These data suggest that non – cholesterol-lowering properties of statins may favorably influence functioning in persons with and without peripheral arterial disease Simvastatin significantly increased treadmill exercise time until onset of intermittent claudication from baseline by 54 seconds ( a 24 % increase , p < 0.0001 ) at 6 months after treatment and by 95 seconds ( a 42 % increase , p < 0.0001 ) at 1 year after treatment . At 6 months and 1 year after treatment with placebo , treadmill exercise time until onset of intermittent claudication was not significantly different from baseline exercise time Background —Cholesterol modification reduces cardiovascular events in patients with atherosclerosis , including those with peripheral arterial disease . The purpose of this study was to determine whether cholesterol lowering with atorvastatin improves walking performance in patients with intermittent claudication . Methods and Results —This r and omized , double-blind , parallel- design study included 354 persons with claudication attributable to peripheral arterial disease . Patients were treated with placebo , atorvastatin ( 10 mg per day ) , or atorvastatin ( 80 mg per day ) for 12 months . The outcome measures included change in treadmill exercise time and patient-reported measures of physical activity and quality of life based on question naires . Maximal walking time after 12 months of treatment with atorvastatin did not change significantly . However , there was improvement in pain-free walking time after 12 months of treatment for the 80-mg ( P = 0.025 ) group compared with placebo . A physical activity question naire demonstrated improvement in ambulatory ability for the 10- and 80-mg groups ( P = 0.011 ) , whereas 2 quality of life instruments , the Walking Impairment Question naire and Short Form 36 Question naire , did not show significant change . Conclusions —Atorvastatin improves pain-free walking distance and community-based physical activity in patients with intermittent claudication . When treated with atorvastatin , patients with peripheral arterial disease may experience improvement in symptoms to complement the anticipated reduction in cardiovascular events reported in other studies of statins Background — Cardiovascular-related morbidity and mortality in patients with peripheral arterial obstructive disease remain high . We performed an international , multicenter , r and omized , double-blind , placebo-controlled trial to investigate whether long-term administration of oral buflomedil could reduce the rate of cardiovascular events in patients with intermittent claudication . Methods and Results — Patients > 40 years of age with documented peripheral arterial obstructive disease , intermittent claudication , and an ankle-brachial index between 0.30 and 0.80 were eligible for inclusion and were r and omized to receive orally either buflomedil or placebo for 2 to 4 years . Aspirin was recommended for all patients ( unless they were receiving other antithrombotic treatments at inclusion ) . The primary efficacy outcome was critical cardiovascular events , defined as the composite of cardiovascular death , nonfatal myocardial infa rct ion , nonfatal stroke , symptomatic deterioration of peripheral arterial obstructive disease , or leg amputation . A total of 2078 patients were recruited . Mean treatment duration was 33 months . The rate of critical cardiovascular events was significantly lower in buflomedil-r and omized patients than in placebo-r and omized patients ( 9.1 % versus 12.4 % ; hazard ratio , 0.742 ; 95 % confidence interval , 0.603 to 0.915 ; P=0.0163 ) . Ankle-brachial index increased by 9.2 % in buflomedil-r and omized patients and decreased by 3.6 % in placebo-r and omized patients ( P<0.001 ) . Tolerance of buflomedil and placebo was comparable . Conclusions — Compared with placebo , buflomedil administered for 3 years reduced the occurrence of symptomatic cardiovascular events by 26 % . The main contributor to the difference in the composite outcome was the reduction in symptomatic deterioration of peripheral arterial disease . The use of buflomedil should be considered in addition to an antiplatelet agent in patients with peripheral arterial obstructive disease and intermittent claudication BACKGROUND Changes in blood rheology have been described in diabetes mellitus . Buflomedil , a vasoactive substance with hemorheological properties , has been widely used in the treatment of intermittent claudication . The aim of this study was to evaluate the effect of buflomedil on clinical and hemorheological parameters in subjects with type 2 diabetes and intermittent claudication . METHODS Forty patients were r and omly assigned to oral buflomedil or matching placebo for six months in a double-blind manner . Initial and absolute walking distances were assessed by a st and ard treadmill testing protocol . Erythrocyte deformability was estimated with a whole blood filtration technique . ADP- and collagen-induced platelet aggregation was assessed with an aggregation profiler . beta-thromboglobulin and platelet factor-4 were measured with radioimmunoassays . All tests were performed at baseline and after three and six months of treatment . RESULTS A significant increase in the mean initial ( 71 % ) and absolute ( 68 % ) walking distance was achieved only in the buflomedil group . ADP- and collagen-induced platelet aggregation was significantly reduced in the buflomedil group , while no significant changes in erythrocyte deformability , beta-thromboglobulin and platelet factor-4 levels were noticed . However , beta-thromboglobulin levels increased significantly in the placebo group . CONCLUSIONS These findings suggest the therapeutic efficacy of buflomedil in diabetic subjects with intermittent claudication . The inhibition of platelet aggregation and the influence on platelet activity exerted by the drug could play an important role in its clinical effect and may be of value in the treatment of such patients The efficacy , safety , and cost of pentoxifylline ( PXF ) in long-range ( > 400 m interval ) intermittent claudication was studied comparing PXF and placebo in a 12-month study . A st and ardized treadmill test was performed at inclusion and at 6 and 12 months . A training plan based on walking was associated with the control of risk factor levels . Of the 194 included patients , 135 completed the study : 75 in the PXF group and 60 in the placebo group . There were 59 dropouts ( due to low compliance ) . The authors observed a 148 % increase in total walking distance ( TWD ) at 6 months with PXF ( vs 110 % with placebo ; p<0.05 ) ; at 12 months , the increase was 170 % with PXF ( vs 131 % with placebo ; p<0.02 ) . There was a 38 % difference at 6 months and 39 % at 12 months in favor of PXF . Treatment was well tolerated . In conclusion , PXF improved walking distance significantly better than placebo This study compared the safety and efficacy of cilostazol and clopidogrel after coronary stenting . Patients ( n = 689 ) who underwent successful stenting were r and omly assigned to receive cilostazol ( group 1 , n = 344 , 612 lesions ) or clopidogrel ( group 2 , n = 345 , 628 lesions ) . The incidence of subacute stent thrombosis or major adverse cardiac events , including death , myocardial infa rct ion , and target lesion revascularization within 30 days ( 2.6 % in group 1 vs 2.0 % in group 2 , p = 0.61 ) and side effects that required cessation of study drug ( 0.6 % each ) did not differ statistically between groups . These results indicate that cilostazol is as safe and effective as clopidogrel in preventing thrombotic complications after stenting The efficacy , safety , and cost of pentoxifylline ( PXF ) in the treatment of severe intermittent claudication were studied comparing PXF and placebo in a r and omized 40-week study . A treadmill test was performed at inclusion and at the end of weeks 20 and 40 . A progressive training plan and the control of risk factors ( with antiplatelet treatment ) were used in both groups . Of the 200 included patients , 178 completed the study : 88 in the PXF group and 90 in the placebo group . There were 22 dropouts . The two groups were comparable for age , sex distribution , and for the presence of risk factors and smoking . There was a significant increase in pain-free walking distance ( PFWD ) in both groups . The absolute and percent increase in PFWD was significantly greater in the PXF group ( p<0.05 ) . At 20 weeks , the increase was 360.5 % in the PXF vs 252 % in the placebo group . At 40 weeks , the increase was 386 % in the PXF and 369 % in the placebo group ( p<0.02 ) . Total walking distance ( TWD ) increased at 20 weeks ( up to 254 % ) and up to 329 % at 40 weeks . In the placebo groups the increase was 158 % at 20 weeks and 183 % at 40 weeks . The excess increase produced by PXF treatment was 30 % at 20 weeks and 38 % at 40 weeks ( p<0.02 ) . Unwanted effects treatment was well tolerated . No serious drug-related side effects were observed . In summary , between-group analysis favors PXF considering walking distance and costs . Results indicate good efficacy and tolerability The Statin Safety Assessment Conference of the National Lipid Association ( NLA ) , reported in this supplement to The American Journal of Cardiology , provides a comprehensive evaluation of old and new experience on adverse events associated with the 3-hydroxy-3-methylglutaryl coenzyme A ( HMG-CoA ) reductase inhibitors , or statins . To place these in context , one can express both the risk of side effects and the benefits for cardiovascular disease in terms of events per person-year of statin treatment . The mortality risk from fatal rhabdomyolysis is approximately 0.3 per 100,000 person-years , and the risks of nonfatal rhabdomyolysis and of putative statin-attributable peripheral neuropathy are approximately 3 and 12 events , respectively , per 100,000 person-years . Reports of acute liver failure and acute or chronic kidney disease give lower rate estimates that , even when corrected for underreporting , are approximately equal to the background rates of these conditions in the general population , lending scant support for statin-attributable etiology . In contrast , the benefit of statin use is to avert several hundred deaths and several hundred cases each of heart and brain infa rct ion per 100,000 person-years in appropriately treated high-risk patients . Although population estimates such as these are useful , they must be translated repeatedly to individual patient-provider encounters , where clinical skill and art must combine with scientific evidence . The continued publication of individual case reports and small r and omized trials among groups of patients with potential side effects should be encouraged . Statins should not be used in situations where minimal benefit is expected , as safety data and risk-benefit analysis must be meshed with guidelines that help the clinician decide whom to treat and how aggressively to treat The aims of this study were to evaluate the effect of PXF ( 1600 mg daily ) in diabetic patients with intermittent claudication . Of the 60 included patients , 53 completed the study ( 27 in the PXF group ) . There were seven dropouts . The groups were comparable for age , sex distribution , and total walking distance ( TWD ) , and risk factors . There was an increase in TWD at 3 and 6 months in both groups ( p<0.05 ) possibly due to exercise . However the increase ( both absolute and percentage ) in TWD was significantly larger in the PXF group . At 6 months , PXF produced a 292 % increase in TWD ( vs 180 % produced by placebo ) ( p<0.02 ) . The excess increase produced by PXF treatment was 112 % at 6 months in comparison with placebo ( p<0.02 ) . Treatment was well tolerated . Between-group analysis favors PXF considering TWD , and results indicate good efficacy and tolerability BACKGROUND We report in this paper the findings of a pooled analysis of 3 previously published studies undertaken in Germany , France and Belgium to assess the effects of naftidrofuryl on the quality of life of patients with intermittent claudication . METHODS A total of 754 patients were r and omised in the 3 studies , 709 of whom ( 358 naftidrofuryl , 351 placebo ) were available for the primary intention-to-treat analysis . The primary outcome variable was the change in the disease-related limitation of the quality of life as measured by the CLAU-S question naire . This instrument which has been vali date d in an international study , comprises 47 questions covering 5 dimensions : " daily living " , " pain " , " social life " , " disease specific anxiety " and " mood " . RESULTS A multivariate analysis of covariance adjusted for baseline values , study effect and first order study treatment interaction , demonstrated the global superiority of naftidrofuryl over placebo ( p<0.001 ) . A separate covariance analysis for the 5 dimensions showed highly significant differences for " daily living " , " pain " , " social life " and " mood " ( all p<0.01 ) . CONCLUSIONS In conclusion , this pooled analysis has shown that naftidrofuryl can significantly improve the quality of life of patients with intermittent claudication . These findings , taken together with evidence from previous studies that it improves treadmill walking distances , suggest that naftidrofuryl can play a useful role in the treatment of this condition The efficacy , safety and cost of pentoxifylline ( PXF ) in severe intermittent claudication was studied comparing PXF and placebo in a 12-month study . A treadmill test and microcirculatory evaluation with laser Doppler flowmetry were performed at inclusion and at the end of 6 and 12 months . A physical training plan ( based on walking ) and reduction in risk factor levels plan was used in both groups . Of the 120 included patients , 101 completed the study : 56 in the PXF group and 45 in the placebo group . There were 19 dropouts ( due to low compliance ) . The two groups were comparable for age , sex distribution , walking distance , and the presence of risk factors and smoking . Intention-to-treat analysis indicated a 268 % increase in walking distance in the PXF group ( vs 198 % in the placebo group ; p<0.05 ) at 6 months and an increase of 404 % ( vs 280 % in the placebo group ; p<0.02 ) at 12 months . The absolute and percent increase in pain-free walking distance ( PFWD ) was greater in the PXF group ( p<0.05 ) . Treatment was well tolerated . No serious drug-related side effects were observed . Microcirculatory evaluation indicated an increase in flux ( p < 0.05 ) in the PXF group ( not significant in the placebo group ) ; the after-exercise flux ( AEF ) was increased ( p<0.05 ) in both groups at 6 months but the increase in AEF was greater in the PXF group at 12 month . In conclusion , between-group analysis favors PXF considering walking distance and microcirculatory parameters . Results indicate good efficacy and tolerability OBJECTIVES We sought to evaluate the impact of cilostazol on neointimal hyperplasia after drug-eluting stent ( DES ) implantation in patients with diabetes mellitus ( DM ) . BACKGROUND Although cilostazol has reduced the extent of neointimal hyperplasia and restenosis in patients after bare-metal stent implantation , it is not known whether this effect occurs after DES implantation in diabetic patients . METHODS This r and omized , multicenter , prospect i ve study compared triple antiplatelet therapy ( aspirin , clopidogrel , and cilostazol , triple group , n = 200 ) and dual antiplatelet therapy ( aspirin and clopidogrel , st and ard group , n = 200 ) for 6 months in patients with DM receiving DES . The primary end point was in-stent late loss at 6 months . RESULTS The 2 groups had similar baseline clinical and angiographic characteristics . The in-stent ( 0.25 + /- 0.53 mm vs. 0.38 + /- 0.54 mm , p = 0.025 ) and in-segment ( 0.42 + /- 0.50 mm vs. 0.53 + /- 0.49 mm , p = 0.031 ) late loss were significantly lower in the triple versus st and ard group , as were 6-month in-segment restenosis ( 8.0 % vs. 15.6 % , p = 0.033 ) and 9-month target lesion revascularization ( TLR ) ( 2.5 % vs. 7.0 % , p = 0.034 ) . At 9 months , major adverse cardiac events , including death , myocardial infa rct ion , and TLR , tended to be lower in the triple than in the st and ard group ( 3.0 % vs. 7.0 % , p = 0.066 ) . Multivariate analysis showed that sirolimus-eluting stents and the use of cilostazol were strong predictors of reduced restenosis or TLR . CONCLUSIONS Triple antiplatelet therapy after DES implantation decreased angiographic restenosis and extent of late loss , result ing in a reduced risk of 9-month TLR compared with dual antiplatelet therapy in diabetic patients |
13,624 | 26,657,467 | Some differences in job satisfaction were however observed within different subgroups of nurses .
There were no statistically significant differences in either stress or job tension .
Due to the limited number of quantitative studies identified for inclusion in this systematic review it is not possible to determine whether organizing nursing work in a team nursing or total patient care model is more effective in terms of staff wellbeing in acute care setting s. Neither a team nursing or total patient care model had a significant influence on nurses ' overall job satisfaction , stress levels or staff turnover .
This review demonstrates the need for further quantitative studies of these models of care that are well design ed with sufficient sample sizes to allow for attrition of participants , and that explore the impact each model has on nurse 's wellbeing , in particular , studies that address burnout and absenteeism . | BACKGROUND The organization of the work of nurses , according to recognized models of care , can have a significant impact on the wellbeing and performance of nurses and nursing teams .
This review focuses on two models of nursing care delivery , namely , team and total patient care , and their effect on nurses ' wellbeing .
OBJECTIVES To examine the effectiveness of team nursing compared to total patient care on staff wellbeing when organizing nursing work in acute care wards . | Objectives : To describe ( 1 ) the extent to which acute and intensive care units use the elements of nursing models ( team , functional , primary , total patient care , patient-focused care , case management ) and ( 2 ) the deployment of non-unit-based personnel re sources . Background : The lack of current data -based behavioral descriptions of the extent to which elements of nursing models are implemented makes it difficult to determine how work models may influence outcomes . Methods : Nurse managers of 56 intensive care units and 80 acute care adult units from 40 r and omly selected US hospitals participated in a structured interview regarding ( 1 ) day-shift use of patient assignment behaviors associated with nursing models and ( 2 ) the availability and consistency of assignment of non-unit-based support personnel . Results : No model was implemented fully . Almost all intensive care units reported similar assignment behaviors except in the consistency of patient assignment . Non-intensive care units demonstrated wide variation in assignment patterns . Patterns differed intrainstitutionally . There were large differences in the availability and deployment of non-unit-based supportive re sources . Conclusions : Administrators must recognize the differences in work models within their institutions as a part of any quality improvement effort . Attempts to test new work models must be rigorous in the measurement of their implementation AIM To examine factors within the nursing work environment that may affect nurse outcomes . BACKGROUND Primary data were acquired from unit managers and staff nurses on the study units . Secondary data were collected from health records administrative data bases . The sample included adult medical and surgical units within all 19 teaching hospitals in Ontario , Canada . METHODS A cross-sectional study design was employed in this study . A r and om sampling process was used to recruit the number of nurses ( n = 1,116 ) required to provide a statistically adequate sample for the survey . RESULTS Perceptions of the quality of care at the unit level were found to have a statistically significant positive influence on nurses ' job satisfaction , and a statistically significant negative influence on nurses ' job pressure and job threat . CONCLUSIONS The results of this study underscore the importance of examining the environment in which nurses ' work as a potential factor that influences outcomes experienced by patients and nurses BACKGROUND Recently , restructuring of the nursing workforce has been undertaken in a number of countries in an effort to provide efficient and cost-effective services to users . This often takes the form of the introduction of unregulated workers to carry out support roles with registered nurses . However , these changes have not been evaluated for efficacy or impact on nurses , patients or the health care system . PURPOSE The purpose of this study was to determine the relationship between staff mix models comprising regulated staff ( Registered Nurses and Registered Practical Nurses ) or regulated and unregulated staff ( Registered Nurses and unregulated workers ) , and nursing and quality outcomes . METHODS This comparative correlational study was conducted in a r and om sample of 30 adult , acute care patient units within eight hospitals located in Toronto , Canada . Registered Nurses employed on 30 r and omly selected hospital units , grouped by the two staff mix models ( 15 units per group ) , were surveyed using previously vali date d instruments to measure role conflict , role ambiguity , job satisfaction , perceived effectiveness of care and perceived quality of care . RESULTS Results indicated that Registered Nurses in this study experienced high levels of role conflict , regardless of the type of staff mix model within which they worked . Registered Nurses on units employing both Registered Nurses and unregulated workers reported higher levels of job satisfaction . On units employing both Registered Nurses and unregulated workers , Registered Nurses perceived that the quality of care was lower . CONCLUSIONS Staff mix model was related to Registered Nurses ' perceptions of the quality of patient care . It was also evident that other variables within the work environment might have more influence on the outcomes examined than the independent variable of staff mix The employment of unlicensed personnel in Canadian acute care hospitals has been undertaken without clear evidence of outcomes for patients , caregivers , and hospital organizations . This quasi-experimental evaluation study was completed in a metropolitan Toronto acute care hospital to examine the effects of a new nursing care delivery system which included unlicensed assistive personnel . Most of the expected benefits of the newly implemented nursing care delivery system did not material ize leading to the conclusion that the employment of unlicensed assistive personnel in acute care hospital systems may not offer additional benefits for patients , caregivers , or hospital organizations . The processes and results of this study provide useful information for nurse administrators who are seeking effective and innovative care delivery systems that are design ed to optimize patient , caregiver , and hospital outcomes Background This systematic review set out to examine the impact , if any , of nursing workload and staffing on creating and maintaining healthy work environments . For the purpose s of this review , the term ‘ healthy work environment ’ was defined as ‘ … a practice setting that maximizes the health and well‐being of nurses , quality patient outcomes and organizational performance ’ . This definition identifies nurse , patient and organisational outcomes as indicators of the establishment and maintenance of a healthy work environment . Objectives The review sought to determine the impact of : Patient characteristics , nurse characteristics , system characteristics and system processes on workload , scheduling and concepts of productivity and utilisation Workload , scheduling and concepts of productivity and utilisation on the quality of outcomes for clients , nurses and the system/organisation Search strategy The search strategy sought to find both published and unpublished studies and papers written in the English language . A three‐step search strategy approach was used . An initial limited search of MEDLINE and CINAHL data bases was undertaken to identify optimal search terms followed by an analysis of the text words contained in the title and abstract , and of the index terms used to describe the article . A second extensive search using all identified keywords and index terms was then undertaken . The third step consisted of a search of the reference lists of all identified reports and articles for additional studies . Selection criteria Types of studies : This review considered research papers that addressed the appropriateness and effectiveness of workload and staffing concepts in fostering a healthy work environment in healthcare . The types of papers to be considered included : meta‐ analysis , r and omised controlled trials , quasi‐r and omised controlled trials , cohort studies , case‐control studies , descriptive studies and correlational studies . Types of participants : The review considered all participants involved or affected by workload and staffing concepts within the nursing workforce in a healthcare environment , including staff and patients . System and policy issues were also considered . Types of interventions : All workload and staffing strategies that impact on the work environment , patient and nurse outcomes were considered in this review . Types of outcome measures : Outcomes of interest were categorised into four groups : nursing staff outcomes , patient outcomes , organisational outcomes and system outcomes . Data collection and analysis Following assessment of method ological quality , data were extracted using data extraction tools based on the work of the Cochrane Collaboration and the Centre for Review s and Dissemination . Statistical pooling was not possible and findings were presented in narrative form . Results Of the 2162 papers identified in the search , 171 were selected for full paper retrieval and assessed independently by two review ers for method ological quality . A total of 40 papers were included in the review : one systematic review ; one cohort study ; and 38 correlational descriptive studies . Results were summarised in narrative form . The evidence suggests strong correlations between patient characteristics and work environments ; and workload and staffing and the quality of outcomes for clients , nurses and the system/organisation . This gave rise to a number of recommendations for practice and for further research , such as : A greater proportion of regulated staffing ( i.e. registered nurses , enrolled nurses , practical or vocational nurses ) is associated with improved outcomes related to the Functional Independence Measure score , the Short Form Health Survey ( SF‐36 ) vitality score , patient satisfaction with nursing care , patient adverse events ( including atelectasis , decubitus ulcers , falls , pneumonia , postsurgical and treatment infection and urinary tract infections ) An increase in the number of registered nurse hours available is associated with improved patient outcomes in relation to falls , pneumonia , pressure ulcers , urinary tract infection , length of stay and postoperative infection A study was conducted in a Dutch hospital to evaluate the effects of the implementation of a Dutch form of Primary Nursing on nurses ' well-being in the work situation . The variables used as indicators of well-being at work were job satisfaction , experienced job significance , health complaints and absenteeism . The study included three measuring periods : one pre-intervention ( t1 ) and two post-intervention periods ( t2 , 8 months after t1 , and t3 , 14 months after t1 ) . Primary Nursing was implemented in group 1 ( consisting of two nursing units ) after t1 . At this time no changes were introduced into group 2 ( three nursing units ) but after t2 . Primary Nursing was also implemented in group 2 . The research variables were measured by means of question naires . The results of the study indicate that most of the expected effects of Primary Nursing did not occur . Some method ological and practical explanations for this outcome are given Abstract A nursing job satisfaction question naire was design ed by a project group of nurses seeking a suitable job satisfaction measure to track as an outcome in a large Sydney hospital-wide models of nursing care project . Existing tools were rejected by the group as overly lengthy , US-biased and over-using respondent assessment of the character of the work environment as a proxy for job satisfaction , or happiness at work . A one-page , 14-item tool was developed after instrument review ing and facilitated groupwork . The tool reduces to three measurable domains : intrinsic , extrinsic and relational job satisfaction . Exploratory factor analysis ( n = 220 responses ) confirmed the validity of this ‘ three-way ’ conceptualisation of nursing job satisfaction . Internal consistency analysis on a larger sample of responses ( n = 459 ) yielded high Cronbach ’s Alpha values for all three domains and for the total overall , suggesting a stable and reliable measure . The NWSQ is short , one page , sensibly worded for Australian conditions and yields scoring against three vali date d domains . It holds significant potential utility as a st and ard metric for prospect i ve ward-based or institution-wide performance trending BACKGROUND As the European population ages , the dem and for nursing care increases . Yet , a shortage of nurses at the labour market exists or is predicted for most European countries . There are no adequate solutions for this shortage yet , and recruitment of future nurses is difficult . Therefore , retaining nurses for the profession is urgent . OBJECTIVE To determine factors associated with nurses ' intention to leave the profession across European countries . DESIGN A multi-country , multi-centre , cross-sectional analysis of survey data . SETTING 2025 surgical and medical units from 385 hospitals in ten European countries that participated in the RN4Cast study . Hospital selection was based on a stratified r and omised selection procedure . PARTICIPANTS All nurses from the participating medical and surgical hospital wards received a survey . 23,159 nurses ( 64 % ) returned the survey . METHODS The nurse survey included questions about intention to leave the profession , nurse characteristics , factors related to work environment , patient-to-nurse staffing ratio , burnout and perceived quality and safety of care . Multilevel regression analyses with ' intention to leave the profession ' as dependent variable were conducted for all 10 countries combined as well as per country . RESULTS Overall , 9 % of the nurses intended to leave their profession . This varied from 5 to 17 % between countries . Seven factors were associated with intention to leave the profession at European level : nurse-physician relationship ( OR 0.86 ; 95%CI 0.79 - 0.93 ) , leadership ( OR 0.78 ; 95 % CI 0.70 - 0.86 ) , participation in hospital affairs ( 0.68 ; 95%CI 0.61 - 0.76 ) , older age ( OR 1.13 ; 95%CI 1.07 - 1.20 ) , female gender ( OR 0.67 ; 95%CI 0.55 - 0.80 ) , working fulltime ( OR 0.76 ; 95%CI 0.66 - 0.86 ) and burnout ( OR 2.02 ; 95%CI 1.91 - 2.14 ) . The relevance of these factors differed for the individual countries . Nurse perceived staffing adequacy , patient-to-nurse staffing ratio , perceived quality and safety of care and hospital size were not associated with intention to leave at a European level . CONCLUSION Burnout is consistently associated with nurses ' intention to leave their profession across the 10 European countries . Elements of work environment are associated with intention to leave the nursing profession but differ between countries , indicating the importance of national context s in explaining and preventing nurses ' intention to leave their profession Abstract Agreement was reached with 12 acute medical and surgical wards/units at Sydney ’s Prince of Wales Hospital to participate in a trial of team nursing ( TN ) . Six units employed action research principles to undertake a change to a team nursing model and six remained with the pre-existing individual patient allocation ( IPA ) model . Task-based teaming was widely discarded by the team nursing units in favour of allocating patients within the team and introducing more supportive and communicative processes aim ed at fostering responsibility sharing . Localised team-based models of care arose in the change wards and were outlined , implemented and refined using social action research principles . A 12-month prospect i ve experimental comparison of job satisfaction and staff retention between the TN and IPA groups indicated statistically significant job satisfaction benefits and practically important staff retention benefits associated with moving away from an IPA model of nursing care delivery towards a team-based model of care delivery . Perhaps not surprisingly , job satisfaction gains were most marked among new graduate nurses , who reported real benefits from a teaming inspired shift in model of care in the acute inpatient environment |
13,625 | 30,240,473 | Treatment with mesalazine seems to be effective in achieving symptom relief and in the primary prevention of diverticulitis in patients with SUDD | BACKGROUND AND AIMS Symptomatic Uncomplicated Diverticular disease ( SUDD ) affects about 25 % of patients harboring colonic diverticula .
We assessed the effectiveness of mesalazine in improving symptoms ( namely abdominal pain , primary outcome ) and in preventing diverticulitis occurrence ( secondary outcome ) in patients with SUDD . | Goals To investigate the effectiveness and safety of mesalazine , with or without Lactobacillus casei , in preventing recurrence of symptomatic diverticular disease of the colon . Background Both mesalazine and probiotics showed recently their effectiveness in obtaining remission of symptomatic uncomplicated diverticular disease of the colon . Consistent data are not available on the optimal therapy to prevent recurrence of symptomatic diverticular disease of the colon . Study Multicenter , prospect i ve , r and omized , open-label study . Ninety consecutive patients ( 36 men , 54 women , mean age 67.5 y , range 39 to 84 y ) , previously affected by symptomatic uncomplicated diverticular disease of the colon ( remission obtained with rifaximin 800 mg/d plus mesalazine 2.4 g/d for 10 d , followed by mesalazine 1.6 g/d for 8 wk ) , were enrolled in a 12-month follow-up . The following symptoms were assessed at entry and through follow-up by using a quantitative scale : ( 1 ) constipation , ( 2 ) diarrhea , ( 3 ) abdominal pain , ( 4 ) rectal bleeding , and ( 5 ) mucus with the stools . After recruitment , the patients were r and omly assigned to one of the following 3 groups : mesalazine 1.6 g/d ( group M ) , L. casei DG 16 billion/d for 15 d/mo ( group L ) ; mesalazine 1.6 g/d+L. casei DG 16 billion/d for 15 d/mo ( group LM ) . Results Eighty-five patients completed the study ( 94.5 % ) : 2 patients ( 2.22 % , 1 of group M and 1 of group LM ) were withdrawn from the study for protocol violation and 1 ( 1.11 % ) for hospital admission due to acute pulmonary disease ( group L ) ; 2 patients ( 2.22 % ) were lost to follow-up . Seventy-five patients ( 88.2 % ) were symptom free after the 12th month of treatment ( overall symptomatic score : ( 0 ) : 23/27 patients of group M [ on intention to treat : 76.7 % confidence interval ( CI 95 % : 61.5 to 91.8 ) ] , 23/29 of group L [ on intention to treat : 76.7 % ( CI 95 % : 61.5 to 91.8 ) ] , 29/29 of group LM [ on intention to treat : 96 % ( CI 95 % : 94.2 to 100 ) ] ( P<0.05 ) . Only 10 patients ( 11.1 % ) showed recurrence of symptoms ( overall symptomatic score : 68 ) . Conclusions Both mesalazine and L. casei DG seem to be effective in preventing recurrence of symptomatic uncomplicated diverticular disease of the colon , but their association seems to be more promising in this field Forty consecutive patients affected by recurrent attacks of symptomatic uncomplicated diverticular disease of the colon were evaluated to investigate the effectiveness of 2 different mesalazine therapeutic schedules in preventing recurrence of the disease . The patients were r and omly enrolled and treated with mesalazine 1.6 g/d ( group A ) or mesalazine 1.6 g/d 10 days per month ( group B ) . Thirty-four patients completed the study ( 85 % ) : 3 ( 7.5 % , 1 in group A and 2 in group B ) were lost to follow-up , 2 ( 5 % , both group B ) were withdrawn from the study for protocol violation , and 1 ( 2.5 % ) for hospital admission for stroke ( group A ) . Twenty-three patients ( 67.65 % ) were symptom free after 24 months of treatment ( overall symptomatic score , 0 ) : 14 of 18 in group A ( per- protocol , 77.78 % ; intention to treat , 70 % [ 95 % confidence interval [ CI ] , 61.5–91.8 ] ) , 9 of 16 in group B ( per protocol , 56.25 % ; intention to treat , 45 % [ 95 % CI , 61.5–91.8 ] ; P < 0.05 ) . Four patients ( 10 % ) improved , but were not completely symptom free . Six patients ( 15 % ) showed recurrence of symptoms : 1 in group A ( 5.56 % ) and 5 in group B ( 31.25 % ; P < 0.005 ; overall symptomatic score , 68 ) . Daily mesalazine supplying seems to be more effective than cyclic supplying in maintaining remission in recurrent symptomatic uncomplicated diverticular disease Previous studies have reached conflicting conclusions regarding the efficacy of mesalazine in the prevention of recurrent diverticulitis BACKGROUND & AIMS No therapy has been proven to prevent the recurrence of diverticulitis . Mesalamine has shown efficacy in preventing relapse in inflammatory bowel disease , and there is preliminary evidence that it might be effective for diverticular disease . We investigated the efficacy of mesalamine in preventing recurrence of diverticulitis in 2 identical but separate phase 3 , r and omized , double-blind , placebo-controlled , multicenter trials ( identical confirmatory trials were conducted for regulatory reasons ) . METHODS We evaluated the efficacy and safety of multimatrix mesalamine vs placebo in the prevention of recurrent diverticulitis in 590 ( PREVENT1 ) and 592 ( PREVENT2 ) adult patients with ≥1 episodes of acute diverticulitis in the previous 24 months that resolved without surgery . Patients received mesalamine ( 1.2 g , 2.4 g , or 4.8 g ) or placebo once daily for 104 weeks . The primary end point was the proportion of recurrence-free patients at week 104 . Diverticulitis recurrence was defined as surgical intervention at any time for diverticular disease or presence of computed tomography scan results demonstrating bowel wall thickening ( > 5 mm ) and /or fat str and ing consistent with diverticulitis . For a portion of the study , recurrence also required the presence of abdominal pain and an increase in white blood cells . RESULTS Mesalamine did not reduce the rate of diverticulitis recurrence at week 104 . Among patients in PREVENT1 , 53%-63 % did not have disease recurrence , compared with 65 % of those given placebo . Among patients in PREVENT2 , 59%-69 % of patients did not have disease recurrence , compared with 68 % of those given placebo . Mesalamine did not reduce time to recurrence , and the proportions of patients requiring surgery were comparable among treatment groups . No new adverse events were identified with mesalamine administration . CONCLUSIONS Mesalamine was not superior to placebo in preventing recurrent diverticulitis . Mesalamine is not recommended for this indication . Clinical Trials.gov ID : NCT00545740 and NCT00545103 In uncomplicated diverticular disease , treatment is aim ed at relieving symptoms . The aim of the present study was to evaluate the efficacy of mesalazine for symptomatic relief of uncomplicated diverticular disease of the colon . Two hundred sixty-eight consecutive eligible out patients ( 122 male , 146 female ; age , 66.1 years ; range , 31–81 years ) were enrolled in four treatment schedules in a r and omized fashion : Group R1 ( 66 patients ) , rifaximin , 200 mg bid ; Group R2 ( 69 patients ) , rifaximin , 400 mg bid ; Group M1 ( 67 patients ) , mesalazine , 400 mg bid ; and Group M2 ( 66 patients ) , mesalazine , 800 mg bid . Treatments were administered for 10 days every month for 12 months . Clinical evaluations were performed at admission and at 3-month intervals for 12 months considering 12 clinical variables ( upper and lower abdominal pain/discomfort , tenesmus , diarrhea , abdominal tenderness , fever , bloating , general illness , nausea , emesis , dysuria , bleeding ) grade d as 0 = no symptoms , 1 = mild , 2 = moderate , and 3 = severe . The Global Symptomatic Score ( GSS ) was calculated using the sum of each symptom score . Two hundred forty-four patients completed the 12- month study ; 24 were discontinued ( 14 treated with rifaximin and 10 treated with mesalazine ) either as voluntary dropouts or because they developed side effects and /or complications . Group M2 demonstrated a lower frequency of many symptoms after 6 and 12 months of treatment ; the mean GSS was significantly lower in Group M2 after 6 and 12 months of therapy by both intention-to-treat and per- protocol analyses . Patients treated with mesalazine ( Groups M1+M2 ) had a lower GSS than subjects treated with rifaximin ( Groups R1+R2 ) during the 12-month follow-up period . We conclude that cyclic administration of mesalazine is effective for symptomatic relief of uncomplicated diverticular disease of the colon . Some symptoms showed greater improvement with mesalazine , 800 mg bid , than with the other treatment schedules BACKGROUND / AIMS Four different therapeutic schedules with mesalazine and /or probiotics were assessed in preventing recurrence of symptomatic diverticular disease ( DD ) of the colon . METHODOLOGY A prospect i ve , dose-finding study was conducted on 75 patients , enrolled in an open fashion : mesalazine 800mg/daily ( group M1 ) or mesalazine 1.6gr 10 days/month ( group M2 ) ; mesalazine 800mg/daily + Lactobacillus casei DG 16 billion/day for 10 day/month ( group LM1 ) or mesalazine 1.6gr + Lactobacillus casei DG 16 billion/day for 10 day/month ( group LM2 ) ; Lactobacillus casei DG 16 billion/day for 10 day/month ( group L ) . RESULTS Seventy one patients completed the study ( 94.66 % ) . Sixty six patients ( 88 % ) were symptom-free after the 24th month of treatment : 11 of group M1 ( on i-t-t : 84 % [ CI 95 % : 55.5 - 98.8 ] ) , 8 of group M2 ( on i-t-t : 80 % [ CI 95 % : 44.39 - 97.48 ] ) , 15 of group LM1 ( on i-t-t : 93.75 % [ CI 95 % : 69.77 - 99.84 ] ) , 12 of group LM2 ( on i-t-t : 92.30 % [ CI 95 % : 63.97 - 99.81 ] ) , 20 in group L ( on i-t-t : 86.95 % [ CI 95 % : 66.41 - 97.22 ] ) ( p-ns ) . Four patients ( 5.33 % ) suspended the treatment during the follow-up : all experienced recurrence of symptoms ( 100 % ) , and 2 of them developed diverticulitis ( 50 % ) . CONCLUSIONS Mesalazine and /or Lactobacillus casei seem to be effective in maintaining remission of DD for long-time . Moreover , we found recurrence of the disease and complications in all patients suspending treatments In order to evaluate the efficacy and tolerability of mesalazine ( 5-ASA ) in the prophylaxis of symptomatic relapses , of major complications and of microhemorrhagic phenomena in diverticular disease of the large intestine ( MDC ) , prospect i ve clinical study was conducted on patients with light-moderate symptomatic MDC under treatment with sulbactam-ampicillin 1.5 g/12 h i.m . and rifaximine 400 mg/12 h per os for 7 days . Follow-up period of 5 years with seriated checkups and laboratory and instrumentation controls . End points are represented by the relapse on inflammation and /or by the occurrence of major complications . On enrollment , 166 patients were r and omized to receive mesalazine ( Pentacol tablets -- SOFAR S.p . A. ) 400 mg b.i.d . per os for 8 weeks ( 81 patients ; group M ) or no supplementary treatment ( 85 patients ; group C ) . After 4 years of follow-up , 44 patients dropped out of the study ( 9 because of major complications , 3 for massive hemorrhage , and 32 drop outs ) . Symptomatic relapses occurred in 51 patients ( 12 M ; 39 C ) , while minor diverticular hemorrhages occurred in 43 patients ( 12 M ; 31 C ) , with an estimated probability of remaining free respectively from symptomatic relapse ( p=0.00005 ) and from microhemorrhagic phenomena ( p=0.001 ) decisively in favor of the group treated with mesalazine . The duration of abdominal pain due to diverticolitis was also shorter in patients of group M ( p=0.0002 ) , while the incidence of major complications and side effects was comparable in the two groups . In conclusion , supplementary treatment with mesalazine in patients affected with MDC -- at a follow-up limited to 48 months -- proved to be well tolerated and effective in reducing the frequency of symptomatic relapses and microhemorrhagic phenomena and in reducing the duration of abdominal pain AIM To comparatively evaluate the long term efficacy of Rifaximin and dietary fibers in reducing symptoms and /or complication frequency in symptomatic , uncomplicated diverticular disease . METHODS 307 patients ( 118 males , 189 females , age range : 40 - 80 years ) were enrolled in the study and r and omly assigned to : Rifaximin ( 400 mg bid for 7 d every month ) plus dietary fiber supplementation ( at least 20 gr/d ) or dietary fiber supplementation alone . The study duration was 24 mo ; both clinical examination and symptoms ' question naire were performed every two months . RESULTS Both treatments reduced symptom frequency , but Rifaximin at a greater extent , when compared to basal values . Symptomatic score declined during both treatments , but a greater reduction was evident in the Rifaximin group ( 6.4 + /- 2.8 and 6.2 + /- 2.6 at enrollment , P = NS , 1.0 + /- 0.7 and 2.4 + /- 1.7 after 24 mo , P < 0.001 , respectively ) . Probability of symptom reduction was higher and complication frequency lower ( Kaplan-Meyer method ) in the Rifaximin group ( P < 0.0001 and 0.028 , respectively ) . CONCLUSION In patients with symptomatic , uncomplicated diverticular disease , cyclic administration of Rifaximin plus dietary fiber supplementation is more effective in reducing both symptom and complication frequency than simple dietary fiber supplementation . Long term administration of the poorly absorbed antibiotic Rifaximin is safe and well tolerated by the patients , confirming the usefulness of this therapeutic strategy in the overall management of diverticular disease |
13,626 | 30,300,379 | The review indicates that prevalence rates of CSA is high among both boys and girls in India .
Commercial sex workers , men who have sex with men , and women with psychiatric disorders were at higher risks for sexual abuse during childhood .
In addition , the synthesis of qualitative data across studies included in the review suggests that exposure and perpetration of CSA is a multifaceted phenomenon grounded in the interplay between individual , family , community , and societal factors .
The review indicates poor physical , behavioural , social , and mental health outcomes of CSA in India . | OBJECTIVE Child Sexual Abuse ( CSA ) is a pressing human right issue and public health concern .
We conducted a systematic review of quantitative and qualitative studies published in the past decade on CSA in India to examine the distribution of the prevalence estimates for both genders , to improve underst and ing of the determinants and consequences of CSA and identify gaps in the current state of research . | Abstract : Background : Violence against children is a deep-rooted social problem in India . The problem is also related to economic as well as cultural beliefs and practice s. The objective of this study was to ascertain the prevalence and nature of violence experienced by the children in families in Tripura , India and its relationship with socio-economic factors . Methods : A group of 320 children ( 160 males and 160 females ) study ing in Class VIII and IX and aged between 14 - 19 participated in the study after obtaining their informed consent from eight r and omly selected English and Bengali medium schools in Agartala , Tripura ( India ) . Data were collected by using a specially design ed ' Semi-structured Question naire . Results : Findings revealed that about 20.9 % ( 67/320 ) , 21.9 % ( 70/230 ) and 18.1 % ( 58/230 ) of the children experienced psychological , physical and sexual violence respectively . Male children were more likely to be victims of psychological and physical violence while female children experienced more sexual violence ( p less than 0.01).Further analysis of data revealed some relationship between violence against children and nuclear family(p was less than 0.01),uncongenial and /or disturbed family environment ( p was less than 0.01 ) and dominating , short-tempered and /or aggressive parent personality ( p was less than 0.01),irrespective of the nature of the violence . Physical violence was found to be more prevalent in high income families ( p was less than 0.01 ) while children from the lower income group of families experienced more psychological violence ( p was less than 0.01 ) . Sexual violence was found to be equally prevalent in all socio-economic groups . The study also clearly indicated that academic performance of violence-experienced children , irrespective of nature of violence and socio-economic groups was poor compared to academic performance of non-violence-experienced children ( p was less than 0.01 ) . Conclusions : About one-fifth of the children under study did experience violence in Tripura . Findings speak in favor of an intervention program for creating awareness among parents and teachers about the issue of violence against children , targeted at parents when they meet for periodic parent-teachers meetings in the educational institutions INTRODUCTION Sexual interest toward prepubescents and pubescents ( pedophilia and hebephilia ) constitutes a major risk factor for child sexual abuse ( CSA ) and viewing of child abusive images , i.e. , child pornography offenses ( CPO ) . Most child sexual exploitation involving CSA and CPO are undetected and unprosecuted in the " Dunkelfeld " ( German : " dark field " ) . AIM This study assesses a treatment program to enhance behavioral control and reduce associated dynamic risk factors ( DRF ) in self-motivated pedophiles/hebephiles in the Dunkelfeld . METHODS Between 2005 and 2011 , 319 undetected help-seeking pedophiles and hebephiles expressed interest in taking part in an anonymous and confidential 1-year-treatment program using broad cognitive behavioral methodology in the Prevention Project Dunkelfeld . Therapy was assessed using nonr and omized waiting list control design ( n=53 treated group [ TG ] ; n=22 untreated control group [ CG ] ) . MAIN OUTCOME MEASURES Self-reported pre-/posttreatment DRF changes were assessed and compared with CG . Offending behavior characteristics were also assessed via self-reporting . RESULTS No pre-/post assessment changes occurred in the control group . Emotional deficits and offense-supportive cognitions decreased in the TG ; posttherapy sexual self-regulation increased . Treatment-related changes were distributed unequally across offender groups . None of the offending behavior reported for the TG was identified as such by the legal authorities . However , five of 25 CSA offenders and 29 of 32 CPO offenders reported ongoing behaviors under therapy . CONCLUSIONS Therapy for pedophiles/hebephiles in the Dunkelfeld can alter child sexual offending DRF and reduce-related behaviors . Unidentified , unlawful child sexual exploitative behaviors are more prevalent in this population than in officially reported recidivism . Further research into factors predictive of problematic sexual behaviors in the Dunkelfeld is warranted BACKGROUND Adolescents comprise a fifth of the population of India , but there is little research on their mental health . We conducted an epidemiological study in the state of Goa to describe the current prevalence of mental disorders and its correlates among adolescents aged between 12 and 16 years . AIMS To estimate the prevalence and correlates of mental disorders in adolescents . METHOD Population -based survey of all eligible adolescents from six urban wards and four rural communities which were r and omly selected . We used a Konkani translation of the Development and Well-Being Assessment to diagnose current DSM-IV emotional and behavioural disorders . All adolescents were also interviewed on socio-economic factors , education , neighbourhood , parental relations , peer and sexual relationships , violence and substance use . RESULTS Out of 2,684 eligible adolescents , 2,048 completed the study . The current prevalence of any DSM-IV diagnosis was 1.81 % ; 95 % CI 1.27 - 2.48 . The most common diagnoses were anxiety disorders ( 1.0 % ) , depressive disorder ( 0.5 % ) , behavioural disorder ( 0.4 % ) and attention-deficit hyperactivity disorder ( 0.2 % ) . Adolescents from urban areas and girls who faced gender discrimination had higher prevalence . The final multivariate model found an independent association of mental disorders with an outgoing ' non-traditional ' lifestyle ( frequent partying , going to the cinema , shopping for fun and having a boyfriend or girlfriend ) , difficulties with studies , lack of safety in the neighbourhood , a history of physical or verbal abuse and tobacco use . Having one 's family as the primary source of social support was associated with lower prevalence of mental disorders . CONCLUSIONS The current prevalence of mental disorders in adolescents in our study was very low compared with studies in other countries . Strong family support was a critical factor associated with low prevalence of mental disorders , while factors indicative of adoption of a non-traditional lifestyle were associated with an increased prevalence OBJECTIVES To document the prevalence of physical , emotional and sexual abuse during childhood among college students . METHODS The study was conducted among college students of Puducherry , South India . Stratified r and om sampling was done to select colleges . Data were gathered using the adapted ' Ministry of Women and Child Development Question naire on Child Abuse for Young adults ' . RESULTS A total of 936 college students completed the question naire . Mean ± SD age of the participants was 19.2 ± 1.1 years . Half ( 48 % ) of the participants reported being mocked because of their physical appearance . In all , 56 % ( 524/936 ) of the participants reported that they were beaten during their childhood , of which 13.4 % ( 70/524 ) required medical treatment . Around 10 % reported someone exposing his/her private parts to them , while in 6.4 % of the cases , the perpetrator forced the study participants to expose their private parts . CONCLUSIONS Emotional , physical and sexual abuse is common in childhood and dem and s prompt interventions at the familial , community and political levels The broad objective of this study was to underst and the incidence and severity of aggression among sexually abused girls who were trafficked and who were then further used for commercial sexual exploitation ( referred to subsequently as sexually abused trafficked girls ) . In addition , the impact of counseling for minimizing aggression in these girls was investigated . A group of 120 sexually abused trafficked Indian girls and a group of 120 nonsexually abused Indian girls , aged 13 to 18 , participated in the study . The sexually abused trafficked girls were purposively selected from four shelters located in and around Kolkata , India . The nonsexually abused girls were selected r and omly from four schools situated near the shelters , and these girls were matched by age with the sexually abused trafficked girls . Data were collected using a Background Information Schedule and a st and ardized psychological test , that is , The Aggression Scale . Results revealed that 16.7 % of the girls were first sexually abused between 6 and 9 years of age , 37.5 % between 10 and 13 years of age , and 45.8 % between 14 and 17 years of age . Findings further revealed that 4.2 % of the sexually abused trafficked girls demonstrated saturated aggression , and 26.7 % were highly aggressive , that is , extremely frustrated and rebellious . Across age groups , the sexually abused trafficked girls suffered from more aggression ( p < .05 ) , compared with the nonvictimized girls . Psychological interventions , such as individual and group counseling , were found to have a positive impact on the sexually abused trafficked girls . These findings should motivate counselors to deal with sexually abused children . It is also hoped that authorities in welfare homes will underst and the importance of counseling for sexually abused trafficked children , and will appoint more counselors for this purpose PURPOSE To evaluate the acceptability , feasibility , and effectiveness of a population -based intervention to promote health of youth ( age : 16 - 24 years ) in Goa . METHODS Two pairs of urban and rural communities were selected ; one of each was r and omly assigned to receive a multi-component intervention and the other wait-listed . The intervention comprised educational institution-based peer education and teacher training ( in the urban community ) , community peer education , and health information material s. Effectiveness was assessed through before-after population surveys at baseline and at 18 months . Outcomes were measured using a structured interview schedule with all eligible youth . Logistic regression compared each pair , adjusted for baseline differences , on prevalence of outcomes in the domains of reproductive and sexual health ( RSH ) , violence , mental health , substance use , and help seeking for health concerns . RESULTS In both intervention communities , prevalence of violence perpetrated and probable depression was significantly lower and knowledge and attitudes about RSH significantly higher ( p < .05 ) . The rural sample also reported fewer menstrual complaints and higher levels of help-seeking for RSH complaints by women , and knowledge and attitudes about emotional health and substance use ; and , the urban sample reported significantly lower levels of substance use , suicidal behavior , sexual abuse , and RSH complaints . Although information material s were acceptable and feasible in both communities , community peer education was feasible only in the rural community . The institution-based interventions were generally acceptable and feasible . CONCLUSIONS Multicomponent interventions comprising information material s , educational-institution interventions and , in rural context s , community peer interventions are acceptable and feasible and likely to be effective for youth health promotion BACKGROUND The Cochrane Collaboration is strongly encouraging the use of a newly developed tool , the Cochrane Collaboration Risk of Bias Tool ( CCRBT ) , for all review groups . However , the psychometric properties of this tool to date have yet to be described . Thus , the objective of this study was to add information about psychometric properties of the CCRBT including inter-rater reliability and concurrent validity , in comparison with the Effective Public Health Practice Project Quality Assessment Tool ( EPHPP ) . METHODS Both tools were used to assess the method ological quality of 20 r and omized controlled trials included in our systematic review of the effectiveness of knowledge translation interventions to improve the management of cancer pain . Each study assessment was completed independently by two review ers using each tool . We analysed the inter-rater reliability of each tool 's individual domains , as well as final grade assigned to each study . RESULTS The EPHPP had fair inter-rater agreement for individual domains and excellent agreement for the final grade . In contrast , the CCRBT had slight inter-rater agreement for individual domains and fair inter-rater agreement for final grade . Of interest , no agreement between the two tools was evident in their final grade assigned to each study . Although both tools were developed to assess ' quality of the evidence ' , they appear to measure different constructs . CONCLUSIONS Both tools performed quite differently when evaluating the risk of bias or method ological quality of studies in knowledge translation interventions for cancer pain . The newly introduced CCRBT assigned these studies a higher risk of bias . Its psychometric properties need to be more thoroughly vali date d , in a range of research fields , to underst and fully how to interpret results from its application |
13,627 | 30,777,888 | No clear difference in substance use was seen .
HF approaches successfully improve housing stability and may improve some aspects of health .
Implementation of HF would likely reduce homelessness and non-routine health service use without an increase in problematic substance use . | BACKGROUND Homelessness is associated with poor health .
A policy approach aim ing to end homelessness across Europe and North America , the ' Housing First ' ( HF ) model , provides rapid housing , not conditional on abstinence from substance use .
We aim ed to systematic ally review the evidence from r and omised controlled trials for the effects of HF on health and well-being . | Background Recent studies in North American context s have suggested that the Housing First model is a promising strategy for providing effective services to homeless people with mental illness . In the context of the highly generous French national health and social care system , which is easily accessible and does not require out-of-pocket payment , the French Health Ministry insists on rigorous techniques , including r and omized protocol s , to evaluate the impact of Housing First approaches in France . Method and design A prospect i ve r and omized trial was design ed to assess the impact of a Housing First intervention on health outcomes and costs over a period of 24 months on homeless people with severe mental illness , compared to Treatment-As-Usual . The study is being conducted in four cities in France : Lille , Marseille , Paris and Toulouse . The inclusion criteria are as follows : over 18 years of age , absolutely homeless or in precarious housing , and possessing a ‘ high ’ level of need : diagnosis of schizophrenia or bipolar disorder and moderate to severe disability according to the Multnomah Community Ability Scale ( score ≤ 62 ) and at least one of the following three criteria : 1 ) having been hospitalized for mental illness two or more times in any one year during the preceding five years ; 2 ) co-morbid alcohol or substance use ; and 3 ) having been recently arrested or incarcerated . Participants will be r and omized to receiving the Housing First intervention or Treatment-As-Usual . The Housing First intervention provides immediate access to independent housing and community care . The primary outcome criterion is the use of high-cost health services ( that is , , number of hospital admissions and number of emergency department visits ) during the 24-month follow-up period . Secondary outcome measures include health outcomes , social functioning , housing stability and contact with police services . An evaluation of the cost-effectiveness and cost-utility of Housing First will also be conducted . A total of 300 individuals per group will be included . Discussion This is the first study to examine the impact of a Housing First intervention compared to Treatment-As-Usual in France . It should provide key information to policymakers concerning the cost-effectiveness and health outcomes of the Housing First model in the French context .Trial registration The current clinical trial number is BACKGROUND Homelessness is associated with increased risks of mortality but it has not previously been possible to distinguish whether this is typical of other socio-economically deprived population s , the result of a higher prevalence of morbidity or an independent risk of homelessness itself . The aim of this study was to describe mortality among a cohort of homeless adults and adjust for the effects of morbidity and socio-economic deprivation . METHODS Retrospective 5-year study of two fixed cohorts , homeless adults and an age- and sex-matched r and om sample of the local non-homeless population in Greater Glasgow National Health Service Board area for comparison . RESULTS Over 5 years of observation , 1.7 % ( 209/12 451 ) of the general population and 7.2 % ( 457/6323 ) of the homeless cohort died . The hazard ratio of all-cause mortality in homeless compared with non-homeless cohorts was 4.4 ( 95 % CI : 3.8 - 5.2 ) . After adjustment for age , sex and previous hospitalization , homelessness was associated with an all-cause mortality hazard ratio of 1.6 ( 95 % CI : 1.3 - 1.9 ) . Homelessness had differential effects on cause-specific mortality . Among patients who had been hospitalized for drug-related conditions , the homeless cohort experienced a 7-fold increase in risk of death from drugs compared with the general population . CONCLUSIONS Homelessness is an independent risk factor for deaths from specific causes . Preventive programmes might be most effectively targeted at the homeless with these conditions OBJECTIVE Housing First with assertive community treatment ( ACT ) is a promising approach to assist people with serious mental illness to exit homelessness . The article presents two-year findings from a multisite trial on the effectiveness of Housing First with ACT . METHODS The study design was a r and omized controlled trial conducted in five Canadian cities . A sample of 950 participants with serious mental illness who were absolutely homeless or precariously housed were r and omly assigned to receive either Housing First with ACT ( N=469 ) or treatment as usual ( N=481 ) . RESULTS Housing First participants spent more time in stable housing than participants in treatment as usual ( 71 % versus 29 % , adjusted absolute difference [AAD]=42 % , p<.01 ) . Compared with treatment-as-usual participants , Housing First participants who entered housing did so more quickly ( 73 versus 220 days , AAD=146.4 , p<.001 ) , had longer housing tenures at the study end-point ( 281 versus 115 days , AAD=161.8 , p<.01 ) , and rated the quality of their housing more positively ( adjusted st and ardized mean difference [ASMD]=.17 , p<.01 ) . Housing First participants reported higher quality of life ( ASMD=.15 , p<.01 ) and were assessed as having better community functioning ( ASMD=.18 , p<.01 ) over the two-year period . Housing First participants showed significantly greater gains in community functioning and quality of life in the first year ; however , differences between the two groups were attenuated by the end of the second year . CONCLUSIONS Housing First with ACT is an effective approach in various context s for assisting individuals with serious mental illness to rapidly exit homelessness Objective No previous experimental trials have investigated Housing First ( HF ) in both scattered site ( SHF ) and congregate ( CHF ) formats . We hypothesized that CHF and SHF would be associated with a greater percentage of time stably housed as well as superior health and psychosocial outcomes over 24 months compared to treatment as usual ( TAU ) . Methods Inclusion criteria were homelessness , mental illness , and high need for support . Participants were r and omised to SHF , CHF , or TAU . SHF consisted of market rental apartments with support provided by Assertive Community Treatment ( ACT ) . CHF consisted of a single building with supports equivalent to ACT . TAU included existing services and supports . Results Of 800 people screened , 297 were r and omly assigned to CHF ( 107 ) , SHF ( 90 ) , or TAU ( 100 ) . The percentage of time in stable housing over 24 months was 26.3 % in TAU ( reference ; 95 % confidence interval ( CI ) = 20.5 , 32.0 ) , compared to 74.3 % in CHF ( 95 % CI = 69.3 , 79.3 , p<0.001 ) and 74.5 % in SHF ( 95 % CI = 69.2 , 79.7 , p<0.001 ) . Secondary outcomes favoured CHF but not SHF compared to TAU . Conclusion HF in scattered and congregate formats is capable of achieving housing stability among people experiencing major mental illness and chronic homelessness . Only CHF was associated with improvement on select secondary outcomes . Registration Current Controlled Trials : IS RCT N57595077 IMPORTANCE Scattered-site housing with Intensive Case Management ( ICM ) may be an appropriate and less-costly option for homeless adults with mental illness who do not require the treatment intensity of Assertive Community Treatment . OBJECTIVE To examine the effect of scattered-site housing with ICM services on housing stability and generic quality of life among homeless adults with mental illness and moderate support needs for mental health services . DESIGN , SETTING , AND PARTICIPANTS The At Home/Chez Soi project was an unblinded , r and omized trial . From October 2009 to July 2011 , participants ( N = 1198 ) were recruited in 4 Canadian cities ( Vancouver , Winnipeg , Toronto , and Montreal ) , r and omized to the intervention group ( n = 689 ) or usual care group ( n = 509 ) , and followed up for 24 months . INTERVENTIONS The intervention consisted of scattered-site housing ( using rent supplements ) and off-site ICM services . The usual care group had access to existing housing and support services in their communities . MAIN OUTCOMES AND MEASURES The primary outcome was the percentage of days stably housed during the 24-month period following r and omization . The secondary outcome was generic quality of life , assessed by a EuroQoL 5 Dimensions ( EQ-5D ) health question naire . RESULTS During the 24 months after r and omization , the adjusted percentage of days stably housed was higher among the intervention group than the usual care group , although adjusted mean differences varied across sites . [ table : see text ] The mean change in EQ-5D score from baseline to 24 months among the intervention group was not statistically different from the usual care group ( 60.5 [ 95%CI , 58.6 to 62.5 ] at baseline and 67.2 [ 95%CI , 65.2 to 69.1 ] at 24 months for the intervention group vs 62.1 [ 95 % CI , 59.9 to 64.4 ] at baseline and 68.6 [ 95%CI , 66.3 to 71.0 ] at 24 months for the usual care group , difference in mean changes , 0.10 [ 95%CI , −2.92 to 3.13 ] , P=.95 ) . CONCLUSIONS AND RELEVANCE Among homeless adults with mental illness in 4 Canadian cities , scattered site housing with ICM services compared with usual access to existing housing and community services result ed in increased housing stability over 24 months , but did not improve generic quality of life . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N42520374 OBJECTIVES We examined the longitudinal effects of a Housing First program for homeless , mentally ill individuals ' on those individuals ' consumer choice , housing stability , substance use , treatment utilization , and psychiatric symptoms . METHODS Two hundred twenty-five participants were r and omly assigned to receive housing contingent on treatment and sobriety ( control ) or to receive immediate housing without treatment prerequisites ( experimental ) . Interviews were conducted every 6 months for 24 months . RESULTS The experimental group obtained housing earlier , remained stably housed , and reported higher perceived choice . Utilization of substance abuse treatment was significantly higher for the control group , but no differences were found in substance use or psychiatric symptoms . CONCLUSIONS Participants in the Housing First program were able to obtain and maintain independent housing without compromising psychiatric or substance abuse symptoms CONTEXT Homeless adults , especially those with chronic medical illnesses , are frequent users of costly medical services , especially emergency department and hospital services . OBJECTIVE To assess the effectiveness of a case management and housing program in reducing use of urgent medical services among homeless adults with chronic medical illnesses . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial conducted at a public teaching hospital and a private , nonprofit hospital in Chicago , Illinois . Participants were 407 social worker-referred homeless adults with chronic medical illnesses ( 89 % of referrals ) from September 2003 until May 2006 , with follow-up through December 2007 . Analysis was by intention-to-treat . INTERVENTION Housing offered as transitional housing after hospitalization discharge , followed by placement in long-term housing ; case management offered on-site at primary study sites , transitional housing , and stable housing sites . Usual care participants received st and ard discharge planning from hospital social workers . MAIN OUTCOME MEASURES Hospitalizations , hospital days , and emergency department visits measured using electronic surveillance , medical records , and interviews . Models were adjusted for baseline differences in demographics , insurance status , prior hospitalization or emergency department visit , human immunodeficiency virus infection , current use of alcohol or other drugs , mental health symptoms , and other factors . RESULTS The analytic sample ( n = 405 [ n = 201 for the intervention group , n = 204 for the usual care group ] ) was 78 % men and 78 % African American , with a median duration of homelessness of 30 months . After 18 months , 73 % of participants had at least 1 hospitalization or emergency department visit . Compared with the usual care group , the intervention group had unadjusted annualized mean reductions of 0.5 hospitalizations ( 95 % confidence interval [ CI ] , -1.2 to 0.2 ) , 2.7 fewer hospital days ( 95 % CI , -5.6 to 0.2 ) , and 1.2 fewer emergency department visits ( 95 % CI , -2.4 to 0.03 ) . Adjusting for baseline covariates , compared with the usual care group , the intervention group had a relative reduction of 29 % in hospitalizations ( 95 % CI , 10 % to 44 % ) , 29 % in hospital days ( 95 % CI , 8 % to 45 % ) , and 24 % in emergency department visits ( 95 % CI , 3 % to 40 % ) . CONCLUSION After adjustment , offering housing and case management to a population of homeless adults with chronic medical illnesses result ed in fewer hospital days and emergency department visits , compared with usual care . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00490581 BACKGROUND AND OBJECTIVES : " Housing First " has been shown to improve housing stability in homeless individuals with mental illness , but had not been empirically tested in homeless youth . We aim ed to evaluate the effect of " Housing First " on housing stability in homeless youth aged 18 to 24 years participating in At Home/Chez Soi , a 24-month r and omized trial of " Housing First " in 5 Canadian cities . METHODS : Homeless individuals with mental illness were r and omized to receive " Housing First " ( combined with assertive community treatment or intensive case management depending on their level of need ) or treatment as usual . We defined our primary outcome , housing stability , as the percent of days stably housed as a proportion of days for which residence data were available . RESULTS : Of 2148 participants who completed baseline interviews and were r and omized , 7 % ( n = 156 ) were youth aged 18 to 24 years ; 87 received " Housing First " and 69 received treatment as usual . In an adjusted analysis , youth in " Housing First " were stably housed a mean of 437 of 645 ( 65 % ) days for which data were available compared with youth in treatment as usual , who were stably housed a mean of 189 of 582 ( 31 % ) days for which data were available , result ing in an adjusted mean difference of 34 % ( 95 % confidence interval , 24%–45 % ; P < .001 ) . CONCLUSIONS : " Housing First " was associated with improved housing stability in homeless youth with mental illness . Future research should explore whether adaptations of the model for youth yield additional improvements in housing stability and other outcomes This article introduces the approach of GRADE to rating quality of evidence . GRADE specifies four categories-high , moderate , low , and very low-that are applied to a body of evidence , not to individual studies . In the context of a systematic review , quality reflects our confidence that the estimates of the effect are correct . In the context of recommendations , quality reflects our confidence that the effect estimates are adequate to support a particular recommendation . R and omized trials begin as high- quality evidence , observational studies as low quality . " Quality " as used in GRADE means more than risk of bias and so may also be compromised by imprecision , inconsistency , indirectness of study results , and publication bias . In addition , several factors can increase our confidence in an estimate of effect . GRADE provides a systematic approach for considering and reporting each of these factors . GRADE separates the process of assessing quality of evidence from the process of making recommendations . Judgments about the strength of a recommendation depend on more than just the quality of evidence Homelessness affects HIV risk and health , but little is known about the longitudinal effects of rental assistance on the housing status and health of homeless and unstably housed people living with HIV/AIDS . Homeless/unstably housed people living with HIV/AIDS ( N = 630 ) were r and omly assigned to immediate Housing Opportunities for People with AIDS ( HOPWA ) rental assistance or customary care . Self-reported data , CD4 , and HIV viral load were collected at baseline , 6 , 12 , and 18 months . Results showed that housing status improved in both groups , with greater improvement occurring in the treatment group . At 18 months , 51 % of the comparison group had their own housing , limiting statistical power . Intent-to-treat analyses demonstrated significant reductions in medical care utilization and improvements in self-reported physical and mental health ; significant differential change benefiting the treatment group was observed for depression and perceived stress . Significant differences between homeless and stably housed participants were found in as-treated analyses for health care utilization , mental health , and physical health . HOPWA rental assistance improves housing status and , in some cases , health outcomes of homeless and unstably housed people living with HIV/AIDS Despite the increase in consumer-driven interventions for homeless and mentally ill individuals , there is little evidence that these programs enhance psychological outcomes . This study followed 197 homeless and mentally ill adults who were r and omized into one of two conditions : a consumer-driven “ Housing First ” program or “ treatment as usual ” requiring psychiatric treatment and sobriety before housing . Proportion of time homeless , perceived choice , mastery , and psychiatric symptoms were measured at six time points . Results indicate a direct relationship between Housing First and decreased homelessness and increased perceived choice ; the effect of choice on psychiatric symptoms was partially mediated by mastery . The strong and inverse relationship between perceived choice and psychiatric symptoms supports expansion of programs that increase consumer choice , thereby enhancing mastery and decreasing psychiatric symptoms OBJECTIVES We assessed the health impact of a housing and case management program , the Chicago Housing for Health Partnership , for homeless people with HIV . METHODS HIV-positive homeless in patients at a public hospital ( n = 105 ) were r and omized to usual care or permanent housing with intensive case management . The primary outcome was survival with intact immunity , defined as CD4 count > or = 200 and viral load < 100,000 . Secondary outcomes were viral loads , undetectable viral loads , and CD4 counts . RESULTS Outcomes were available for 94 of 105 enrollees ( 90 % ) . Of 54 intervention participants , 35 ( 65 % ) reached permanent housing in program housing agencies . After 1 year , 55 % of the intervention and 34 % of the usual care groups were alive and had intact immunity ( P = .04 ) . Seventeen intervention ( 36 % ) and 9 usual care ( 19 % ) participants had undetectable viral loads ( P = .051 ) . Median viral loads were 0.89 log lower in the intervention group ( P = .03 ) . There were no statistical differences in CD4 counts . CONCLUSIONS Homelessness is a strong predictor of poor health outcomes and complicates the medical management of HIV . This housing intervention improved the health of HIV-positive homeless people OBJECTIVE This study compares the effect of Housing First on older ( ≥50 years old ) and younger ( 18 - 49 years old ) homeless adults with mental illness participating in At Home/Chez Soi , a 24-month multisite r and omized controlled trial of Housing First . METHOD At Home/Chez Soi , participants ( n = 2148 ) were r and omized to receive rent supplements with intensive case management or assertive community treatment , based on their need level for mental health services , or usual care in their respective communities . A subgroup analysis compared older ( n = 470 ) and younger ( n = 1678 ) homeless participants across baseline characteristics and 24-month outcomes including housing stability ( primary outcome ) , generic and condition-specific quality of life , community functioning , physical and mental health status , mental health symptom severity , psychological community integration , recovery , and substance use ( secondary outcomes ) . RESULTS At 24 months , Housing First significantly improved the percentage of days stably housed among older ( + 43.9 % , 95 % confidence interval [ CI ] : 38.4 % to 49.5 % ) and younger homeless adults ( + 39.7 % , 95 % CI : 36.8 % to 42.6 % ) , compared with usual care , with no significant differences between age groups ( difference of differences = + 4.2 % , 95 % CI : -2.1 % to 10.5 % , p = 0.188 ) . Improvements from baseline to 24 months in mental health and condition-specific quality of life were significantly greater among older homeless adults than among younger homeless adults . CONCLUSION Housing First significantly improved housing stability among older and younger homeless adults with mental illness , result ing in superior mental health and quality of life outcomes in older homeless adults compared with younger homeless adults at 24 months . Copyright © 2017 John Wiley & Sons , |
13,628 | 28,133,957 | Children with SIRDs generally achieved seroprotection and seroconversion ; nevertheless , the antibody levels were often lower when compared with healthy children .
Glucocorticoids and conventional disease-modifying anti-rheumatic drugs do not seem to significantly hamper the immune responses , whereas TNF inhibitors may reduce antibody production , particularly in response to pneumococcal conjugate , influenza , meningococcal C and hepatitis A vaccine .
There were no serious adverse events , nor evidence of a relevant worsening of the underlying rheumatic disease .
Concerning live attenuated vaccines , the evidence is scarce , but no episodes of overt disease were reported , even in patients under biological therapy .
Existing literature demonstrates that vaccines are generally well tolerated and effective in stable SIRD patients , yet antibody titers are frequently lower than in healthy controls .
There is some evidence that biological therapy could hamper the immune response . | INTRODUCTION Children and adolescents with systemic rheumatic diseases have an increased risk of infections .
Although some infections are vaccine-preventable , immunization among patients with juvenile rheumatic diseases is suboptimal , partly due to some doubts that still persist regarding its efficacy and safety in this patient population .
OBJECTIVES To review the available evidence regarding the immunological response and the safety of vaccination in children and adolescents with systemic inflammatory rheumatic diseases ( SIRD ) . | Recent findings demonstrated a reduced immunogenicity of the influenza A H1N1/2009 vaccine in juvenile rheumatic diseases . However , a point of concern is whether the vaccine could induce disease flares . The aim of this study was to assess the disease safety of and the possible influence of disease parameters and therapy on nonadjuvant influenza A H1N1 vaccine response of juvenile systemic lupus erythematosus ( SLE ) patients OBJECTIVES The aim of the present paper is to assess the influence of demographic , muscle enzymes , JDM scores and treatment on non-adjuvanted influenza A H1N1/2009 vaccine immunogenicity in juvenile dermatomyositis ( JDM ) patients . METHODS Thirty JDM patients and 81 healthy age-matched controls were vaccinated . All participants were evaluated pre- and 21 days post-vaccination and serology for anti-H1N1 was performed by haemagglutination inhibition assay . Muscle enzymes , JDM scores and treatment were evaluated before and after vaccination . Adverse events were reported . RESULTS After immunisation , seroconversion rates were significantly lower in JDM patients compared to age-matched controls ( 86.7 vs. 97.5 % , p=0.044 ) , whereas seroprotection ( p=0.121 ) , geometric mean titres ( GMT ) ( p=0.992 ) and factor increase ( FI ) in GMT ( p=0.827 ) were similar in both groups . Clinical and laboratorial evaluations revealed that JDM scores and muscle enzymes remained stable throughout the study ( p>0.05 ) . A higher frequency of chronic course was observed in non-seroconverted compared to seroconverted ( 100 % vs. 27 % , p=0.012 ) . Regarding treatment , a lower rate of seroconversion was observed in patients under prednisone>20mg/day ( 50 % vs. 4 % , p=0.039 ) , and in those treated with a combination of prednisone , methotrexate and cyclosporine ( 50 % vs. 4 % , p=0.039 ) . Local and systemic vaccine adverse events were mild and similar in patients and controls ( p>0.05 ) . CONCLUSIONS This study identified that chronic course and immunosuppressive therapy are the major factors hampering seroconversion in JDM , suggesting that a specific protocol may be required for this subgroup of patients . In spite of that , a single dose of non-adjuvanted influenza A/H1N1 2009 vaccine was generally seroprotective in this disease with no evident deleterious effect in disease itself ( Clinical Trials.gov , no. NCT01151644 ) OBJECTIVES To evaluate the influence of low-dose MTX and etanercept treatment on efficacy of measles , mumps and rubella ( MMR ) revaccination in children with juvenile idiopathic arthritis . METHODS A prospect i ve nested case-control study was performed to investigate markers of MMR revaccination induced humoral and cell-mediated immunity in 15 patients with juvenile idiopathic arthritis ( ages 6 - 17 yrs ) , treated with either low-dose MTX therapy alone or in combination with etanercept . The control group consisted of 22 healthy children . Production of IFN-gamma by T memory cells upon in vitro stimulation with measles , mumps and rubella antigens and seroprevalence of virus-specific IgG antibodies were assessed . Medication use , disease activity and patients ' comments on side-effects were observed during the period of 6 months before and after revaccination . RESULTS Low-dose MTX therapy following MMR vaccination proved not to hamper T-cell mediated immunity in vitro . Neither low-dose MTX nor etanercept treatment , given simultaneously with revaccination , markedly interfered with generation of long-lived virus-restricted T cells and protective levels of virus-specific IgG antibodies . No increase in disease activity or medication use was seen within 6 months after MMR revaccination , including JIA patients using etanercept . No overt measles , mumps , rubella or secondary severe infections were noted . CONCLUSIONS Low-dose MTX and etanercept treatment do not seem to interfere with intended outcome of MMR revaccination in children with JIA OBJECTIVES In this study , we examined the antibody responses after recombinant hepatitis B vaccine in juvenile SLE patients and whether antibody levels were affected by immunosuppressive therapy . METHODS This study consisted of 64 juvenile SLE patients and 24 healthy controls . We evaluated HBsAg , Anti-HBs and Anti-HbcIgG titers in SLE patients . 24 patients ( 37 % ) were non-immunised , 39 patients were immunised ( 61 % ) and 1 patient ( 1.5 % ) was chronic hepatitis B carrier . Of the 24 non-immunised patients , 3 had active disease ( SLEDAI>10 ) and 1 was being treated for tuberculosis infection so they were not included in the vaccination program . Twenty non-immunised SLE patients were given 3 dose recombinant hepatitis B vaccine doses at 0,1,6 months . AntiHBs antibody titer > 10 IU/ml one month after the last dose of vaccine was accepted as seroconversion . RESULTS After 3 doses of vaccination , 16 ( 80 % ) of SLE patients and all of the healthy controls had seroconversion . Since two patients had SLEDAI score > 10 after the first 2 doses of vaccine and one patient had SLEDAI score > 10 after the first dose , these patients were given only two doses of hepatitis B vaccine . These patients had already seroconverted . One patient had exacerbation of the disease one month after the third dose of the vaccine . Protective antibody responses were statistically insignificant between the two groups ( p=0.49 ) . Geometric mean antibody titers of SLE patients were lower than those of the healthy controls . Adequate antibody response was not affected by immunosuppressive treatment as prednisone , azathioprine , and hydroxychloroquine . CONCLUSIONS Juvenile SLE patients could reach an adequate antibody response after recombinant hepatitis B vaccination and this response is not affected by immunosuppressive treatment Objectives To compare the immunogenicity and safety of the bivalent human papillomavirus (HPV)16/18 vaccine between female patients with juvenile idiopathic arthritis ( JIA ) and healthy female adolescents . Methods 68 patients and 55 healthy girls aged 12–18 years were included in a prospect i ve controlled observational cohort and were vaccinated at 0 , 1 and 6 months . Primary outcomes were immunogenicity expressed as seropositivity rate after three vaccine doses at 7 and 12 months and HPV-specific geometric mean antibody concentrations . Secondary outcomes were HPV16/18-specific memory B cell responses in a subset of participants and safety , defined as adverse events and the effect of vaccination on JIA disease activity . Results All participants were seropositive for HPV16 and HPV18 at 7 months . One patient turned seronegative at 12 months for HPV16/18 . No significant differences were found between patients and controls in HPV-specific antibody concentrations ; however , antibody concentrations were consistently lower in patients . No effect of methotrexate on HPV16 antibodies ( p=0.79 ) or HPV18 antibodies ( p=0.37 ) was detected . All patients on anti-TNFα treatment were seropositive after vaccination . The kinetics of HPV16/18 memory B cell responses was comparable between patients and controls , but the magnitude of B cell responses at 7 and 12 months appeared lower in patients . No relevant differences in adverse events were found . HPV vaccination did not aggravate JIA disease . Conclusions The bivalent HPV16/18 vaccine is immunogenic and well tolerated in JIA patients . However , HPV-specific antibodies and B cell responses tended to be lower in patients compared with healthy controls . Clinical trial listing OBJECTIVE Influenza immunization is recommended for children with chronic conditions and children receiving chronic acetylsalicylic acid therapy . Our study assessed the safety and immunogenicity of this vaccination in children with chronic arthritis . METHODS The frequency of possible adverse reactions following influenza vaccination , and virus specific HI antibody levels prior to and 4 weeks after vaccination with an inactivated split virus vaccine prepared for the 1991/92 season , were assessed in a prospect i ve open study of children with chronic arthritis . Thirty-four patients were assessed clinical ly at vaccination and one month later . Local symptoms at the injection site and systemic symptoms were assessed by diary in 26 patients and 13 immunized healthy control children . RESULTS Tenderness and /or redness at the injection site , and fever occurred equally in patients and controls . Malaise/nausea occurred in 12 patients and 3 controls ( p = 0.3 ) , but patients had more symptomatic days than controls ( p = 0.01 ) . No child with inactive arthritis developed a swollen joint following immunization . There were no significant differences between the 2 visits for a.m. stiffness , pain ( VAS ) , global assessment , joint count or erythrocyte sedimentation rate ( ESR ) . More patients improved than deteriorated by each measure . Three patients deteriorated by global assessment , 7 patients had an increased joint count . At least 95 % of patients developed presumably protective levels of antibodies ( HI titers > or = 40 ) to each virus . Preimmunization titers , seroresponse rates ( 4 x rise or rise from < 20 to > or = 40 ) and final titers were the same between patients ( whether or not they were taking prednisone or a second line antirheumatic drug ) and controls . CONCLUSION There was no convincing evidence that influenza vaccination is associated with significant adverse reactions or arthritis flares in children with chronic arthritis . Children with chronic arthritis appeared to respond adequately to influenza vaccination OBJECTIVE To determine whether vaccinations aggravate the course of autoimmune diseases such as juvenile idiopathic arthritis ( JIA ) and whether the immune response to vaccinations may be hampered by immunosuppressive therapy for the underlying disease . METHODS In this multicenter cohort study , 234 patients with JIA ( ages 1 - 19 years ) were vaccinated with meningococcal serogroup C ( MenC ) conjugate to protect against serogroup C disease ( caused by Neisseria meningitidis ) . Patients were followed up for disease activity for 1 year , from 6 months before until 6 months after vaccination . IgG antibody titers against MenC polysaccharide and the tetanus carrier protein were determined by enzyme-linked immunosorbent assay and toxin binding inhibition assay , respectively . A serum bactericidal assay was performed to determine the function of the anti-MenC antibodies . RESULTS No change in values for any of the 6 components of the core set criteria for juvenile arthritis disease activity was seen after MenC vaccination . Moreover , no increase in the frequency of disease relapse was detected . Mean anti-MenC IgG concentrations in JIA patients rose significantly within 6 - 12 weeks after vaccination . Of 157 patients tested , 153 were able to mount anti-MenC IgG serum levels > 2 micro g/ml , including patients receiving highly immunosuppressive medication . The 4 patients with a lower anti-MenC antibody response displayed sufficient bactericidal activity despite receiving highly immunosuppressive medication . CONCLUSION The MenC conjugate vaccine does not aggravate JIA disease activity or increase relapse frequency and results in adequate antibody levels , even in patients receiving highly immunosuppressive medication . Therefore , patients with JIA can be vaccinated safely and effectively with the MenC conjugate OBJECTIVES Hepatitis B is a vaccine preventable disease with intermediate endemicity in Greece . Patients with juvenile idiopathic arthritis ( JIA ) on immunomodulating therapy are prone to infection or reactivation of hepatitis B virus ( HBV ) . The aim of this study is to define the immune status against HBV in children newly-diagnosed with JIA . METHODS Case-control prospect i ve study including 89 JIA patients and 89 controls matched for age and gender . Eighty-nine JIA patients were included in the study ( 22 males ) , with a mean age of 6.8 years . Sera were tested for hepatitis B surface antigen , hepatitis B core antibody , and anti-HBs . Patients with anti-HBs titers ≥10 IU/L were considered immune . Data were analysed with SPSS 18.0 version . RESULTS In the JIA group 55 % were HBV immune ( anti-HBs level ≥10 IU/L ) while in the control group 92 % were immune against HBV ( p<0.001 ) . Antibody levels in the patient group were significantly lower compared to the control group . The mean concentration of anti-HBs levels in JIA patients was 18.3 IU/L versus 82.6 IU/L in the control group ( p<0.001 ) . CONCLUSIONS Antibody titers against HBV in fully vaccinated JIA patients due to start treatment are significantly lower compared to matched healthy children in this study . Diagnosis of JIA and older age were associated with the absence of protective antibodies . Although there is no evidence to support the introduction of a booster HBV dose in healthy children who mount low antibody response following immunisation , further studies are required to address this question in patients with JIA Objectives : To evaluate the responsiveness of children with juvenile idiopathic arthritis ( JIA ) to hepatitis B vaccination and to determine the most useful vaccination schedule . Methods : 39 children with JIA were enrolled in the study ; all were in remission and negative to serological testing for hepatitis B surface antigen ( HbsAg ) . The control group consisted of 41 healthy children . There were two different vaccination schedules : group I was vaccinated at 0 , 1 , and 3 months ; group II was vaccinated at 0 , 1 , and 6 months . Positive responsiveness to the vaccine was defined as an anti-hepatitis B antibody titre above 10 mIU/ml . Results : All the children except one with systemic JIA developed an antibody response . None of the JIA patients experienced a flare up or clinical deterioration related to the vaccination . The antibody levels in children with JIA were significantly lower than in the healthy controls . Comparison of the antibody levels between the two vaccination schedules showed no statistical difference in the controls ; in the JIA subjects the group II schedule result ed in a trend to a greater response than the group I schedule ( p<0.07 ) . Vaccine responsiveness was not influenced by either methotrexate or prednisolone treatment . Conclusions : Children with JIA had an adequate response to hepatitis B vaccination and the response was not affected by immunosuppressive treatment . A vaccination schedule at 0 , 1 , and 6 months seems to be preferable to 0 , 1 , and 3 months Clinicians often witness impressive treatment results in practice and may wish to pursue research to formally explore their anecdotal experiences . The potential to further new knowledge both within the profession and to the greater healthcare system is compelling . An obvious next step for a practitioner considering research is to connect with experienced research ers to convey their idea for a study , who may in turn ask , “ What is your research question ? ” With limited underst and ing of how to respond , this interaction may result in the first and last experience these clinicians will have with the research community . It has been estimated that between 1 % and 7 % of the chiropractic profession in Canada is engaged in research . 1,2 Arguably , this low engagement could be the result of practitioners ’ perceived importance of research and levels of research literacy and capacity . However , increasing dem and s for evidence -based approaches across the health system puts pressure on all clinicians to base their decisions on the best available scientific evidence . Lack of clinician representation in research has the probable effect of limiting growth and new developments for the profession . Furthermore , lack of clinician involvement in research complicates the transfer of study findings into practical setting s. The Canadian Institutes of Health Research describes integrated knowledge translation as a process that involves collaboration between research ers and knowledge users at all stages of a research project.3 This necessitates involvement of clinicians to help in forming a research question , interpreting the results , and moving research findings into practice . This shared effort between clinicians and research ers increases the likelihood that research initiatives will be relevant to practice .3 Conversely , it has been reported that there is a growing communication gap between clinicians and academics in chiropractic . 4 Clinicians have important practice -related questions to ask , but many may lack the ability to map out their research strategy , specifically in communicating their question in a manner required to develop a research protocol . David L. Sackett , Officer of the Order of Canada and the founding Chair of Canada ’s first Department of Clinical Epidemiology & Biostatistics at McMaster University , highlights the importance of mapping one ’s research strategy in exploration of the research question : “ one-third of a trial ’s time between the germ of your idea and its publication in the New Engl and Journal of Medicine should be spent fighting about the research question . ” ( personal communication , November 30 , 2011 ) We describe a r and omized controlled trial ( RCT ) example to highlight how clinicians may use existing literature and the PICOT format to formulate a research question on treatment efficacy Objective : To assess the effect of measles , mumps and rubella ( MMR ) vaccination on disease activity in children with juvenile idiopathic arthritis ( JIA ) . Methods : A retrospective observational multicentre cohort study was performed in 314 patients with JIA , born between 1989 and 1996 . Disease activity and medication use were compared during the period of 6 months before vaccination versus 6 months after vaccination . Disease activity was measured by joint counts , the Physician ’s global assessment scale and erythrocyte sedimentation rate . Next , we compared disease activity in patients vaccinated between 8 and 9 years of age with the activity in patients who had not been vaccinated at this time ( who received MMR between the ages of 9 and 10 years ) . Results : No increase in disease activity or medication use was seen in the 6 months after MMR vaccination ( n = 207 ) , including in patients using methotrexate ( n = 49 ) . No overt measles infections were noted . When disease activity in vaccinated patients ( n = 108 ) was compared with activity in those not yet vaccinated ( n = 86 ) , there were no significant differences . Conclusions : The MMR booster vaccination does not seem to aggravate disease activity in JIA . This indicates that the most patients with JIA can be vaccinated safely with the MMR vaccine . A prospect i ve study is recommended Objectives : To assess the vaccine response in juvenile idiopathic arthritis ( JIA ) as an extension of previous observation of immunogenicity and safety of a non-adjuvanted influenza A H1N1/2009 vaccine in a large population of juvenile rheumatic diseases . Moreover , to assess the possible influence of demographic data , disease subtypes , disease activity , and treatment on immunogenicity and the potential deleterious effect of the vaccine in the disease itself , particularly in the number of arthritis and inflammatory markers . Methods : A total of 95 patients with JIA and 91 healthy controls were evaluated before and 21 days after vaccination , and serology for anti-H1N1 was performed by haemagglutination inhibition assay ( HIA ) . Patient and physician visual analogue scales ( VAS ) , Childhood Health Assessment Question naire ( CHAQ ) , number of active joints , acute phase reactants , and treatments were evaluated before and after vaccination . Adverse events were also reported . Results : JIA patients and controls were comparable regarding mean current age ( 14.9 ± 3.2 vs. 14.6 ± 3.7 years , p = 0.182 ) . After vaccination , the seroconversion rate was significantly lower in JIA patients compared to controls ( 83.2 % vs. 95.6 % , p = 0.008 ) , particularly in the polyarticular subtype ( 80 % vs. 95.6 % , p = 0.0098 ) . Of note , JIA subtypes , number of active joints , acute phase reactants , CHAQ , patient and physician VAS , and use of disease-modifying anti-rheumatic drugs (DMARDs)/immunosuppressive drugs were similar between seroconverted and non-seroconverted patients ( p > 0.05 ) . Regarding vaccine safety , no deterioration was observed in the number of active joints and acute phase reactants during the study period . Conclusion : Influenza A H1N1/2009 vaccination in JIA induces a lower but effective protective antibody response probably independent of disease parameters and treatment with an adequate disease safety profile OBJECTIVES The aim of the present paper is to evaluate the immune response and tolerability of varicella vaccine in children and adolescents with systemic lupus erythematosus previously exposed to varicella-zoster virus . METHODS We performed a prospect i ve and controlled study on a group of 54 SLE patients that were chosen at r and om to be or not to be vaccinated ( 28 were vaccinated and 26 were not ) . Twenty-eight healthy controls , of matching age and sex were also vaccinated . All were su bmi tted to a question naire , physical evaluation and laboratory assays : lymphocyte immune-phenotyping by flow cytometry , plasma varicella zoster virus ( VZV ) serology by ELISA and in vitro interferon gamma ( IFNγ ) production by T-cells after stimulus with VZV antigen . They were evaluated before vaccination and at 30 , 45 , 180 and 360 days afterwards . RESULTS We did not observe any differences in the frequency of adverse events in both vaccinated groups . At study entry , all individuals were seropositive for VZV antibodies . The serum VZV antibody titres similarly increased after vaccination . The frequency of flares and the SLEDAI score were also similar among the patients . Thirty days after vaccination the production of IFNγ specific to VZV was lower in the SLE group compared to healthy controls . In the follow-up we observed 4 cases of herpes zoster in the SLE unvaccinated group , but no zoster in the vaccinated group . CONCLUSIONS The varicella vaccine was well tolerated in SLE group , who had pre-existing immunity to varicella . The varicella vaccine immunogenicity measurement by serum antibody titres was appropriate . The incidence of HZ was lower in the vaccinated lupus group Tumor necrosis factor-alpha ( TNF-α ) inhibitors are effective treatment for juvenile idiopathic arthritis ( JIA ) but may increase infection rates . However , active JIA may also render patients vulnerable to infection . In this study , we prospect ively assessed infection rates in JIA patients treated with and without TNF-α inhibitors and correlated disease activity with infection risk . TNF-α inhibitor-naïve JIA subjects were followed up for 12 months . Subjects initiated on TNF-α inhibitors after enrollment were analyzed in the TNF group . Subjects treated without TNF-α inhibitors were analyzed in the non-TNF group . Question naires captured mild or severe infections . JIA disease activity by Childhood Health Assessment Question naire ( CHAQ ) disability index/pain score and physician joint count/global assessment was recorded . Twenty TNF and 36 non-TNF subjects were analyzed . The total infection rate ratio for TNF versus non-TNF group subjects was 1.14 ( 95 % CI , 0.78–1.66 ; p = 0.51 ) . The average rate of infections per month was 0.29 for TNF and 0.24 for non-TNF subjects . No severe infections or hospitalizations occurred in either group . Secondary infectious outcomes were also similar between groups . Controlling for study group , an increase in CHAQ pain score correlated with an increase in several infectious outcome measures . Our results suggest no difference in infection rates between JIA subjects treated with and without TNF-α inhibitors . Additionally , JIA disease activity may have contributed to infection risk in our cohort , irrespective of immunosuppressive therapy . Future analysis of the relationship between treatment regimens , disease activity , and infection rates may help to further delineate predictors of infection risk in JIA patients IMPORTANCE The immunogenicity and the effects of live attenuated measles-mumps-rubella ( MMR ) vaccination on disease activity in patients with juvenile idiopathic arthritis ( JIA ) are matters of concern , especially in patients treated with immunocompromising therapies . OBJECTIVES To assess whether MMR booster vaccination affects disease activity and to describe MMR booster immunogenicity in patients with JIA . DESIGN , SETTING , AND PARTICIPANTS R and omized , multicenter , open-label clinical equivalence trial including 137 patients with JIA aged 4 to 9 years who were recruited from 5 academic hospitals in The Netherl and s between May 2008 and July 2011 . INTERVENTION Patients were r and omly assigned to receive MMR booster vaccination ( n=68 ) or no vaccination ( control group ; n=69 ) . Among patients taking biologics , these treatments were discontinued at 5 times their half-lives prior to vaccination . MAIN OUTCOMES AND MEASURES Disease activity as measured by the Juvenile Arthritis Disease Activity Score ( JADAS-27 ) , ranging from 0 ( no activity ) to 57 ( high activity ) . Disease activity in the year following r and omization was compared between revaccinated patients and controls using a linear mixed model . A difference in JADAS-27 of 2.0 was the equivalence margin . Primary immunogenicity outcomes were seroprotection rates and MMR-specific antibody concentrations at 3 and 12 months . RESULTS Of 137 r and omized patients , 131 were analyzed in the modified intention-to-treat analysis , including 60 using methotrexate and 15 using biologics . Disease activity during complete follow-up did not differ between 63 revaccinated patients ( JADAS-27 , 2.8 ; 95 % CI , 2.1 - 3.5 ) and 68 controls ( JADAS-27 , 2.4 ; 95 % CI , 1.7 - 3.1 ) , with a difference of 0.4 ( 95 % CI , -0.5 to 1.2 ) , within the equivalence margin of 2.0 . At 12 months , seroprotection rates were higher in revaccinated patients vs controls ( measles , 100 % vs 92 % [ 95 % CI , 84%-99 % ] ; mumps , 97 % [ 95 % CI , 95%-100 % ] vs 81 % [ 95 % CI , 72%-93 % ] ; and rubella , 100 % vs 94 % [ 95 % CI , 86%-100 % ] , respectively ) , as were antibody concentrations against measles ( 1.63 vs 0.78 IU/mL ; P = .03 ) , mumps ( 168 vs 104 RU/mL ; P = .03 ) , and rubella ( 69 vs 45 IU/mL ; P = .01 ) . Methotrexate and biologics did not affect humoral responses , but low patient numbers precluded definite conclusions . CONCLUSION AND RELEVANCE Among children with JIA who had undergone primary immunization , MMR booster vaccination compared with no booster did not result in worse JIA disease activity and was immunogenic . Larger studies are needed to assess MMR effects in patients using biologic agents . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00731965 To evaluate the safety and immunogenicity of varicella vaccine ( VV ) in susceptible patients with juvenile rheumatic diseases receiving methotrexate and corticosteroids Objectives The kinetics of the antibody response induced by meningococcal serogroup C ( MenC ) conjugate vaccination was analysed in patients with juvenile idiopathic arthritis ( JIA ) to assess their long-term protection against MenC disease . Methods In The Netherl and s , a nationwide catch-up campaign was performed in 2002 during which children aged 1–19 years , including JIA patients , received the MenC conjugate vaccination . From 127 JIA patients , IgG antibody concentrations against MenC-polysaccharide were determined by a fluorescent-bead-based immunoassay in 402 serum sample s collected between 2002 and 2010 . Using a hierarchical linear regression model , the 8 years course of MenC-specific antibodies was analysed in four age groups ( 13–19 , 9–12.9 , 5–8.9 and 1–4.9 years ) , and in patients starting with methotrexate or biologicals . In 65 r and omly selected sample s , the correlation of MenC-specific IgG concentrations with serum bactericidal assay ( SBA ) titres was assessed . MenC-specific IgG concentrations at 4.2 years after vaccination were compared with those of 1527 age-matched healthy controls . Results MenC-specific IgG concentrations postvaccination were highest in patients aged 13–19 years at time of vaccination . Antibodies gradually waned over time in patients , but their estimated concentrations at 4.2 years postvaccination were similar to those measured in controls . MenC-specific IgG concentrations correlated well with SBA titres ( r=0.72 , p<0.001 ) . By contrast with methotrexate , starting treatment with biologicals induced a trend towards accelerated decline of MenC-specific antibodies . Conclusions Persistence of MenC-specific IgG antibodies in JIA patients is similar to healthy controls , but treatment with biologicals may induce accelerated antibody waning , result ing in unprotected patients who may need revaccination |
13,629 | 22,161,391 | Workplace interventions to prevent HIV are feasible .
There is moderate quality evidence that VCT offered at the work site increases the uptake of testing .
Even though this did no lower HIV-incidence , there was a decrease in self-reported sexual transmitted diseases and a decrease in risky sexual behaviour .
There is low quality evidence that educational interventions decrease sexually transmitted diseases , unprotected sex and sex with commercial sex workers but not sex with multiple partners and the use of alcohol before sex . | BACKGROUND The workplace provides an important avenue to prevent HIV .
OBJECTIVES To evaluate the effect of behavioral interventions for reducing HIV on high risk sexual behavior when delivered in an occupational setting . | Objective : To investigate HIV incidence during a trial of two voluntary counselling and testing ( VCT ) strategies . Counselling may promote beneficial behavioural change , although knowledge of negative status does not appear to contribute further benefit . Design : The parent cluster-r and omized trial demonstrated much greater uptake of VCT when counselling and rapid testing were available on-site ( intensive VCT ) than through pre-paid vouchers to an external provider ( st and ard VCT ) . Anonymous HIV tests had been requested from all employees at enrolment and after 2 years intervention . Methods : The study setting was 22 businesses in Harare , Zimbabwe . Participants were 3146 HIV-negative individuals remaining in employment at the end of intervention , of whom 2966 ( 94.3 % ) consented to repeat testing . VCT linked to basic HIV care was provided and the main outcome measures were HIV incidence under each study arm , as a retrospective secondary analysis . Results : Mean VCT uptake in this cohort was 70.7 and 5.2 % , respectively , in the intensive and st and ard arms . Crude HIV incidence was 1.21 per 100 person-years , with non-significantly higher rates in the intensive VCT arm [ mean site incidence 1.37 and 0.95 per 100 person-years , respectively ; adjusted rate ratio 1.49 ( 95 % confidence interval 0.79–2.80 ) . Conclusions : Highly acceptable VCT did not reduce HIV incidence in this predominantly male cohort . HIV incidence was highest in the high uptake VCT arm , lending support to a US trial in which rapid testing appeared to have adverse behavioural consequences in some HIV-negative clients . Careful comparison of outcomes under different counselling and testing strategies is needed to maximize HIV prevention from global scale-up of VCT Background HIV counselling and testing is a key component of both HIV care and HIV prevention , but uptake is currently low . We investigated the impact of rapid HIV testing at the workplace on uptake of voluntary counselling and testing ( VCT ) . Methods and Findings The study was a cluster-r and omised trial of two VCT strategies , with business occupational health clinics as the unit of r and omisation . VCT was directly offered to all employees , followed by 2 y of open access to VCT and basic HIV care . Businesses were r and omised to either on-site rapid HIV testing at their occupational clinic ( 11 businesses ) or to vouchers for off-site VCT at a chain of free-st and ing centres also using rapid tests ( 11 businesses ) . Baseline anonymised HIV serology was requested from all employees . HIV prevalence was 19.8 % and 18.4 % , respectively , at businesses r and omised to on-site and off-site VCT . In total , 1,957 of 3,950 employees at clinics r and omised to on-site testing had VCT ( mean uptake by site 51.1 % ) compared to 586 of 3,532 employees taking vouchers at clinics r and omised to off-site testing ( mean uptake by site 19.2 % ) . The risk ratio for on-site VCT compared to voucher uptake was 2.8 ( 95 % confidence interval 1.8 to 3.8 ) after adjustment for potential confounders . Only 125 employees ( mean uptake by site 4.3 % ) reported using their voucher , so that the true adjusted risk ratio for on-site compared to off-site VCT may have been as high as 12.5 ( 95 % confidence interval 8.2 to 16.8 ) . Conclusions High-impact VCT strategies are urgently needed to maximise HIV prevention and access to care in Africa . VCT at the workplace offers the potential for high uptake when offered on-site and linked to basic HIV care . Convenience and accessibility appear to have critical roles in the acceptability of community-based VCT Objectives : To assess self‐ selection in a population ‐based voluntary HIV testing and counseling ( VTC ) program by comparing the HIV risk characteristics of users and nonusers of VTC in rural Ug and a. Design : A 1994 to 1995 community‐r and omized trial in the Rakai District of Ug and a enrolled adults aged 15 to 59 years and ascertained their HIV status , sociodemographic characteristics , risk behaviors , and AIDS‐associated symptoms . All subjects were offered confidential individual VTC at no cost . Methods : We compared users and nonusers of VTC among 10,950 participants ( 4764 male and 6186 female ) enrolled at baseline using multivariate logistic regression . Results : Women were significantly less likely to receive VTC than men ( 31.5 % vs. 34.8 % , p < .001 ) . In multivariate analysis , younger age , HIV‐positive status , and having no sexual partners in the past 5 years ( and , significant for women only , having 2 or more sexual partners ) were associated with lower VTC participation for both men and women . Among women , higher VTC participation was associated with symptoms suggestive of AIDS and other illnesses and shopkeeper occupations . Conclusions : During the initial phase of a population ‐based free VTC program in rural Ug and a , certain high‐risk groups were underrepresented among VTC recipients . There is a need to target VTC to ensure participation by high‐risk individuals most in need of services Recent debate about the evaluation of community based , HIV/AIDS behavioural interventions has focused on the appropriateness of the r and omised controlled trial ( RCT ) design , and the difficulty of obtaining reliable outcome measures . A community based HIV AIDS behavioural change RCT , recently conducted in rural Ug and a , used HIV incidence as the principal outcome measure . This paper examines the acceptability of the trial from the community perspective . It asks whether , in a rural African setting , it is possible to implement a scientifically rigorous evaluation without compromising acceptability of the trial to the community . Opinions of the trial held by community members working as trial field workers were collected by semi-structured interview ( n = 37 ) , and focus group discussion s ( 4 ) Community opinions of the trial were ascertained through 10 focus groups . For both field workers and the community , the sero-survey was more salient than the intervention , and the source of many rumours and disputes . Despite intensive mobilisation and close monitoring of field workers , it was impossible to ensure the veracity of explanations about the survey at ground level , and to protect each individual from coercion . The community expected a reward in return on their blood . Although the introduction of incentives at the final survey round increased the acceptability of the trial , they not only created jealousies and tensions , but also led to expectations of greater rewards in future . We conclude that RCTs in poor , rural communities are feasible , but the challenges involved should not be underestimated . Obtaining community support for the trial , respecting established hierarchies , and close supervision of field workers are all essential , but even then , controversies should be anticipated . There is an urgent need for relevant guidelines to help research ers navigate the complex ethical issues involved The Zimbabwe AIDS Prevention Project ( ZAPP ) conducted a r and omized trial to investigate the effectiveness of peer education in preventing HIV infection . Initial research revealed that if health education could successfully promote a reduction in the number of sex partners and condom use , HIV risk could be greatly reduced . In 1993 , ZAPP began enrolling men working at 40 factories in a study . The men were tested for sexually transmitted diseases ( STD ) and HIV every six months and had access to a ZAPP clinic for counseling , testing , and STD treatment . In June 1994 , ZAPP r and omly chose 20 factories to receive an additional peer education intervention . Educators were trained for a week and were given refresher courses every six months . Comparison of the incidence of HIV between the control and intervention groups was measured by determining incidence for all individuals and by comparing overall incidence at each factory . Of the 2219 men who were HIV negative after the introduction of peer education , 78 % completed one follow-up , and HIV incidence was 2.52%/year . Controlling for time enrolled in the program revealed that the peer education result ed in significantly fewer new HIV infections . Because the voluntary testing and counseling were available at factories with control and intervention programs , this study exposed the independent impact of peer education . It is concluded that peer education , condom distribution , and treatment of STDs should be the cornerstone of HIV prevention policies BACKGROUND In the early years of the worldwide p and emic , there were no reported cases of acquired immunodeficiency syndrome in Lesotho , a small , mountainous country in South Africa . Since 1986 , when the first case of acquired immunodeficiency syndrome was identified , reported diagnoses have risen precipitously . The initiation of the Lesotho Highl and s Water Project has result ed in the influx of a migrant workforce of predominantly single males into a relatively isolated , mountainous area where human immunodeficiency virus ( HIV ) was previously unknown . OBJECTIVE To ascertain the HIV seroprevalence among a cohort of laborers at the Katse Dam construction site in Bokong , Lesotho . METHODS During the 5-week study period in late 1992 , construction workers ( age range , 15 to 59 years ) who were first-time clinic users for any chief complaint were r and omly selected for serological study . Surveillance complied with the Lesotho National AIDS Control Programme guidelines , which required unlinked , anonymous testing . Serum sample s were screened by an enzyme-linked immunosorbent assay ; the results were confirmed by the Western blot technique . RESULTS Unlinked , anonymous HIV testing of 486 persons revealed a seroprevalence of 5.3 % ( 26/486 ; 95 % confidence interval , 3.3 % to 7.3 % ) . These data contrasted with a 0.8 % seroprevalence in a similar age group in nearby villages that surrounded the construction project . CONCLUSIONS Lesotho , in the early phase of the HIV/acquired immunodeficiency syndrome epidemic in Africa in the 1980s , was seemingly protected by its relative isolation . Grave concern is now warranted as the country is destined to experience a rapid rise in HIV seroprevalence . Increased surveillance , health education opportunities , and aggressive prevention activities at the Katse Dam construction site are imperative to arrest the spread of HIV from construction workers to nearby villagers OBJECTIVE The study was aim ed at assessing the knowledge of the drivers and conductors on HIV/AIDS epidemic and its preventive measures . METHODS This descriptive study was prospect ively conducted among r and omly selected city commuter-bus drivers and conductors from December 2006 to April 2007 in Dar Es Salaam , Tanzania . The study parameters included the general knowledge of the respondents on HIV/AIDS , treatment by anti-retroviral therapy and different types of preventive measures . Data was collected through face-to-face interviews using semi- structured question naires . RESULTS A total of 333 respondents voluntarily participated in the study . It was found that out of all respondents who had heard about HIV/AIDS , 93.9 % heard it from the media particularly radios , televisions and newspapers . The results further showed no significant difference ( p=0.08 ) of knowledge on HIV/AIDS between the drivers and conductors . Drivers ( 84.3 % ) and conductors ( 80.1 % ) pointed out condom as the common method of prevention from contracting HIV/AIDS . Among other preventive measures known to them , 75.5 % and 52.9 % of the drivers and conductors pointed out faithfulness respectively . However results indicated that 49.30 % of the respondents were practicing faithfulness to their partners as a preventive measure while 40.9 % were using condoms and only 9.6 % were practicing abstinence . CONCLUSION This study has shown that city commuter-bus drivers and conductors in Dar Es Salaam , have " adequate " knowledge on HIV/AIDS and preventive measures and the major source of this knowledge is through the public media Objectives : To measure the prevalence of HIV and other STIs in communities neighbouring new large scale gold mines in northern Tanzania in order to inform the design of a targeted HIV/STI intervention programme . Methods : Cross sectional surveys were conducted in adults aged 16–54 years from different sectors of communities neighbouring two newly opened , large scale gold mines near Lake Victoria . Mine workers , men , women , and female food and recreational facility workers ( FRFW ) from the community were r and omly selected for interview and HIV and STI testing . Results : 207 male Tanzanian mine workers , 206 FRFW , 202 other male and 205 female community members were enrolled . Overall , 42 % of FRFW were HIV positive , compared to 6 % of male mine workers , and 16 % and 18 % of other community men and women respectively . HIV prevalence in FRFW was significantly associated with alcohol consumption ( adjusted odds ratio ( aOR ) = 2.5 , 95 % confidence interval ( CI ) 1.1 to 5.5 ) , past or present syphilis ( TPPA+ ) ( aOR = 2.7 , 95 % CI 1.4 to 5.1 ) and single status ( aOR = 3.8 , 95 % CI 1.2 to 11.9 ) . Among FRFW , 24 % had active syphilis ( RPR+ , TPPA+ ) , 9 % Chlamydia trachomatis , and 4 % Neisseria gonorrhoeae . Overall , 50 % of FRFW and 50 % of community men never used condoms during sex , and 55 % mineworkers , 61 % male , and 20 % female community members reported receiving/giving payment for sex during the previous year . Conclusions : There is a high prevalence of HIV and other STIs in communities around new goldmines in Tanzania , especially in FRFW . HIV and STI prevalence in the mining workforce is still relatively low , but high risk sexual behaviour is reported by all adult subgroups surveyed in this study . Programmes focusing on HIV/STI prevention , with targeted interventions for high risk women such as FRFW , will be extremely important in such high transmission communities where there is substantial recent in-migration of men and women seeking work . Such programmes have recently been initiated by a private/public/NGO partnership The incidence of HIV/AIDS in India is increasing drastically , and truck drivers are seen as critical sources of HIV transmission due to their high rates of unprotected sex with multiple partners . An intervention based on the Information-Motivation-Behavioral Skills ( IMB ) model was compared to an information-only control condition in a r and omized trial . IMB constructs were assessed among 250 male truck drivers immediately prior to and following implementation of the intervention , and sexual and condom use behaviors were assessed approximately 10 months later . The intervention consisted of a single-session group workshop with 5 interactive activities design ed to address HIV prevention-related IMB constructs and to motivate condom use . Findings showed mixed support for the effectiveness of the intervention . There was an effect of the IMB intervention on attitudes , norms , behavioral skills , and intentions specific to condom use with marital partners , but no effects on constructs related to non-marital partners . There was some evidence of greater condom use with marital and non-marital partners at behavioral follow-up for participants in the IMB condition , and effects on condom use with marital partners were mediated by changes in IMB constructs . These findings provide initial evidence for the effectiveness of theoretically-based approaches to HIV prevention in India BACKGROUND During 1991 through 1993 , sexually transmitted infections among conscripts in the Royal Thai Army in the upper-northern provinces were common : human immunodeficiency virus ( HIV ) prevalence at induction was 12 % , HIV incidence was 2.4 % per year , and incidence of sexually transmitted diseases was 17 % per year . We evaluated a behavioral intervention to reduce incident sexually transmitted infections among conscripts inducted into the Thai Army in 1993 . METHODS We developed a preventive intervention that addressed consistent condom use , reducing alcohol consumption and brothel patronage , and improving sexual negotiation and condom skills . Companies were assigned to 1 of 3 groups matched on military mission : 450 men were in the intervention group , 681 were in barracks at the same base but did not receive the intervention ( diffusion group ) , and 414 were in distant camps ( controls ) . Baseline HIV serological testing and behavioral interviews were conducted during basic training in 1993 . The intervention was applied for 15 months , and men were followed up at 6-month intervals ( with repeated HIV serological testing , sexually transmitted disease assessment s , and behavioral interviews ) through May 1995 . RESULTS Incident sexually transmitted diseases were 7 times less frequent among men assigned to the intervention than the combined controls ( relative risk , 0.15 ; 95 % confidence interval , 0.04 - 0.55 ) , after adjusting for baseline risk factors ( P<.005 ) . There was no diffusion of the intervention to adjacent barracks . The intervention decreased incident HIV by 50 % in the intervention group . CONCLUSION Intensive interventions in structured institutions can successfully reduce risk in setting s confronting exp and ing heterosexual HIV epidemics Abstract Mobile population s are vulnerable to contracting HIV . The present study aims to evaluate the relative efficacy of the voluntary counseling and testing plus information dissemination ( VCT-ID ) approach versus the information dissemination ( ID ) approach for promoting HIV preventive behaviors in a mobile population , cross-border truck drivers . A total of 301 adult male cross-border truck drivers who self-reported having had sex with female sex workers ( FSW ) or non-regular sex partners ( NRPs ) in mainl and China in the last 12 months were recruited and r and omized into the VCT-ID intervention group ( Group I ) or ID control group ( Group C ) . Anonymous structured question naires , administered through a computer-assisted method , were used to collect data . At the follow-up survey ( about 8–9 weeks since the baseline survey ) , Group I participants , as compared to Group C participants , were more likely to be consistent condom users when having sex with FSW ( 85.5 % versus 68.5 % , p<0.05 ) and with NRP ( 54.8 % versus 36.4 % , p<0.1 ) , more knowledgeable about HIV , and were less likely to have contracted sexually transmitted diseases ( STD ) in the last two months . The VCT-ID approach is shown to be more efficacious than the ID approach in promoting safer sex and HIV-related knowledge among local cross-border truck drivers . Feasibility of providing voluntary counseling and testing ( VCT ) services at locations which are convenient to the target population is demonstrated . It also shows that VCT services can be used as a means of HIV prevention . The findings of this study result ed in up-scaled VCT services for the local target population The project aim ed to conduct a pilot study and intervention trials among youths in a factory of Khon Kaen . After contacting and obtaining agreement from owners/managers of factories , a survey using a self administered question naire , in-depth interview and focus group with workers to determine their level of knowledge and awareness of AIDS and high risk behaviour . A series of in-depth interviews with 16 workers and group discussion with 8 groups were conducted to find out their possible motivation for prevention and their acceptance of interventions /media . The data was used as a baseline for evaluating change after interventions and to modify the intervention education strategies and content . The study showed that the groups of factory workers which were not involved in the AIDS prevention had a different level of knowledge , attitudes , and behavior related to AIDS prevention than the groups which received the intervention and the methods used in the intervention achieved a level of success . The information we collected also showed that the best kinds of media for this purpose were videos and informational cartoons , which were also of special interest to the study group . It is hoped that the models will be adopted by relevant government and non-government agencies to be used in factories throughout the country Latinos in the United States are at increased risk for HIV and sexually transmitted disease ( STD ) infection . We evaluated the efficacy of a pilot lay health adviser ( LHA ) intervention design ed to increase condom use and HIV testing among Latino men . Fifteen LHAs ( mean age = 35.6 ; range 23 - 60 years ) from 15 Latino soccer teams were trained and worked with their teammates for 18 months . Another 15 teams served as the control group . Data were collected at baseline and at 18 months post-LHA training from a r and om sample of teammates from intervention and control teams . Data were collected from 222 men ( mean age = 29 years ) who participated in one of the 30 teams . Relative to the control condition , participants in the intervention reported more consistent condom use in the 30 days preceding follow-up ( unadjusted analysis , intervention , 65.6 % vs. control , 41.3 % ; p < .001 ) . Participants in the intervention were more likely to report condom use ( adjusted odds ratio [ AOR ] = 2.3 ; confidence interval [ CI = 1.2 - 4.3 ) and HIV testing ( AOR = 2.5 ; CI = 1.5 - 4.3 ) . LHA interventions for Latino men that are developed in partnership with community members , rely on male-centered intrapersonal networks , and are culturally congruent can enhance preventive behaviors and may reduce HIV infection We developed and evaluated a military-focused HIV prevention intervention to enhance HIV risk-reduction knowledge , motivation , and behaviors among Angolan soldiers . Twelve bases were r and omly assigned to HIV prevention or control conditions , yielding 568 participants . HIV prevention participants received training in preventing HIV ( 4.5 days ) and malaria ( 0.5 days ) . Control participants received the reverse . Monthly booster sessions were available after each intervention . We assessed participants at baseline , 3 and 6 months after the training . HIV prevention participants reported greater condom use and less unprotected anal sex at 3 months , as well as greater HIV-related knowledge and perceived vulnerability at 3 and 6 months . Within-group analyses showed HIV prevention participants increased condom use , reduced unprotected vaginal sex , and reduced numbers of partners at both follow-ups , while control participants improved on some outcomes at 3 months only . A military-focused HIV prevention intervention may increase HIV-related knowledge , motivation , and risk reduction among African soldiers Anecdotal evidence suggests that the HIV/AIDS prevalence rates in several African armed forces are high , with gender ine quality rendering female military personnel more vulnerable to the disease . The objective of this study was to replicate a successful videotape-based HIV prevention intervention among Nigerian female military personnel in an effort to establish the cross-cultural stability , feasibility and cost-effectiveness of this approach in re source -limited countries . Enlisted women ( N346 ) were recruited from two cantonments in Southwestern Nigeria and r and omly assigned to either ( a ) a 5-session video-based , small group , cognitive-behavioral , HIV prevention intervention , or ( b ) a 5-session , video-based , contact-matched , HIV education control condition . Participants provided self-report of their HIV/AIDS-related knowledge and sexual behaviors at baseline , 3 and 6 months after completing the intervention . The results indicate that the motivational skills-building intervention did not improve participants ' knowledge of HIV/AIDS any better than did the HIV education control condition at each assessment period , but it significantly increased condom use among women in this group by 53.6 % at 3-month follow-up . HIV preventive behaviors among women in the motivational skills-building intervention group improved significantly , being 2 and 3 times more , compared to women in the HIV education control group at 3-month and 6-month follow-up assessment s. The intervention also significantly improved behavioral intentions of participants as well as reduced alcohol use before sex by 25 % , after 3 months ; and number of sexual partners by 12 % after 6 months . Women in the intervention group were five times more likely than women in HIV education control group to suggest that their new male partners use condom . These findings indicate that a videotape-based , HIV prevention intervention is a feasible and effective approach to HIV prevention among female military personnel from sub-Saharan Africa This article conceptualizes employees ' fears for their health on the job as a form of stress with a collective , detrimental impact on work behavior . It tests a job-control of stress reduction that focuses on reducing uncertainty . Results indicate that fear levels are lower in organizations that have policies providing employees with certain types of information about the stressor . Analysis reveals that mechanisms conveying explicit information , rather than information that is indirect or implied , have the strongest association with lower fear levels . Hypotheses are tested in the context of nursing staff fears of contagion from HIV-infected patients , using data from 558 r and omly selected hospitals nationwide . Implication s for the policymaking dilemma of conflicting rights to privacy and disclosure are discussed While much descriptive research has documented positive associations between social capital and a range of economic , social and health outcomes , there have been few intervention studies to assess whether social capital can be intentionally generated . We conducted an intervention in rural South Africa that combined group-based microfinance with participatory gender and HIV training in an attempt to catalyze changes in solidarity , reciprocity and social group membership as a means to reduce women 's vulnerability to intimate partner violence and HIV . A cluster r and omized trial was used to assess intervention effects among eight study villages . In this paper , we examined effects on structural and cognitive social capital among 845 participants and age and wealth matched women from households in comparison villages . This was supported by a diverse portfolio of qualitative research . After two years , adjusted effect estimates indicated higher levels of structural and cognitive social capital in the intervention group than the comparison group , although confidence intervals were wide . Qualitative research illustrated the ways in which economic and social gains enhanced participation in social groups , and the positive and negative dynamics that emerged within the program . There were numerous instances where individuals and village loan centres worked to address community concerns , both working through existing social networks , and through the establishment of new partnerships with local leadership structures , police , the health sector and NGOs . This is among the first experimental trials suggesting that social capital can be exogenously strengthened . The implication s for community interventions in public health are further explored A pre-posttest , r and omized pilot study evaluated the effect of two selective prevention interventions on knowledge , attitudes , intentions , and behaviors to prevent and /or reduce substance use and risky sexual behaviors among 50 predominantly Mexican-American , low-income young women . Women were r and omly assigned to either a risk and resilience workshop or a health information correspondence course . Comparison tests using t tests and chi-square analyses were conducted to determine the baseline equivalence and pre- and posttest effects of the interventions . Both interventions had consistently similar effects . Neither significantly decreased use of alcohol or cigarettes . Both interventions significantly improved attitude , sexual self-efficacy , and resilience scores . Contraceptive use increased among women in partnered relationships , and both condom use and contraceptive use increased among sexually active , single young women . Both interventions also had significant positive effects on reported ability to discuss pre caution s to prevent human immunodeficiency virus/acquired immunodeficiency syndrome with sexual partners . Study limitations and implication s for clinical practice and future research are provided OBJECTIVE Zimbabwe , like other countries in sub-Saharan Africa , is experiencing a rapidly growing HIV/AIDS epidemic . It is crucial to determine risk events and socio-demographic characteristics associated with incident infections in order to tailor prevention messages accordingly . A cohort was established among factory workers with the objectives of estimating HIV incidence , seroprevalence , correlates of infection and subsequently evaluating the impact of prevention interventions . SETTING 40 factories in Harare , Zimbabwe . DESIGN AND METHODS HIV seroindicence [ total new infections over person time ( years ) follow up ] was estimated in a longitudinal cohort of male factory workers before and during a r and omised peer education intervention . Correlates of seroconversion were identified using Cox regression analysis . RESULTS Of 2,992 subjects enrolled there were 129 seroconversions during 1993 to 1996 follow up , yielding a 2.96 per 100 person year ( PY ) seroconversion incidence ( 95 % CI = 2.47 to 3.52 ) . Reporting a genital ulcer during follow up ( Hazard ratio [ HR ] = 4.9 , p = 0.001 ) having multiple sexual partners ( HR = 1.9 , p = 0.04 ) , having a urethral discharge ( HR = 2.1 , p = 0.001 ) , being single ( HR = 2.3 , p = 0.001 ) , widowed or married but not residing with wife were independent factors significantly associated with risk of HIV seroconversion . CONCLUSIONS Incidence of HIV identified in this economically productive sector is unacceptably high , and , disturbingly , is increasing in some age groups . Although the impact of the present intervention remains to be evaluated , the high incidence of HIV infection , points to the need for a more aggressive prevention effort in the general population OBJECTIVES This study examined the impact of worksite-based AIDS prevention program among port workers in Santos , Brazil , on sexual risk behavior for HIV infection . METHODS Male port workers ( n = 226 ) were followed in a 3-wave prospect i ve cohort study . A multifaceted intervention costing US $ 90,000 for 20,000 workers was conducted between waves 2 and 3 . RESULTS Heterosexual risk behavior showed no decline between waves 1 and 2 ( before the intervention ) but decreased substantially between waves 2 and 3 ( after the intervention ) . This decrease result ed from both a decrease in non primary partners and an increase in condom use . CONCLUSIONS This worksite-based AIDS program produced marked behavior change at modest cost BACKGROUND Few cognitive-behavioral interventions have focused on preventing sexually transmitted infections ( STIs ) and unintended pregnancies ( UPs ) in young , sexually active women in a single study . Military recruit training provides a well-defined , national , nonclinic sample in which to evaluate such an intervention . METHODS All female Marine recruits ( N=2,288 ) in training were approached . Of these , 2,157 ( 94.3 % ) voluntarily agreed and were r and omly assigned , by platoons , to participate in cognitive-behavioral interventions to prevent STIs or UPs or to prevent physical training injuries and cancer . Participants completed self-administered question naires and were screened for pregnancy , Chlamydia trachomatis , Neisseria gonorrhoeae , and Trichomonas vaginalis at baseline and , on average , 1 and 14 months postintervention . RESULTS A higher proportion of the control group had a postintervention STI or UP [ odds ratio (OR)=1.41 , 95 % confidence interval (CI)=1.01 - 1.98 ] . Among participants who had no history of STIs or pregnancy , but who engaged in risky sexual behaviors just before recruit training , the control group was more likely to acquire a postintervention STI ( OR=3.24 , CI=1.74 - 6.03 ) . Among participants who were not sexually experienced at baseline , the control group was more likely to have casual ( OR=2.05 , 95 % CI=1.04 - 4.08 ) and multiple ( OR=1.87 , 95 % CI=1.01 - 3.47 ) sexual partners postintervention . CONCLUSIONS This r and omized controlled trial indicates that cognitive-behavioral interventions are effective for reducing behavioral risk and preventing STIs and UPs in young , sexually active women who are not seeking health care Objective : To establish a cohort of high‐risk individuals suitable for HIV‐prevention trials , and to measure changes in sexual behaviour and sexually transmitted disease ( STD ) incidence after a behavioural intervention . Design : Prospect i ve cohort study in trucking company depots in Mombasa , Kenya . Participants : A total of 556 male HIV‐seronegative employees of trucking companies . Interventions : HIV serological testing , individual counselling , condom promotion , STD diagnosis and management . Main outcome measures : Sexual risk behaviour and symptomatic STD incidence . Results : Using time‐trend modelling , significant declines in self‐reported high‐risk sexual behaviour were demonstrated during a 1‐year follow‐up . The percentage of men reporting any extramarital sex during the 3‐month period prior to a follow‐up visit decreased from 49 % during the first quarter of follow‐up to 36 % during the last quarter ( P < 0.001 ) . The decline in reported female sex worker contact was from 12 % to 6 % ( P = 0.001 ) . Approximately 30 % of men reported consistent condom use during extramarital sex and this percentage remained unchanged during the study period . The incidence of STD declined from 34 per 100 person years ( PY ) during the first quarter to 10 per 100 PY during the last quarter ( P = 0.001 ) . Significant reductions in gonorrhoea ( 15 to five cases per 100 PY , P = 0.04 ) , non‐gonococcal urethritis ( 10 to two cases per 100 PY , P = 0.05 ) , and genital ulcer disease ( nine to two cases per 100 PY , P = 0.02 ) were observed . Conclusions : Among truck company workers who participated in a cohort study in Mombasa , Kenya , there was a significant decrease in sex with high‐risk partners , but no change in condom use . The change in heterosexual risk behaviour was accompanied by a significant decrease in incidence of gonorrhoea , non‐gonococcal urethritis , and genital ulcer disease Three single-session preventive interventions for reducing sexually transmitted disease ( STD ) and human immunodeficiency virus infection risk behaviors were evaluated with a sample of 400 men who attended a large military STD clinic . A quasi-experimental , pre-evaluation/postevaluation design was used , comparing st and ard clinic care alone versus st and ard care combined with 1 of 3 experimental interventions : health-risk appraisal , interactive video , and targeted situational behaviors . Question naire data were collected at baseline and during follow-up visits at 2 weeks and 2 months . Findings indicated that the health-risk appraisal and interactive video increased adherence with clinic recommendations to abstain from sex ( chi(2)3199=19.67 ; P<.001 ) and increased readiness to change " risky " partner- selection behavior ( chi(2)2194=6.42 ; P<.04 ) . Follow-up data suggested that STD-related risk behavior was particularly resistant to change but that the single-session intervention had some impact , which could be viewed as a " priming " effect that enhances multisession interventions |
13,630 | 26,242,987 | Conclusion There is no compelling evidence that any clinical ly available insulin analogue ( Aspart , Determir , Glargine , Glulisine or Lispro ) , nor human insulin increases breast cancer risk .
Overall , the data suggests that insulin treatment is not involved in breast tumour initiation , but might induce breast tumour progression by up regulating mitogenic signalling pathways | Introduction Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk .
The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development , and plausible mechanisms . | OBJECTIVE Recent epidemiological studies suggested that some insulin analogues could be associated with increased risk of cancer . The present study is aim ed at assessing the long-term association of different insulin analogues with cancer incidence . RESEARCH DESIGN AND METHODS A nested case-control study data set was generated from the cohort study data set ( n = 1,340 insulin-treated diabetic out patients ) by sampling control subjects from the risk sets . For each case subject , the control subjects ( up to five ) were chosen r and omly from those members of the cohort who are at risk for the same follow-up time of the case subject . Five-year age classes , sex , and BMI classes ( < 18.5 , 18.5–24.9 , 25–29.9 , and ≥30 kg/m2 ) were considered as additional categorical matching variables . RESULTS During a median follow-up of 75.9 months ( interquartile range 27.4–133.7 ) , 112 case subjects of incident cancer were compared with 370 matched control subjects . A significantly higher mean daily dose of glargine was observed in case subjects than in control subjects ( 0.24 IU/kg/day [ 0.10–0.39 ] versus 0.16 IU/kg/day [ 0.12–0.24 ] , P = 0.036 ) . Incident cancer was associated with a dose of glargine ≥0.3 IU/kg/day even after adjusting for Charlson comorbidity score , other types of insulin administration , and metformin exposure ( odds ratio 5.43 [ 95 % CI 2.18–13.53 ] , P < 0.001 ) . No association between incident cancer and insulin doses was found for human insulin or other analogues . CONCLUSIONS The possibility of association between cancer and higher glargine doses suggests that dosages should always be considered when assessing the possible association of insulin and its analogues with cancer Aims /hypothesisIn the light of a report suggesting that insulin glargine may increase cancer occurrence , the EASD asked us to perform this study . Methods We followed 114,841 individuals who had a prescription dispensed for insulin between 1 July and 31 December 2005 . From 1 January 2006 to 31 December 2007 , we noted the occurrence of malignancies . Seven different nationwide registers were used to obtain information on insulin exposure , outcome and possible confounders ; these were linked using the unique personal identity number assigned to every Swedish resident . Results After adjustment for age and , when appropriate , sex , users of insulin glargine alone ( no other types of insulin ) , compared with users of types of insulin other than insulin glargine , had an RR of 1.99 ( 95 % CI 1.31–3.03 ) for breast cancer , 0.93 ( 95 % CI 0.61–1.40 ) for gastrointestinal cancer , 1.27 ( 95 % CI 0.89–1.82 ) for prostate cancer and 1.07 ( 95 % CI 0.91–1.27 ) for any type of malignancy . Adjustment for age , smoking , BMI , age at onset of diabetes , age at birth of first child , cardiovascular disease and oestrogen use gave an RR for breast cancer of 1.97 ( 95 % CI 1.29–3.00 ) . The 95 % CIs crossed 1.0 for the RR calculated in all analyses of users of insulin glargine in combination with other types of insulin . Conclusions /interpretationIn Sweden , during 2006 and 2007 , women using insulin glargine alone ( no other types of insulin ) had an increased incidence rate of breast cancer as compared with women using types of insulin other than insulin glargine . This result may be due to a r and om fluctuation ; the possibilities for examining validity are limited , and no statistically significant results were obtained for any other individual cancer site or for the outcome ‘ all malignancies ’ . No definitive conclusions regarding a possible causal relationship between insulin glargine use and the occurrence of malignancies can be drawn from the results of this study OBJECTIVE Epidemiologic studies linking insulin glargine and glucose-lowering therapies to cancers and n-3 fatty acids to cancer prevention have not been confirmed . We aim ed to assess the effect of insulin glargine and n-3 fatty acids on incident cancers within the context of the ORIGIN ( Outcome Reduction with Initial Glargine Intervention ) trial . RESEARCH DESIGN AND METHODS The ORIGIN trial is an international , long-term , r and omized two-by-two factorial study comparing insulin glargine with st and ard care and n-3 fatty acids with placebo ( double blind ) in people with dysglycemia at high risk for cardiovascular events . The primary outcome measure ( cancer sub study ) was the occurrence of any new or recurrent adjudicated cancer . Cancer mortality and cancer subtypes were also analyzed . RESULTS Among 12,537 people ( mean age 63.5 years , SD 7.8 ; 4,388 females ) , 953 developed a cancer event during the median follow-up of 6.2 years . In the glargine and st and ard care groups , the incidence of cancers was 1.32 and 1.32 per 100 person-years , respectively ( P = 0.97 ) , and in the n-3 fatty acid and placebo groups , it was 1.28 and 1.36 per 100 person-years , respectively ( P = 0.39 ) . No difference in the effect of either intervention was noted within predefined subgroups ( P for all interactions ≥0.17 ) . Cancer-related mortality and cancer-specific outcomes also did not differ between groups . Postr and omization HbA1c levels , glucose-lowering therapies ( including metformin ) , and BMI did not affect cancer outcomes . CONCLUSIONS Insulin glargine and n-3 fatty acids have a neutral association with overall and cancer-specific outcomes , including cancer-specific mortality . Exposure to glucose-lowering therapies , including metformin , and HbA1c level during the study did not alter cancer risk BACKGROUND The provision of sufficient basal insulin to normalize fasting plasma glucose levels may reduce cardiovascular events , but such a possibility has not been formally tested . METHODS We r and omly assigned 12,537 people ( mean age , 63.5 years ) with cardiovascular risk factors plus impaired fasting glucose , impaired glucose tolerance , or type 2 diabetes to receive insulin glargine ( with a target fasting blood glucose level of ≤95 mg per deciliter [ 5.3 mmol per liter ] ) or st and ard care and to receive n-3 fatty acids or placebo with the use of a 2-by-2 factorial design . The results of the comparison between insulin glargine and st and ard care are reported here . The co primary outcomes were nonfatal myocardial infa rct ion , nonfatal stroke , or death from cardiovascular causes and these events plus revascularization or hospitalization for heart failure . Microvascular outcomes , incident diabetes , hypoglycemia , weight , and cancers were also compared between groups . RESULTS The median follow-up was 6.2 years ( interquartile range , 5.8 to 6.7 ) . Rates of incident cardiovascular outcomes were similar in the insulin-glargine and st and ard-care groups : 2.94 and 2.85 per 100 person-years , respectively , for the first co primary outcome ( hazard ratio , 1.02 ; 95 % confidence interval [ CI ] , 0.94 to 1.11 ; P=0.63 ) and 5.52 and 5.28 per 100 person-years , respectively , for the second co primary outcome ( hazard ratio , 1.04 ; 95 % CI , 0.97 to 1.11 ; P=0.27 ) . New diabetes was diagnosed approximately 3 months after therapy was stopped among 30 % versus 35 % of 1456 participants without baseline diabetes ( odds ratio , 0.80 ; 95 % CI , 0.64 to 1.00 ; P=0.05 ) . Rates of severe hypoglycemia were 1.00 versus 0.31 per 100 person-years . Median weight increased by 1.6 kg in the insulin-glargine group and fell by 0.5 kg in the st and ard-care group . There was no significant difference in cancers ( hazard ratio , 1.00 ; 95 % CI , 0.88 to 1.13 ; P=0.97 ) . CONCLUSIONS When used to target normal fasting plasma glucose levels for more than 6 years , insulin glargine had a neutral effect on cardiovascular outcomes and cancers . Although it reduced new-onset diabetes , insulin glargine also increased hypoglycemia and modestly increased weight . ( Funded by Sanofi ; ORIGIN Clinical Trials.gov number , NCT00069784 . ) Abstract Aims /hypothesis . To further investigate the association of cancer occurrence with the use of insulin glargine . Methods . We followed 114 838 individuals using insulin between 1 July and 31 December 2005 . From 1 January 2006 to 31 December 2008 , we noted the occurrence of malignancies ( cohort I ) . Insulin users between 1 July and 31 December 2006 were followed for the occurrence of malignancies in 2007 and 2008 ( cohort II ) . Users of insulin during three consecutive six-month periods from 1 July 2005 to 31 December 2006 were followed for the occurrence of malignancies in 2007 and 2008 ( cohort III ) . The Prescribed Drug Register , the Cancer Register , and the Causes of Death Register were used to obtain information on targeted person-time and outcome . We retrieved variables reflecting potential confounding factors from the Swedish National Diabetes Register , the Prescribed Drug Register , the Patient Register , the Medical Birth Register and the National Education Register . With Poisson regression we evaluated the association between insulin use and malignancy outcome with adjustment for confounders . Results . The adjusted incidence rate ratio ( and 95 % confidence interval ) for women who used insulin glargine alone compared with those who used other types of insulin , was 1.60 ( 1.10–2.32 ) for breast cancer but included 1.0 for malignancy outcomes other than breast cancer for men and women when analyzing cohort I with follow-up in 2006–2008 . For cohort II and III the corresponding incidence rate ratios were 1.38 ( 0.87–2.18 ) , and 0.87 ( 0.41–1.85 ) , respectively . Conclusion /interpretation . We do not see an increased risk during 2008 for breast cancer in the insulin glargine group . We need data for additional years before we can state with reasonable certainty that the increase in breast cancer incidence that we observed in Sweden in 2006 and 2007 was due to a r and om fluctuation or whether there is an association with the use of insulin glargine Summary Objective : It is important to establish pharmacokinetic or pharmacodynamic differences between novel insulin analogues and human insulin . This study examined the primary metabolic degradation products of insulin glargine ( LANTUS * ) in humans . Design : In this single dose , open-label study , insulin glargine was administered subcutaneously at a dose of 0.6IU/kg ; placebo was administered to one control subject . Patients : Four healthy male subjects , plus one control subject , aged 18–50 years were enrolled in this study . Measurements : Following insulin glargine administration , blood glucose levels were clamped at the subjects ' fasting concentration for 6 h and the amount of 20 % glucose infused to maintain this baseline concentration was recorded . Metabolite profiling was performed in plasma and injection site tissue using HPLC and radioimmunoassay ( RIA ) . Pharmacokinetics were evaluated by RIA of serum and plasma immunoreactive insulin levels . The primary pharmacodynamic measure was the glucose infusion rate ( GIR ) . Safety was evaluated by measuring blood glucose concentrations during the clamp and adverse events were observed by the investigator or reported by the subject . Results : Metabolic profiling revealed a clear pattern : insulin glargine is metabolised by sequential cleavage at the carboxy terminus of the B chain , to yield products M1 and M2 , which are both structurally similar to human insulin . These degradation products are present both at the injection site and in plasma . Conclusion : Thus , during treatment with a subcutaneous injection of insulin glargine , metabolic degradation is likely to be initiated at the injection site and continued within the circulatory system Aims /hypothesisRecent publications of data extracted from population registries have suggested a possible relationship between treatment with insulin glargine and increased incidence of cancer/breast cancer . The aim of the present study was investigate this possible relationship using data from the manufacturer ’s ( sanofi-aventis ) pharmacovigilance data base . Methods We analysed the manufacturer ’s ( sanofi-aventis ) pharmacovigilance data base for all r and omised clinical trials ( RCTs ; Phase 2–4 ) comparing insulin glargine with any comparator in type 1 or type 2 diabetes . We identified all serious adverse events coded under the System Organ Class of ‘ neoplasms , benign , malignant and unspecified ’ . Treatment-emergent neoplasms judged to be malignant were included in this analysis . Results The data base included 31 studies , 12 in type 1 diabetes and 19 in type 2 diabetes . Twenty compared insulin glargine with NPH insulin , 29 were parallel-group studies and two had a crossover design . Studies were generally of 6 months ’ duration , except for trial reference number 4016 ( n = 1,017 ) , which had a duration of 5 years . Overall , 10,880 people were included in the analysis ( insulin glargine , 5,657 ; comparator , 5,223 ) . Forty-five people ( 0.8 % ) vs 46 people ( 0.9 % ) reported 52 and 48 cases of malignant cancer in the insulin glargine and comparator groups , respectively ( RR 0.90 , 95 % CI 0.60–1.36 ) . Skin ( 12 people with 16 events vs six people with seven events , RR 1.85 , 95 % CI 0.69–4.92 ) , colon and rectum ( six vs ten people , RR 0.55 , 95 % CI 0.20–1.52 ) , breast ( four vs six people , RR 0.62 , 95 % CI 0.17–2.18 ) and gastrointestinal tract ( six vs four people , RR 1.38 , 95 % CI 0.39–4.90 ) were the most commonly reported sites . Conclusions /interpretationIn these 31 RCTs , insulin glargine was not associated with an increased incidence of cancer , including breast cancer , compared with the comparator group OBJECTIVE To investigate the association between type 2 diabetes , glucose-lowering therapies ( monotherapy with either metformin , sulphonylurea or insulin ) and cancer risk in Taiwan . METHODS Using Taiwan 's National Health Research Institutes data base of 1,000,000 r and om subjects from 2000 - 2008 , we found 61777 patients with type 2 diabetes ( age ≥20 years ) and 677378 enrollees with no record of diabetes . RESULTS After adjusting for age and sex , we found patients with diabetes to have significantly higher risk of all cancers ( OR : 1.176 ; 95 % CI : 1.149 - 1.204 , P < 0.001 ) . Diabetic patients treated with insulin or sulfonylureas had significantly higher risk of all cancers , compared to those treated with metformin ( OR : 1.583 ; 95 % CI : 1.389 - 1.805 , P < 0.001 and OR : 1.784 ; 95 % CI : 1.406 - 2.262 , P < 0.001 ) . Metformin treatment was associated with a decreased risk of colon and liver cancer compared to sulphonylureas or insulin treatment . Sulfonylureas treatment was associated with an increased risk of breast and lung cancer compared to metformin therapy . CONCLUSIONS Taiwanese with type 2 diabetes are at a high risk of breast , prostate , colon , lung , liver and pancreatic cancer . Those treated with insulin or sulfonylureas monotherapy are more likely to develop colon and liver cancer than those treated with metformin Purpose There is great interest in whether type 2 diabetes and its treatments alter breast cancer risk and prognosis , but previous studies are inconclusive . We conducted a cohort study within the UK General Practice Research Data base to investigate associations of type 2 diabetes and patterns of diabetes treatment with breast cancer risk and all-cause mortality . Methods We identified 52,657 women with type 2 diabetes , diagnosed between 1987 and 2007 , and 30,210 r and omly selected women without diabetes . We performed a time-dependent analysis using Cox proportional hazards models . Results Diabetes was associated with a 29 % increased overall breast cancer risk ( 95 % CI : 1.16–1.44 ) , but the association markedly attenuated when adjusted for age , period of cohort entry , region , and body mass index ( BMI ) ( HR : 1.12 ; 95 % CI : 0.98–1.29 ) . Women with breast cancer and pre-existing diabetes had a 49 % ( 95 % CI : 1.17–1.88 ) increased all-cause mortality risk compared with women with breast cancer but without diabetes , after controlling for age , period , region , BMI , smoking , alcohol , and deprivation . Compared with sulfonylurea , we found weak evidence that metformin monotherapy ( HR : 1.04 ; 95 % CI : 0.79–1.37 ) and insulin ( HR : 1.33 ; 95 % CI : 0.63–2.83 ) modified breast cancer risk among women with diabetes . Conclusions We found weak evidence that diabetes is associated with a small increased risk of breast cancer . Among treated women , there is no evidence that anti-diabetes treatments modify the risk of developing breast cancer , with wide confidence intervals indicating imprecise effect estimates . Women with breast cancer and diabetes , however , had an increased all-cause mortality risk highlighting the potential importance of maintaining adequate glycemic control alongside anti-cancer treatments and subsequent follow-up The objectives of this study are to assess the impact of pre-existing diabetes and diabetes treatment on breast cancer prognosis . 8,108 women with central ly confirmed invasive breast cancer in the Women ’s Health Initiative diagnosed between 1998 and 2013 were followed through the date of death or September 20 , 2013 . Information on diabetes and diabetes therapy were obtained via self-report and face-to-face review of current medication containers , respectively . Cox proportional hazard regression was used to estimate adjusted relative hazard ratios for overall mortality . The proportional subdistribution hazard model was used to estimate hazard ratios for breast cancer-specific mortality . Compared with women without diabetes , women with diabetes had significantly increased risk of overall mortality ( HR 1.26 95 % CI 1.06–1.48 ) , especially among those who took insulin or had longer duration of diabetes . However , diabetes was not associated with increased risk of breast cancer-specific mortality , regardless of type of treatment and duration of diabetes , despite the significant association of diabetes with unfavorable tumor characteristics . Our large prospect i ve cohort study provides additional evidence that pre-existing diabetes increases risk of total mortality among women with breast cancer . The increased total mortality associated with diabetes was mainly driven by increased risk of dying from diseases other than breast cancer . Thus , the continuum of care for breast cancer patients with diabetes should include careful attention to CVD risk factors and other non-cancer conditions Aims /hypothesisThe aim of this cohort study was to investigate the risk of malignant neoplasms and mortality in patients with diabetes treated either with human insulin or with one of three insulin analogues . Methods Data were provided by the largest German statutory health insurance fund ( time-frame : January 1998 to June 2005 inclusive ) , on patients without known malignant disease who had received first-time therapy for diabetes mellitus exclusively with human insulin , aspart , lispro or glargine . The primary outcome was the diagnosis of a malignant neoplasm . Data were analysed by multiple Cox regression models adjusting for potential confounders . Results A total of 127,031 patients were included , with a mean follow-up time of 1.63 ( median 1.41 , maximum 4.41 ) years . A positive association between cancer incidence and insulin dose was found for all insulin types . Because patients receiving combined therapy with insulin analogues and human insulin were excluded , the mean daily dose was much lower for glargine than for human insulin , and a slightly lower cancer incidence in the glargine group was found . After adjusting for dose , a dose-dependent increase in cancer risk was found for treatment with glargine compared with human insulin ( p < 0.0001 ) : the adjusted HR was 1.09 ( 95 % CI 1.00 to 1.19 ) for a daily dose of 10 IU , 1.19 ( 95 % CI 1.10 to 1.30 ) for a daily dose of 30 IU , and 1.31 ( 95 % CI 1.20 to 1.42 ) for a daily dose of 50 IU . No increased risk was found for aspart ( p = 0.30 ) or lispro ( p = 0.96 ) compared with human insulin . Conclusions /interpretationConsidering the overall relationship between insulin dose and cancer , and the lower dose with glargine , the cancer incidence with glargine was higher than expected compared with human insulin . Our results based on observational data support safety concerns surrounding the mitogenic properties of glargine in diabetic patients . Prospect i ve long-term studies are needed to further evaluate the safety of insulin analogues , especially glargine |
13,631 | 26,856,312 | COPD is common among patients undergoing TAVI , and COPD impacts both short- and long-term survival .
COPD patients , who had a lower BMI , shorter distance of 6MWT and CKD , were at higher risk for TAVI futility | OBJECTIVE The present study was performed to investigate the relationship between chronic obstructive pulmonary disease ( COPD ) and transcatheter aortic valve implantation ( TAVI ) .
BACKGROUND Controversies regarding the relationship between COPD and TAVI have intensified . | Objective Decision making for intervention in symptomatic aortic stenosis should balance the risks of surgery and of transcatheter aortic valve implantation ( TAVI ) . We identified the factors associated with early mortality after TAVI and aim ed to develop and vali date a simple risk score . Methods A population of 3833 consecutive patients was r and omly split into two cohorts comprising 2552 and 1281 patients , used respectively to develop and vali date a scoring system predicting 30-day or in-hospital mortality . Results TAVI was performed using the Edwards Sapien prosthesis in 2551 ( 66.8 % ) patients and the Medtronic Corevalve in 1270 ( 33.2 % ) . Approach was transfemoral in 2801 ( 73.4 % ) patients , transapical in 678 ( 17.8 % ) , subclavian in 219 ( 5.7 % ) and other in 117 ( 3.1 % ) . Early mortality was 10.0 % ( 382 patients ) . A multivariate logistic model identified the following predictive factors of early mortality : age ≥90 years , body mass index < 30 Kg/m2 , New York Heart Association class IV , pulmonary hypertension , critical haemodynamic state , ≥2 pulmonary oedemas during the last year , respiratory insufficiency , dialysis and transapical or other ( transaortic and transcarotid ) approaches . A 21-point predictive score was derived . C-index was 0.67 for the score in the development cohort and 0.59 in the validation cohort . There was a good concordance between predicted and observed 30-day mortality rates in the development and validation cohorts . Conclusions Early mortality after TAVI is mainly related to age , the severity of symptoms , comorbidities and transapical approach . A simple score can be used to predict early mortality after TAVI . The moderate discrimination is however a limitation for the accurate identification of high-risk patients OBJECTIVES This study sought to assess the impact of baseline left ventricular ( LV ) outflow , LV ejection fraction ( LVEF ) , and transvalvular gradient on outcomes following transcatheter aortic valve replacement ( TAVR ) in patients with severe aortic stenosis ( AS ) . BACKGROUND Low flow ( i.e. , reduced stroke volume index [ SVi ] ) can occur with both reduced and preserved LVEF . Low flow is often associated with low gradient despite severe stenosis and with worse outcomes following surgical aortic valve replacement . However , there are few data about the impact of low flow on outcomes following TAVR . METHODS We retrospectively analyzed the clinical , Doppler-echocardiographic , and outcome data prospect ively collected in 639 patients who underwent TAVR for symptomatic severe AS in 2 Canadian centers . RESULTS In this cohort , 334 ( 52.3 % ) patients had a low flow ( SVi < 35 ml/m(2 ) ) and these patients had increased 30-day mortality ( 11.4 vs. 5.9 % , p = 0.01 ) , 2-year all-cause mortality ( 35.3 vs. 30.9 % , p = 0.005 ) , and 2-year cardiovascular mortality ( 25.7 vs. 16.8 % , p = 0.01 ) compared with patients with normal flow . Reduced flow was an independent predictor of 30-day mortality ( odds ratio : 1.94 , p = 0.026 ) , cumulative all-cause mortality ( hazard ratio : 1.27 per 10 ml/m(2 ) SVi decrease , p = 0.016 ) , and cumulative cardiovascular mortality ( hazard ratio : 1.29 per 10 ml/m(2 ) decrease , p = 0.04 ) . Despite significant association in univariable analyses , low LVEF and low mean gradient were not found to be independent predictors of outcomes in multivariable analyses . CONCLUSIONS Low flow but not low LVEF or low gradient is an independent predictor of early and late mortality following TAVR in high-risk patients with severe AS . SVi should be integrated in the risk stratification process of these patients OBJECTIVES The objective was to define the characteristics of a real-world patient population treated with transcatheter aortic valve implantation ( TAVI ) , regardless of technology or access route , and to evaluate their clinical outcome over the mid to long term . BACKGROUND Although a substantial body of data exists in relation to early clinical outcomes after TAVI , there are few data on outcomes beyond 1 year in any notable number of patients . METHODS The U.K. TAVI ( United Kingdom Transcatheter Aortic Valve Implantation ) Registry was established to report outcomes of all TAVI procedures performed within the United Kingdom . Data were collected prospect ively on 870 patients undergoing 877 TAVI procedures up until December 31 , 2009 . Mortality tracking was achieved in 100 % of patients with mortality status reported as of December 2010 . RESULTS Survival at 30 days was 92.9 % , and it was 78.6 % and 73.7 % at 1 year and 2 years , respectively . There was a marked attrition in survival between 30 days and 1 year . In a univariate model , survival was significantly adversely affected by renal dysfunction , the presence of coronary artery disease , and a nontransfemoral approach ; whereas left ventricular function ( ejection fraction < 30 % ) , the presence of moderate/severe aortic regurgitation , and chronic obstructive pulmonary disease remained the only independent predictors of mortality in the multivariate model . CONCLUSIONS Midterm to long-term survival after TAVI was encouraging in this high-risk patient population , although a substantial proportion of patients died within the first year OBJECTIVES The aim of this study was : 1 ) to evaluate the acute and late outcomes of a transcatheter aortic valve implantation ( TAVI ) program including both the transfemoral ( TF ) and transapical ( TA ) approaches ; and 2 ) to determine the results of TAVI in patients deemed inoperable because of either porcelain aorta or frailty . BACKGROUND Very few data exist on the results of a comprehensive TAVI program including both TA and TF approaches for the treatment of severe aortic stenosis in patients at very high or prohibitive surgical risk . METHODS Consecutive patients who underwent TAVI with the Edwards valve ( Edwards Lifesciences , Inc. , Irvine , California ) between January 2005 and June 2009 in 6 Canadian centers were included . RESULTS A total of 345 procedures ( TF : 168 , TA : 177 ) were performed in 339 patients . The predicted surgical mortality ( Society of Thoracic Surgeons risk score ) was 9.8 + /- 6.4 % . The procedural success rate was 93.3 % , and 30-day mortality was 10.4 % ( TF : 9.5 % , TA : 11.3 % ) . After a median follow-up of 8 months ( 25th to 75th interquartile range : 3 to 14 months ) the mortality rate was 22.1 % . The predictors of cumulative late mortality were peri-procedural sepsis ( hazard ratio [ HR ] : 3.49 , 95 % confidence interval [ CI ] : 1.48 to 8.28 ) or need for hemodynamic support ( HR : 2.58 , 95 % CI : 1.11 to 6 ) , pulmonary hypertension ( PH ) ( HR : 1.88 , 95 % CI : 1.17 to 3 ) , chronic kidney disease ( CKD ) ( HR : 2.30 , 95 % CI : 1.38 to 3.84 ) , and chronic obstructive pulmonary disease ( COPD ) ( HR : 1.75 , 95 % CI : 1.09 to 2.83 ) . Patients with either porcelain aorta ( 18 % ) or frailty ( 25 % ) exhibited acute outcomes similar to the rest of the study population , and porcelain aorta patients tended to have a better survival rate at 1-year follow-up . CONCLUSIONS A TAVI program including both TF and TA approaches was associated with comparable mortality as predicted by surgical risk calculators for the treatment of patients at very high or prohibitive surgical risk , including porcelain aorta and frail patients . Baseline ( PH , COPD , CKD ) and peri-procedural ( hemodynamic support , sepsis ) factors but not the approach determined worse outcomes Pulmonary hypertension ( PH ) is prevalent in patients with aortic stenosis ( AS ) ; however , previous studies have demonstrated inconsistent results regarding the association of PH with adverse outcomes after aortic valve replacement ( AVR ) . The goal of this study was to evaluate the effects of preoperative PH on outcomes after AVR . We performed a regional prospect i ve cohort study using the Northern New Engl and Cardiovascular Disease Study Group data base to identify 1,116 consecutive patients from 2005 to 2010 who underwent AVR ± coronary artery bypass grafting for severe AS with a preoperative assessment of pulmonary pressures by right-sided cardiac catheterization . PH was defined as a mean pulmonary artery pressure of ≥25 mm Hg , with severity based on the pulmonary artery systolic pressure-mild , 35 to 44 mm Hg ; moderate , 45 to 59 mm Hg ; and severe , ≥60 mm Hg . We found that PH was present in 536 patients ( 48 % ) . Postoperative acute kidney injury , low-output heart failure , and in-hospital mortality increased with worsening severity of PH . In multivariate logistic regression , severe PH was independently associated with postoperative acute kidney injury ( adjusted odds ratio 4.1 , 95 % confidence interval [ CI ] 1.7 to 10 , p = 0.002 ) and in-hospital mortality ( adjusted odds ratio 6.9 , 95 % CI 2.5 to 19.1 , p < 0.001 ) . There was a significant association between PH and decreased 5-year survival ( adjusted log-rank p value = 0.006 ) , with severe PH being associated with the poorest survival ( adjusted hazard ratio 2.4 , 95 % CI 1.3 to 4.2 , p = 0.003 ) . In conclusion , severe PH in patients with severe AS is associated with increased rates of in-hospital adverse events and decreased 5-year survival after AVR BACKGROUND The Placement of Aortic Transcatheter Valves ( PARTNER ) trial showed that mortality at 1 year , 2 years , and 3 years is much the same with transcatheter aortic valve replacement ( TAVR ) or surgical aortic valve replacement ( SAVR ) for high-risk patients with aortic stenosis . We report here the 5-year outcomes . METHODS We did this r and omised controlled trial at 25 hospitals , in Canada ( two ) , Germany ( one ) , and the USA ( 23 ) . We used a computer-generated r and omisation sequence to r and omly assign high-risk patients with severe aortic stenosis to either SAVR or TAVR with a balloon-exp and able bovine pericardial tissue valve by either a transfemoral or transapical approach . Patients and their treating physicians were not masked to treatment allocation . The primary outcome of the trial was all-cause mortality in the intention-to-treat population at 1 year , we present here predefined outcomes at 5 years . The study is registered with Clinical Trials.gov , number NCT00530894 . FINDINGS We screened 3105 patients , of whom 699 were enrolled ( 348 assigned to TAVR , 351 assigned to SAVR ) . Overall mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 11·7 % . At 5 years , risk of death was 67·8 % in the TAVR group compared with 62·4 % in the SAVR group ( hazard ratio 1·04 , 95 % CI 0·86 - 1·24 ; p=0·76 ) . We recorded no structural valve deterioration requiring surgical valve replacement in either group . Moderate or severe aortic regurgitation occurred in 40 ( 14 % ) of 280 patients in the TAVR group and two ( 1 % ) of 228 in the SAVR group ( p<0·0001 ) , and was associated with increased 5-year risk of mortality in the TAVR group ( 72·4 % for moderate or severe aortic regurgitation vs 56·6 % for those with mild aortic regurgitation or less ; p=0·003 ) . INTERPRETATION Our findings show that TAVR as an alternative to surgery for patients with high surgical risk results in similar clinical outcomes . FUNDING Edwards Lifesciences IMPORTANCE Introducing new medical devices into routine practice raises concerns because patients and outcomes may differ from those in r and omized trials . OBJECTIVE To up date the previous report of 30-day outcomes and present 1-year outcomes following transcatheter aortic valve replacement ( TAVR ) in the United States . DESIGN , SETTING , AND PARTICIPANTS Data from the Society of Thoracic Surgeons/American College of Cardiology ( STS/ACC ) Transcatheter Valve Therapies Registry were linked with patient-specific Centers for Medicare & Medicaid Services ( CMS ) administrative cl aims data . At 299 US hospitals , 12 182 patients linked with CMS data underwent TAVR procedures performed from November 2011 through June 30 , 2013 , and the end of the follow-up period was June 30 , 2014 . EXPOSURE Transcatheter aortic valve replacement . MAIN OUTCOMES AND MEASURES One-year outcomes including mortality , stroke , and rehospitalization were evaluated using multivariate modeling . RESULTS The median age of patients was 84 years and 52 % were women , with a median STS Predicted Risk of Operative Mortality ( STS PROM ) score of 7.1 % . Following the TAVR procedure , 59.8 % were discharged to home and the 30-day mortality was 7.0 % ( 95 % CI , 6.5%-7.4 % ) ( n = 847 deaths ) . In the first year after TAVR , patients were alive and out of the hospital for a median of 353 days ( interquartile range , 312 - 359 days ) ; 24.4 % ( n = 2074 ) of survivors were rehospitalized once and 12.5 % ( n = 1525 ) were rehospitalized twice . By 1 year , the overall mortality rate was 23.7 % ( 95 % CI , 22.8%-24.5 % ) ( n = 2450 deaths ) , the stroke rate was 4.1 % ( 95 % CI , 3.7%-4.5 % ) ( n = 455 stroke events ) , and the rate of the composite outcome of mortality and stroke was 26.0 % ( 25.1%-26.8 % ) ( n = 2719 events ) . Characteristics significantly associated with 1-year mortality included advanced age ( hazard ratio [ HR ] for ≥95 vs < 75 years , 1.61 [ 95 % CI , 1.24 - 2.09 ] ; HR for 85 - 94 years vs < 75 years , 1.35 [ 95 % CI , 1.18 - 1.55 ] ; and HR for 75 - 84 years vs < 75 years , 1.23 [ 95 % CI , 1.08 - 1.41 ] ) , male sex ( HR , 1.21 ; 95 % CI , 1.12 - 1.31 ) , end-stage renal disease ( HR , 1.66 ; 95 % CI , 1.41 - 1.95 ) , severe chronic obstructive pulmonary disease ( HR , 1.39 ; 95 % CI , 1.25 - 1.55 ) , nontransfemoral access ( HR , 1.37 ; 95 % CI , 1.27 - 1.48 ) , STS PROM score greater than 15 % vs less than 8 % ( HR , 1.82 ; 95 % CI , 1.60 - 2.06 ) , and preoperative atrial fibrillation/flutter ( HR , 1.37 ; 95 % CI , 1.27 - 1.48 ) . Compared with men , women had a higher risk of stroke ( HR , 1.40 ; 95 % CI , 1.15 - 1.71 ) . CONCLUSIONS AND RELEVANCE Among patients undergoing TAVR in US clinical practice , at 1-year follow-up , overall mortality was 23.7 % , the stroke rate was 4.1 % , and the rate of the composite outcome of death and stroke was 26.0 % . These findings should be helpful in discussion s with patients undergoing TAVR Risk stratification tools used in patients with severe aortic stenosis have been mostly derived from surgical series . Although specific predictors of early mortality with transcatheter aortic valve replacement ( TAVR ) have been identified , the prognostic impact of their combination is unexplored . We sought to develop a simple score , using preprocedural variables , for prediction of 30-day mortality after TAVR . A total of 1,878 patients from a national multicenter registry who underwent TAVR were r and omly assigned in a 2:1 manner to development and validation data sets . Baseline characteristics of the 1,256 patients in the development data set were considered as c and i date univariate predictors of 30-day mortality . A bootstrap multivariate logistic regression process was used to select correlates of 30-day mortality that were subsequently weighted and integrated into a scoring system . Seven variables were weighted proportionally to their respective odds ratios for 30-day mortality ( glomerular filtration rate < 45 ml/min [ 6 points ] , critical preoperative state [ 5 points ] , New York Heart Association class IV [ 4 points ] , pulmonary hypertension [ 4 points ] , diabetes mellitus [ 4 points ] , previous balloon aortic valvuloplasty [ 3 points ] , and left ventricular ejection fraction < 40 % [ 3 points ] ) . The model showed good discrimination in both the development and validation data sets ( C statistics 0.73 and 0.71 , respectively ) . Compared with the logistic European System for Cardiac Operative Risk Evaluation in the validation data set , the model showed better discrimination ( C statistic 0.71 vs 0.66 ) , goodness of fit ( Hosmer-Lemeshow p value 0.81 vs 0.00 ) , and global accuracy ( Brier score 0.054 vs 0.073 ) . In conclusion , the risk of 30-day mortality after TAVR may be estimated by combining 7 baseline clinical variables into a simple risk scoring system OBJECTIVES The aim of this study was to evaluate the cost-effectiveness of transcatheter aortic valve replacement ( TAVR ) compared with surgical aortic valve replacement ( AVR ) for patients with severe aortic stenosis and high surgical risk . BACKGROUND TAVR is an alternative to AVR for patients with severe aortic stenosis and high surgical risk . METHODS We performed a formal economic analysis based on cost , quality of life , and survival data collected in the PARTNER A ( Placement of Aortic Transcatheter Valves ) trial in which patients with severe aortic stenosis and high surgical risk were r and omized to TAVR or AVR . Cumulative 12-month costs ( assessed from a U.S. societal perspective ) and quality -adjusted life-years ( QALYs ) were compared separately for the transfemoral ( TF ) and transapical ( TA ) cohorts . RESULTS Although 12-month costs and QALYs were similar for TAVR and AVR in the overall population , there were important differences when results were stratified by access site . In the TF cohort , total 12-month costs were slightly lower with TAVR and QALYs were slightly higher such that TF-TAVR was economically dominant compared with AVR in the base case and economically attractive ( incremental cost-effectiveness ratio < $ 50,000/QALY ) in 70.9 % of bootstrap replicates . In the TA cohort , 12-month costs remained substantially higher with TAVR , whereas QALYs tended to be lower such that TA-TAVR was economically dominated by AVR in the base case and economically attractive in only 7.1 % of replicates . CONCLUSIONS In the PARTNER trial , TAVR was an economically attractive strategy compared with AVR for patients suitable for TF access . Future studies are necessary to determine whether improved experience and outcomes with TA-TAVR can improve its cost-effectiveness relative to AVR OBJECTIVES The study aim ed to evaluate the impact of chronic lung disease ( CLD ) on outcomes of severe aortic stenosis patients across all treatment modalities . BACKGROUND Outcomes of patients with CLD undergoing transcatheter aortic valve replacement ( TAVR ) have not been systematic ally examined . METHODS All patients who underwent TAVR in the PARTNER ( Placement of AoRTic TraNscathetER Valve ) trial , including the continued access registry ( n = 2,553 ; 1,108 with CLD ) , were evaluated according to CLD clinical severity . Additionally , outcomes of CLD patients included in the r and omization arms of the PARTNER trial were compared : Cohort A patients ( high-risk operable ) treated by either TAVR ( n = 149 ) or surgical aortic valve replacement ( SAVR ) ; ( n = 138 ) ; and Cohort B patients ( inoperable ) treated by either TAVR ( n = 72 ) or st and ard therapy only ( n = 95 ) . RESULTS Among all TAVR-treated patients , at 1-year follow-up , patients with CLD had higher mortality than those without it ( 23.4 % vs. 19.6 % , p = 0.02 ) . Baseline characteristics of CLD patients who underwent TAVR were similar to respective controls . In Cohort A , 2-year all-cause death rates were similar ( TAVR 35.2 % and SAVR 33.6 % , p = 0.92 ) , whereas in Cohort B , the death rate was lower after TAVR ( 52.0 % vs. 69.6 % after st and ard therapy only , p = 0.04 ) . Independent predictors for mortality in CLD patients undergoing TAVR included poor mobility ( 6-min walk test < 50 m ; hazard ratio : 1.67 , p = 0.0009 ) and oxygen-dependency ( hazard ratio : 1.44 , p = 0.02 ) . Although CLD patients undergoing TAVR have worse outcomes than patients without CLD , TAVR is better in these patients than st and ard therapy and is similar to SAVR . CONCLUSIONS Although patients with CLD undergoing TAVR had worse outcomes than patients without CLD , TAVR performed better in these patients than st and ard therapy and was similar to SAVR . However , CLD patients who were either poorly mobile or oxygen-dependent had poor outcomes . ( THE PARTNER TRIAL : Placement of AoRTic TraNscathetER Valve Trial ; NCT00530894 ) Abstract Background . As patients with severe aortic valve stenosis ( AS ) develop symptoms their survival decreases rapidly , if treated conservatively . Transcatheter aortic valve implantation ( TAVI ) has been introduced as a less invasive treatment alternative , especially in inoperable patients , who often have severe comorbidities , including chronic obstructive pulmonary disease ( COPD ) . Material s and methods . Since the beginning of our TAVI program in March 2008 , data on all 131 TAVI patients were prospect ively and consecutively collected in this registry with complete follow-up . COPD was present in 37 patients . By January 2012 survival data were collected from the Danish Civil Registration System . Median follow-up duration was 559 days . Results . Overall survival and survival from cardiac death was equivalent in both patients with and without COPD ( p = 0.98 and p = 0.26 ) in the follow-up period . Further , patients with COPD had higher New York Heart Association ( NYHA ) class prior to intervention compared with those without ( 3.1 ± 0.5 vs. 2.9 ± 0.5 , p = 0.02 ) . In multivariate regression analysis COPD was associated with 30-day postoperative NYHA class ( 0.43 ; 95 % confidence interval ( CI ) : 0.10–0.75 ; p = 0.01 ) , but not to NYHA class improvement from pre- to postintervention ( 0.25 ; 95 % CI : − 0.12 to −0.63 ; p = 0.18 ) . Conclusions . In patients with symptomatic severe AS treated with TAVI , the presence of COPD neither affects overall survival nor survival from cardiac death . Patients with COPD had , however , both higher pre- and postoperative NYHA class compared with patients without COPD , but NYHA class improvement from pre- to postintervention was equivalent in both groups |
13,632 | 22,095,437 | Treatment with docetaxel alone is associated with a lower incidence of grade 3 diarrhea and stomatitis ( diarrhea , P = 0.011 ; stomatitis , P = 0.0004 ) .
Conclusion Combination chemotherapy regimens with docetaxel show a statistically significant advantage for TTP , but not for OS and ORR in MBC .
This review confirms that it is unlikely that any single agent or combination chemotherapy regimen will emerge as superior in MBC , due to its heterogeneous nature | Purpose Whether combination chemotherapy offers an advantage over sequential therapy in metastatic breast cancer ( MBC ) is still an unsettled issue .
Polychemotherapy regimens containing taxanes has been shown to increase overall survival ( OS ) , time to tumor progression ( TTP ) , and overall response rate ( ORR ) when compared with regimens that did not contain a taxanes , while taxane-based doublets have a statistically significant benefit over single-agent taxane only for progression-free survival .
However , the term “ taxanes ” generally includes both paclitaxel and docetaxel , drugs with different clinical activity .
Aim of this work is to compare OS , TTP , and ORR in patients with MBC receiving docetaxel alone or in combination with chemotherapy using a formal meta- analysis . | PURPOSE To determine whether the combination of pegylated liposomal doxorubicin ( PLD ) and docetaxel significantly prolongs time to disease progression compared with docetaxel alone without an increase in cardiac toxicity in women with advanced breast cancer who had experienced relapse at least 1 year after prior adjuvant or neoadjuvant anthracycline therapy . PATIENTS AND METHODS This international , phase III study r and omly assigned 751 patients to receive either docetaxel 75 mg/m(2 ) ( n = 373 ) or PLD 30 mg/m(2 ) followed by docetaxel 60 mg/m(2 ) every 21 days ( n = 378 ) and continued until disease progression or prohibitive toxicity . The primary end point was time to progression ( TTP ) . Secondary end points were overall survival ( OS ) , objective response rate ( ORR ) , cardiac toxicity , and safety . RESULTS Treatment with PLD-docetaxel significantly improved median TTP from 7.0 to 9.8 months ( hazard ratio [ HR ] = 0.65 ; 95 % CI , 0.55 to 0.77 ; P = .000001 ) and the ORR from 26 % to 35 % ( P = .0085 ) . OS was similar between the two groups ( HR = 1.02 ; 95 % CI , 0.86 to 1.22 ) . The incidence of grade 3 or 4 adverse events were similar ( 78 % v 72 % ) , although a higher incidence of h and -foot syndrome ( 24 % v 0 % ) and mucositis/stomatitis ( 12 % v 1 % ) were observed in the PLD-docetaxel combination . Protocol -defined left ventricular ejection fraction decreases and congestive heart failure were reported in 5 % and 1 % in both treatment arms , respectively . CONCLUSION The PLD-docetaxel combination was more effective than docetaxel alone in women with metastatic breast cancer who had experienced relapse at least 1 year after prior adjuvant anthracycline therapy without an increase in cardiac toxicity , although mucocutaneous toxicity was more common Trastuzumab is considered effective against human epidermal growth factor receptor (HER)-2-positive breast cancer as assessed by immunohistochemistry ( IHC ) and fluorescence or chromogenic in situ hybridization ( FISH/CISH ) on biopsy material . Trastuzumab is now approved in both the adjuvant and metastatic setting s for this patient population . Because HER-2 extracellular domain ( ECD ) levels have been correlated with disease progression in the metastatic setting , we considered trastuzumab salvage therapy plus a taxane in heavily pretreated trastuzumab-naive relapsed breast cancer patients with high serum levels of HER-2 ECD ( > or = 15 ng/ml ) . All patients had previously failed at least two lines of anthracycline- and taxane-based regimens and were HER-2 negative by IHC and FISH/CISH prior to a central ized re analysis , and were serum positive for HER-2 ECD ( > or = 15 ng/ml ) at baseline . Regular serum accounts of HER-2 ECD were recorded and compared with response and survival outcomes . Twenty-two patients were finally eligible for salvage therapy . Minor responses were observed in five ( 23 % ) and stable disease ( SD ) was observed in 11 patients , leading to a clinical benefit rate of 73 % ( 16 of 22 patients ) . The median time to progression and overall survival time were 5 ( 6.5 months in minor responders and SD ) and 12 months , respectively ; 11 and eight patients remained progression free for > 6 and > 12 months , respectively . Eleven and seven patients were alive at 12 and 15 months , respectively , after treatment start . Furthermore , in total , 13 ( 59.1 % ) patients obtained a biochemical response . In our study , patients with conventionally HER-2-negative disease but with expression of HER-2 ECD above the normal limit ( > or = 15 ng/ml ) displayed a rapid response , both biochemically and clinical ly , to the trastuzumab-taxane combination . This is the first study assessing anti-HER-2-based treatment in HER-2-negative advanced breast cancer according to HER-2 ECD positivity ; if our results are confirmed , additional patients with " hidden " HER-2-positive breast cancer might benefit from anti-HER-2 treatment The purpose of this study was to classify breast carcinomas based on variations in gene expression patterns derived from cDNA microarrays and to correlate tumor characteristics to clinical outcome . A total of 85 cDNA microarray experiments representing 78 cancers , three fibroadenomas , and four normal breast tissues were analyzed by hierarchical clustering . As reported previously , the cancers could be classified into a basal epithelial-like group , an ERBB2-overexpressing group and a normal breast-like group based on variations in gene expression . A novel finding was that the previously characterized luminal epithelial/estrogen receptor-positive group could be divided into at least two subgroups , each with a distinctive expression profile . These subtypes proved to be reasonably robust by clustering using two different gene sets : first , a set of 456 cDNA clones previously selected to reflect intrinsic properties of the tumors and , second , a gene set that highly correlated with patient outcome . Survival analyses on a subcohort of patients with locally advanced breast cancer uniformly treated in a prospect i ve study showed significantly different outcomes for the patients belonging to the various groups , including a poor prognosis for the basal-like subtype and a significant difference in outcome for the two estrogen receptor-positive groups BACKGROUND Through different pharmacodynamic-kinetic interactions , weekly administration of proved efficacy agents can overcome resistance with lower toxicity and greater benefit . Based on this assumption , we design ed a phase I-II trial with weekly non-pegylated liposomal anthracycline and taxane in first-line breast cancer patients . PATIENTS AND METHODS We enrolled 56 previously untreated metastatic breast cancer patients ; they were r and omly assigned to receive paclitaxel ( Taxol ) ( 50 mg/mq ) or docetaxel ( Taxotere ) ( 30 mg/mq ) combined with non-pegylated liposomal anthracycline ( 25 mg/mq ) on days 1 , 8 and 15 every 4 weeks . The primary end points were the clinical benefit and treatment-related toxic effects assessment . Secondary end points were time-to-disease progression ( TTP ) and overall survival ( OS ) . RESULTS The overall clinical benefit was 87.04 % . World Health Organization G3 - 4 toxic effects included neutropenia ( 45 % ) , anemia ( 44 % ) , complete alopecia ( 83 % ) , severe onycholysis and neuropathy . The 24 % of patients developed left ventricular ejection fraction reduction but none > 10 % with recover after treatment completion . The median absolute decrease from baseline was 1 % . Median TTP was 11 months and median OS was 23 months . CONCLUSIONS Combined weekly administration of taxane and non-pegylated liposomal anthracycline is well tolerated and clinical benefit data encourage phase III study design PURPOSE Docetaxel and capecitabine , a tumor-activated oral fluoropyrimidine , show high single-agent efficacy in metastatic breast cancer ( MBC ) and synergy in pre clinical studies . This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC . PATIENTS AND METHODS Patients were r and omized to 21-day cycles of oral capecitabine 1,250 mg/m(2 ) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2 ) on day 1 ( n = 255 ) or to docetaxel 100 mg/m(2 ) on day 1 ( n = 256 ) . RESULTS Capecitabine/docetaxel result ed in significantly superior efficacy in time to disease progression ( TTP ) ( hazard ratio , 0.652 ; 95 % confidence interval [ CI ] , 0.545 to 0.780 ; P = .0001 ; median , 6.1 v 4.2 months ) , overall survival ( hazard ratio , 0.775 ; 95 % CI , 0.634 to 0.947 ; P = .0126 ; median , 14.5 v 11.5 months ) , and objective tumor response rate ( 42 % v 30 % , P = .006 ) compared with docetaxel . Gastrointestinal side effects and h and -foot syndrome were more common with combination therapy , whereas myalgia , arthralgia , and neutropenic fever/sepsis were more common with single-agent docetaxel . More grade 3 adverse events occurred with combination therapy ( 71 % v 49 % , respectively ) , whereas grade 4 events were slightly more common with docetaxel ( 31 % v 25 % with combination ) . CONCLUSION The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2 ) , with the manageable toxicity profile , indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2 ) . Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC |
13,633 | 26,482,542 | In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities , increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy .
For people who are not suitable c and i date s for platinum treatment , we have found low- quality evidence suggesting that non-platinum combination and single-agent therapy regimens have similar effects on survival . | BACKGROUND Approximately 50 % of patients with newly diagnosed non-small cell lung cancer ( NSCLC ) are over 70 years of age at diagnosis .
Despite this fact , these patients are underrepresented in r and omized controlled trials ( RCTs ) .
As a consequence , the most appropriate regimens for these patients are controversial , and the role of single-agent or combination therapy is unclear .
In this setting , a critical systematic review of RCTs in this group of patients is warranted .
OBJECTIVES To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced ( stage IIIB and IV ) NSCLC .
To also assess the impact of cytotoxic chemotherapy on quality of life . | Background A r and omized trial of vinorelbine plus gemcitabine followed by docetaxel ( VGD ) versus paclitaxel plus carboplatin ( PC ) in patients with advanced non-small-cell lung cancer showed no difference in overall survival ( median survival time : 13.6 versus 14.1 months ) between the two treatment groups . We report here the results of quality -of-life ( QOL ) study initiated in the mid-course of this r and omized trial . Methods The patients themselves assessed the Functional Assessment of Cancer Therapy (FACT)-Lung ( FACT-L ) , FACT-Taxane and the Functional Assessment of Chronic Illness Therapy - Spirituality ( FACIT-Sp ) QOL instruments at baseline and 6 , 12 and 18 weeks after the treatment . The primary endpoint was a comparison of total QOL score for each assessment instrument between the two groups . Results Sixty-eight patients from the trial ( VGD , 34 ; PC , 34 ) who su bmi tted baseline question naires and at least one question naire over the course of treatment were eligible . Longitudinal analysis showed a significant difference in slope of the FACT-Taxane score ( p = 0.004 ) between treatment regimens over time , but no difference was found in FACT-L score ( p = 0.311 ) and FACIT-Sp score ( p = 0.466 ) between the two groups . Conclusions The significant difference in slope of FACT-Taxane score favored the VGD regimen . These data should be considered in treatment decision-making for patients with advanced non-small-cell lung cancer . Trial registration NCT00242983 Summary We studied the efficacy of cisplatin-based polychemotherapy for adenocarcinoma of the lung . A total of 136 patients were r and omized for treatment with either cyclophosphamide , Adriamycin , cisplatin and mitomycin C ( CAPM ) or mitomycin C , cytosine arabinoside and tegafur ( MCT ) . Radiation was given to the chests of patients at stage III . The differences in the response rate ( 35 % in the CAPM arm and 13 % in the MCT arm ) were statistically significant ( P < 0.01 ) . However , the significant difference was observed in stage-IV patients ( CAPM , 33 % ; MCT , 4%;P < 0.001 ) and not in stage-III patients ( CAPM , 40 % ; MCT , 40 % ) . The median period of survival was 9.5 months for the CAPM arm and 5.5 months for the MCT arm ( P < 0.035 , Wilcoxon-Gehan test;P < 0.1 , log-rank test ) . Improved median survival for the CAPM regimen was demonstrated only by stage-IV patients ( CAPM , 10 months ; MCT , 5.5 months;P < 0.025 , Wilcoxon-Gehan test;P < 0.05 , log-rank test ) . The duration of the response , including PRs and NCs , was significantly different depending on the treatment , showing 5 months for the CAPM arm and 3 months for the MCT arm ( P < 0.05 ) . The significant difference was also only observed in stage-IV patients . Myelosuppression was more severe with CAPM than with the MCT regimen . Nausea and vomiting were significantly increased in patients receiving the CAPM regimen . However , all toxicities were acceptable and there were no treatment-related deaths . We concluded that cisplatin-based chemotherapy , CAPM therapy , was of more benefit to patients with adenocarcinoma of the lung than MCT therapy The aim of this study was to assess whether a combination of gemcitabine ( GEM ) with either paclitaxel ( PTX ) or vinorelbine ( VNR ) could be more effective than GEM or PTX alone in elderly or unfit advanced non-small-cell lung cancer ( NSCLC ) patients . A total of 264 NSCLC patients aged > 70 years with ECOG performance status (PS)⩽2 , or younger with PS=2 , were r and omly treated with : GEM 1200 mg m−2 on days 1 , 8 and 15 every 28 days ; PTX 100 mg m−2 on days 1 , 8 and 15 every 28 days ; GEM 1000 mg m−2 plus PTX 80 mg m−2 ( GT ) on days 1 and 8 every 21 days ; GEM 1000 mg m−2 plus VNR 25 mg m−2 ( GV ) on days 1 and 8 every 21 days . In all arms , an intra- patients dose escalation was applied over the first three courses , provided that no toxicity of WHO grade ⩾2 had previously occurred . At present time , 217 ( 82 % ) patients had died . The median ( months ) and 1-year survival probability were 5.1 and 29 % for GEM , 6.4 and 25 % for PTX , 9.2 and 44 % for GT , and 9.7 and 32 % for GV . Multivariate analysis showed that PS⩽1 ( hazard ratio (HR)=0.67 ; 95 % CI 0.51–0.90 ) , and doublet treatments ( HR=0.76 ; 95 % CI 0.59–0.99 ) were significantly associated with longer survival . Doublets produced no more toxicity than single agents . GT should be considered a reference regimen for elderly NSCLC patients with PS⩽1 We present experience from a phase II r and omized clinical trial , comparing st and ard gemcitabine as monotherapy with low-dose gemcitabine in long infusion in a doublet with cisplatin at reduced dose for patients with non-small cell lung cancer ( NSCLC ) and who are unfit for st and ard platin-based chemotherapy . Eligible patients had microscopically confirmed NSCLC in stage IIIB ( wet ) or IV , were chemo-naive , and were in poor performance status or presented with significant comorbidity . St and ard treatment with gemcitabine , 1250 mg/m2 in 20–30 min on days 1 and 8 as monotherapy ( arm A ) was compared with low-dose gemcitabine in long infusion ( 200 mg/m2 in 6 h on day 1 ) and cisplatin at 60 mg/m2 on day 2 ( arm B ) . Both treatment schedules were repeated every 3 weeks until disease progression , unacceptable toxicity , or to a maximum of six cycles . A total of 112 patients ( 83 male , 29 female , median age 66 years ) were r and omized between arm A ( 57 patients ) and B ( 55 patients ) . The two groups were balanced for prognostic factors . Fifty-three patients in arm A and 52 in arm B received at least one application of chemotherapy and were evaluable for toxicity and response . The median number of cycles was four and five for arms A and B , respectively . Except for grade 3 anemia ( one patient in arm A and two in arm B ) , no other major toxicity was seen . Regarding response to treatment , arm B was superior : 1 complete response and 13 partial remissions ( response rate 26.9 % ) as compared with five partial remissions ( response rate 9.4 % ) in arm A ( P<0.01 ) . The median time to progression was 3.8 and 5.6 months , and the median survival was 4.3 and 6.8 months for arms A and B , respectively ( P<0.05 ) . Treatment with low-dose gemcitabine in long infusion and cisplatin at reduced dose has very low toxicity , is effective , was found to be superior to monotherapy with gemcitabine in st and ard doses , and is suitable for patients with NSCLC who can not tolerate a st and ard platin-based doublet PURPOSE The objective of this trial was to compare two vinorelbine-based doublets with carboplatin ( CBDCA-VC ) or with gemcitabine ( VG ) in patients with stage IIIB-IV non-small cell lung cancer ( NSCLC ) . PATIENTS AND METHODS A total of 316 patients with advanced NSCLC previously untreated were r and omized to either vinorelbine 30 mg/m(2 ) D1,8 with carboplatin AUC 5 D1 ( VC ) or vinorelbine 25mg/m(2 ) with gemcitabine ( VG ) 1000 mg/m(2 ) both given D1,8 every 3 weeks . The primary endpoint was response rate with secondary parameters being survival ( OS ) , progression-free survival ( PFS ) , tolerance and clinical benefit . RESULTS The median number of cycles was four in each arm with a total of 1268 cycles . The objective response ( OR ) on intent-to-treat was 20.8 % in VC and 28 % in VG ( p=0.15 ) . Median PFS was 3.9 months in VC and 4.4 months ( mo ) in VG ( p=0.18 ) . Median survival was significantly longer ( p=0.01 ) for VG with 11.5 mo compared to 8.6 mo in VC with 1 year survival at 48.9 and 34.4 % , respectively . Tolerance was better in the VG arm as compared to the VC patients . Four toxic deaths were recorded in the VC group . Clinical benefit response rate was 32.4 % compared to 40.9 % in 111 and 110 evaluable patients in VC and VG , respectively . CONCLUSION VG compared to VC result ed in a similar overall response rate , favourable median survival and a better toxicity profile . For non-cisplatin-based chemotherapy , VG is a useful alternative PURPOSE To compare mitomycin C plus vindesine plus etoposide ( MEV ) vs. mitomycin C plus vindesine plus cisplatin ( MVP ) in the treatment of stage IV non-small-cell lung cancer . PATIENTS AND METHODS 204 patients were entered in a phase III multicentre r and omised trial from June 1990 to December 1994 and stratified according to the ECOG performance status ( 0 - 1 vs. 2 ) . MVP was given in the following dosages : mitomycin C 8 mg/m2+vindesine 3 mg/m2+cisplatin 100 mg/m2 i.v . day 1 and vindesine 3 mg/m2 i.v . day 8 with cycles repeated every 4 weeks . MEV was given in the following dosages : mitomycin C 8 mg/m2+vindesine 3 mg/ m2 i.v . day 1 and etoposide 100 mg/m2 i.v . days 1 to 3 with cycles repeated every 3 weeks . For both treatments a maximum of 6 cycles was planned . Response and toxicity were evaluated according to WHO . Subjective responses were assessed by numerical scales . Analyses were made on the basis of intent to treat . RESULTS The objective response rate was 21.4 % ( 1 CR + 21 PR among 103 patients ) in the MEV and 28.7 % ( 1 CR + 28 PR among 101 patients ) in the MVP arm ( P = 0.48 ) . Symptoms were similar in the two arms . 196 patients progressed and 182 died . The median times to progression were 10 weeks ( 95 % CI 9 - 12 ) and 12 weeks ( 95 % CI 10 - 15 ) and median survivals were 29 weeks ( 95 % CI 25 - 36 ) and 28 weeks ( 95 % CI 25 - 35 ) in the MEV and MVP arms , respectively . The relative risks of progressing and of dying were 0.89 ( 95 % CL 0.66 - 1.20 ) and 0.96 ( 95 % CL 0.71 - 1.30 ) , respectively , for patients receiving MVP as compared with those receiving MEV at multivariate analysis adjusted by sex , age , histologic type , number of metastatic sites , performance status at entry , and centre . CONCLUSIONS In the present study , no significant differences were observed in response rate , survival or palliation of symptoms between the MEV and MVP regimens , while toxicity was significantly more frequent and severe with MVP . Thus , MEV should be considered a reasonable alternative to the MVP regimen in the treatment of stage IV NSCLC Introduction : This r and omized phase II trial evaluated single-agent pemetrexed or sequential pemetrexed/gemcitabine in patients with non-small cell lung cancer ( NSCLC ) who were elderly ( ≥70 years ) or younger than 70 years and ineligible for platinum-based chemotherapy . Methods : Chemonaive patients with stage IIIB/IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2 received either 500 mg/m2 of pemetrexed ( day 1 , every 3 weeks ) for eight cycles , or the same dosage of pemetrexed for cycles 1 and 2 and then 1200 mg/m2 of gemcitabine ( days 1 and 8 , every 3 weeks ) for cycles 3 and 4 ( repeated once for a total of eight cycles ) . All patients were given vitamin B12 and folic acid supplementation . Results : From July 2003 to July 2004 , 87 patients ( 44 pemetrexed ; 43 pemetrexed/gemcitabine ) received treatment . The median time to progression was 4.5 ( 95 % confidence interval : 3.0–9.3 ) and 4.1 months ( 95 % confidence interval : 1.7–5.8 ) for the pemetrexed and pemetrexed/gemcitabine arms , respectively , and the median progression-free survival time was 3.3 months for both arms . Tumor response rates for the pemetrexed and pemetrexed/gemcitabine arms were 4.5 % and 11.6 % , respectively . The median overall survival time was 4.7 months for the pemetrexed arm and 5.4 months for the pemetrexed/gemcitabine arm , with respective 1-year survival rates of 28.5 % and 28.1 % . Grade 3/4 hematologic toxicity consisted of neutropenia ( 4.5 % pemetrexed ; 2.3 % pemetrexed/gemcitabine ) , febrile neutropenia ( 4.5 % pemetrexed ; 4.7 % pemetrexed/gemcitabine ) , thrombocytopenia ( 4.5 % pemetrexed ; 7.0 % pemetrexed/gemcitabine ) , and anemia ( 6.8 % pemetrexed ; 4.7 % pemetrexed/gemcitabine ) . No grade 3/4 nonhematologic toxicities exceeded 4.7 % in either arm . Conclusions : Single-agent pemetrexed and sequential pemetrexed/gemcitabine have shown moderate activity and are well tolerated as first-line treatments for advanced NSCLC in elderly patients or patients unsuitable for platinum-based combination chemotherapy PURPOSE Sufficient data are currently unavailable to assist in defining suitable regimens for patients ≥ 70 years with advanced non-small cell lung cancer ( NSCLC ) . METHODS Chemonaïve patients with a performance status ( PS ) of 0 or 1 and stage IIIB or IV NSCLC were r and omized to gemcitabine 1000mg/m(2 ) on days 1 and 8 plus carboplatin area under the curve ( AUC ) 5.5 on day 1 ; the same schedule of gemcitabine plus paclitaxel 200mg/m(2 ) on day 1 ; or paclitaxel 225mg/m(2 ) on day 1 plus carboplatin AUC 6.0 on day 1 . Cycles were every 21 days up to 6 . Efficacy and toxicity results were compared by age groups . RESULTS Overall survival ( OS ) between patients < 70 years ( 8.6 months , 95 % CI : 7.9 , 9.5 ) and ≥ 70 years ( 7.9 months , 95 % CI : 7.1 , 9.5 ) was similar . OS was 8.8 months ( 95 % CI : 7.5 , 10.3 ) among patients 70 - 74 years , 6.5 months ( 95 % CI : 5.6 , 9.3 ) among patients 75 - 79 years , and 7.9 months ( 95 % CI : 6.3 , 10.3 ) among patients ≥ 80 years . OS was lower among patients 75 - 79 years compared with patients 70 - 74 years ( P=0.04 ) . Compared with patients < 70 years , patients ≥ 70 years experienced similar rates of myelosuppresion , but younger patients experienced more vomiting and nausea . There was no clear pattern with respect to differences in efficacy by treatments across age groups . CONCLUSIONS Based on the similarity of patient outcomes across age groups , doublet chemotherapy is feasible among carefully selected elderly patients with good PS OBJECTIVE To determine , in stage IV non-small-cell lung cancer ( NSCLC ) , if the combination of gemcitabine-a new active drug-with ifosfamide ( IG ) or with the cisplatin-carboplatin association ( CCG ) will improve survival ( primary end point ) in comparison with a first-generation regimen , cisplatin-carboplatin-ifosfamide ( CCI ) . PATIENTS AND METHODS A total of 284 chemotherapy-naïve patients with metastatic NSCLC were r and omised . Four were ineligible and 16 were not assessable for responses . Cisplatin was given at 60 mg/m2 on day 1 , carboplatin AUC 3 mg.min/ml on day 1 , ifosfamide 4.5 g/m2 on day 1 and gemcitabine 1 g/m2 on days 1 , 8 and 15 . Courses were repeated every 4 weeks . Response was assessed after three courses and chemotherapy was continued in responding patients until best response . There were 94 eligible patients in the CCI arm , 92 in CCG and 94 in the IG arm . RESULTS The objective response rates for CCI , CCG and IG were 23 % [ 95 % confidence interval ( CI ) 15 % to 32 % ] , 29 % ( 95 % CI 20 % to 39 % ) and 25 % ( 95 % CI 16 % to 33 % ) , respectively ( P = 0.61 ) . Median survival time was 24 , 34 and 30 weeks , respectively ( P = 0.20 ) . One-year survival was 23 , 33 and 35 % , and 2-year survival was 11 , 14 and 17 % , respectively . In some subgroups ( older patients , women ) , there was a significant survival advantage for CCG and IG compared with CCI . Toxicity was tolerable : severe alopecia was less frequent in the CCG arm , and IG was associated with significantly more thrombopenia while CCG was associated with more leucopenia . CONCLUSION In stage IV NSCLC , treatment with regimens including the new drug gemcitabine were associated with a better but not statistically significant observed survival compared with a classical first-generation cisplatin-containing regimen . The non-platinum combination of gemcitabine was as effective as its combination with platinum Combination chemotherapy with cytotoxic agents is the regular treatment for patients with advanced non-small cell lung cancer ( NSCLC ) , good performance status , and no major clinical contraindications . Since the early 1980s , platinum-based chemotherapy is the cornerstone of this treatment , while combinations containing long-acting alkylating agents have been nearly ab and oned , and represent a sort of historical treatment . Nevertheless , the real survival benefits of cisplatin are uncertain and still debated . To attempt an answer , the Cuneo Lung Cancer Study Group ( CuLCaSG ) carried out a clinical trial comparing a platinum ( MVP ) versus a non-platinum-based combination chemotherapy ( MACC ) . The study comprised 156 patients with advanced NSCLC r and omly assigned to the two treatment arms . MACC and MVP chemotherapies were given as originally described and continued until progression of disease , unacceptable toxicity , or refusal by the patient . For a medium of four cycles of MVP and three cycles of MACC , the median dose intensity ( DI ) reached was , respectively , 95 % and 100 % of the intended ( P = 0.0132 ) . In all , 27 objective responses ( 1 complete and 16 partial responses in patients allocated to MVP versus 10 partial responses of the MACC group ) were observed . Median progression-free and global survivals were , respectively , 21 and 34 weeks for MVP and 20 and 31 weeks for MACC ( non-significant differences ) . The treatment plan was found non-significant also multivariate analysis of survival . Toxicity was rather similar in the two arms , except for more severe neurological toxicity , anemia , thrombocytopenia , nausea , and vomiting in patients on MVP . Alopecia was more common after MACC . Subjective tolerance to treatment , and perception of physical and psychological well-being were rated similarly by patients of both groups . In conclusion , MVP was moderately more active than MACC , and showed a foreseeable and reversible toxicity , of a low-medium grade . However , this CuLCaSG study failed to substantiate any survival benefit from the use of platinum in combination with other cytotoxic agents Docetaxel plus cisplatin and docetaxel plus irinotecan are active and well-tolerated chemotherapy regimens for advanced non-small-cell lung cancer ( NSCLC ) . A r and omised phase II study compared their efficacy and toxicity in 108 patients with stage IIIb/IV NSCLC , who were r and omised to receive docetaxel 60 mg m−2 and cisplatin 80 mg m−2 on day 1 ( DC ; n=51 ) , or docetaxel 60 mg m−2 on day 8 and irinotecan 60 mg m−2 on day 1 and 8 ( DI ; n=57 ) every 3 weeks . Response rates were 37 % for DC and 32 % for DI patients . Median survival times and 1- and 2-year survival rates were 50 weeks ( 95 % confidence interval : 34–78 weeks ) , 47 and 25 % for DC , and 46 weeks ( 95 % confidence interval : 37–54 weeks ) , 40 and 18 % for DI , respectively . The progression-free survival time was 20 weeks ( 95 % confidence interval : 14–25 weeks ) with DC and 18 ( 95 % confidence interval : 12–22 weeks ) with DI . Significantly more DI than DC patients had grade 4 leucopenia and neutropenia ( P<0.01 ) ; more DC patients had grade ⩾2 thrombocytopenia ( P<0.01 ) . Nausea and vomiting was more pronounced with DC ( P<0.01 ) ; diarrhoea was more common with DI ( P=0.01 ) . Three treatment-related deaths occurred in DC patients . In conclusion , although the DI and DC regimens had different toxicity profiles , there was no significant difference in survival Objectives The aim of the present study was to evaluate the efficacy and safety of carboplatin plus paclitaxel versus gemcitabine plus vinorelbine in patients with advanced nonsmall cell lung cancer ( NSCLC ) and an Eastern Cooperative Oncology Group performance status ( PS ) of 2 . Methods Chemotherapy-naive patients with NSCLC of stage IIIB or IV and a PS of 2 were eligible . The patients received 3-week cycles of carboplatin ( area under the curve of 6 ) plus paclitaxel ( 200 mg/m2 ) on day 1 ( CP ) or gemcitabine ( 1000 mg/m2 ) plus vinorelbine ( 25 mg/m2 ) on days 1 and 8 ( GV ) . The primary end point was 1-year survival rate for selection of the better treatment arm for further study . Results Of the 89 patients enrolled , 84 were assessable ( 41 in the CP arm , 43 in the GV arm ) . The overall response rate , median survival time , and 1-year survival rate were 29.3 % , 5.9 months , and 22.0 % , respectively , for the CP arm and 20.9 % , 6.0 months , and 27.9 % for the GV arm . Common toxicities of grade 3 or 4 included neutropenia ( 67.5 % for the CP arm vs. 65.1 % for the GV arm ) , febrile neutropenia ( 20 % vs. 14 % ) , and infection ( 25.0 % vs. 23.2 % ) . The frequency of nausea of grade 3 was greater for the CP arm ( 17.5 % vs. 2.3 % ) , whereas that of anemia of grade 3 or 4 ( 30.2 % vs. 12.5 % ) or treatment-related death ( 7.0 % vs. 2.4 % ) was greater for the GV arm . Conclusions The 1-year survival rate did not exceed 30 % for either doublet chemotherapy . Furthermore , each treatment was associated with a substantial degree of toxicity The purpose of our study was to compare progression-free survival and quality of life ( QOL ) after cisplatin – gemcitabine ( CG ) or epirubicin – gemcitabine ( EG ) in chemotherapy-naive patients with unresectable non-small-cell lung cancer . Patients ( n=240 ) were r and omised to receive gemcitabine 1125 mg m−2 ( days 1 and 8) plus either cisplatin 80 mg m−2 ( day 2 ) or epirubicin 100 mg m−2 ( day 1 ) every 3 weeks for a maximum of five cycles . Eligible patients had normal organ functions and Eastern Cooperative Oncology Group performance status ⩽2 . QOL was measured with European Organisation for Research and Treatment of Cancer QLQ-C30 and LC13 question naires . There were no significant differences in median progression-free survival ( CG 26 weeks , EG 23 weeks ) , median overall survival ( CG 43 weeks , EG 36 weeks ) , or tumour response rates ( CG 46 % , EG 36 % ) . Toxicity was mainly haematologic . In the EG arm granulocytopenia occurred more frequently , leading to more febrile neutropenia . Also , elevation of serum transaminases , mucositis , fever , and decline in LVEF were more common in the EG arm . In the CG arm , more patients experienced elevated serum creatinine levels , sensory neuropathy , nausea , and vomiting . Global QOL was not different in both arms . Progression-free survival , overall survival , response rate , and QOL were not different between both arms ; however , overall toxicity was more severe in the EG arm In a phase III trial , 191 patients aged over 70 with stage IIIB/IV non-small cell lung cancer were r and omized to receive best supportive care ( BSC ) alone or BSC plus vinorelbine on days 1 and 8 , q 21 days for up to six cycles . Increasing difficulties in recruitment meant that the investigators , blinded to the results , stopped the trial early . Data from 161 patients have been analyzed . The vinorelbine regimen was well tolerated . Grade 3/4 neutropenia occurred in 10 % of patients and grade 2/3 anemia in 16 % . The principle nonhematological toxicities were constipation and fatigue . An objective response rate was recorded in 19.7 % of the 76 patients treated with vinorelbine . The survival experience of these patients was significantly superior to that among control patients . The median duration of survival was longer ( 28 versus 21 weeks ) and patients receiving vinorelbine were significantly more likely to survive to one year ( 32 % versus 14 % ) . The relative risk of death in the vinorelbine group was 0.65 ( 95 % confidence interval : 0.45 - 0.93 ) . Quality of life was extensively investigated using European Organization for Research and Treatment of Cancer scales . While aspects of quality -of-life issues that were directly related to drug toxicity ( such as nausea and constipation ) were lower in the vinorelbine group , patients who received vinorelbine fared better than controls on measures related to lung cancer symptoms and pain and on social , cognitive , and physical functioning Background : Platinum-based doublet chemotherapy is the st and ard first-line treatment for advanced non-small cell lung cancer ( NSCLC ) , but earlier studies have suggested that non-platinum combinations are equally effective and better tolerated . We conducted a national , r and omised study to compare a non-platinum with a platinum combination . Methods : Eligible patients had stage IIIB/IV NSCLC and performance status ( PS ) 0–2 . Patients received up to three cycles of vinorelbine 60 mg m−2 p.o.+gemcitabine 1000 mg m−2 i.v . day 1 and 8 ( VG ) or vinorelbine 60 mg m−2 p.o . day 1 and 8+carboplatin area under the curve=5 ( Calvert 's formula ) i.v . day 1 ( VC ) . Patients ⩾75 years received 75 % of the dose . Endpoints were overall survival , health-related quality of life ( HRQoL ) , toxicity , and the use of radiotherapy . Results : We r and omised 444 patients from September 2007 to April 2009 . The median age was 65 years , 58 % were men and 25 % had PS 2 . Median survival was VG : 6.3 months ; VC : 7.0 months , P=0.802 . Vinorelbine plus carboplatin patients had more grade III/IV nausea/vomiting ( VG : 4 % , VC : 12 % , P=0.008 ) and grade IV neutropenia ( VG : 7 % , VC : 19 % , P<0.001 ) . Infections , HRQoL and the use of radiotherapy did not differ significantly between the treatment groups . Conclusion : The two regimens yielded similar overall survival . The VG combination had only a slightly better toxicity profile The aim of this study was to compare the efficacy of single‐agent weekly docetaxel with the combination of docetaxel and gemcitabine in elderly and /or poor performance status patients with advanced nonsmall cell lung cancer ( NSCLC ) BACKGROUND The purpose of this study was to compare quality of life and overall toxicity in patients with advanced non-small-cell lung cancer ( NSCLC ) treated with vinorelbine-gemcitabine ( VG ) or carboplatin-paclitaxel ( Taxol ) ( CP ) . PATIENTS AND METHODS A total of 165 previously untreated patients were r and omized to the two regimens . Quality of life was assessed by the Lung Cancer Symptom Scale ( LCSS ) . Overall toxicity and secondary efficacy end points were evaluated by st and ard WHO criteria . RESULTS There was no significant difference in overall quality of life between the two treatments . Neutropenia , thrombocytopenia , peripheral neuropathy , and alopecia , were more common in the CP arm , whereas constipation was more frequent in the VG arm . Response rates were 14.6 % in the VG arm and 16.9 % in the CP arm . Median survival times were 7.8 and 8.6 months , and 1 year survival rates were 38.4 % and 31.9 % , respectively . CONCLUSIONS Patients treated with VG experienced lower toxicity , but overall quality of life was similar in both arms . Efficacy seemed comparable between VG and CP . Our study shows that VG is a viable alternative to platinum-based chemotherapy in patients with advanced NSCLC BACKGROUND Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer ( NSCLC ) in fit , non-elderly adults , but monotherapy is recommended for patients older than 70 years . We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC . METHODS In this multicentre , open-label , phase 3 , r and omised trial we recruited patients aged 70 - 89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0 - 2 . Patients received either four cycles ( 3 weeks on treatment , 1 week off treatment ) of carboplatin ( on day 1 ) plus paclitaxel ( on days 1 , 8 , and 15 ) or five cycles ( 2 weeks on treatment , 1 week off treatment ) of vinorelbine or gemcitabine monotherapy . R and omisation was done central ly with the minimisation method . The primary endpoint was overall survival , and analysis was done by intention to treat . This trial is registered , number NCT00298415 . FINDINGS 451 patients were enrolled . 226 were r and omly assigned monotherapy and 225 doublet chemotherapy . Median age was 77 years and median follow-up was 30.3 months ( range 8.6 - 45.2 ) . Median overall survival was 10.3 months for doublet chemotherapy and 6.2 months for monotherapy ( hazard ratio 0.64 , 95 % CI 0.52 - 0.78 ; p<0.0001 ) ; 1-year survival was 44.5 % ( 95 % CI 37.9 - 50.9 ) and 25.4 % ( 19.9 - 31.3 ) , respectively . Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group ( most frequent , decreased neutrophil count ( 108 [ 48.4 % ] vs 28 [ 12.4 % ] ; asthenia 23 [ 10.3 % ] vs 13 [ 5.8 % ] ) . INTERPRETATION Despite increased toxic effects , platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC . We feel that the current treatment paradigm for these patients should be reconsidered . FUNDING Intergroupe Francophone de Cancérologie Thoracique , Institut National du Cancer Background In the United Kingdom ( UK ) , there is an extensive market for the class ' A ' drug heroin . Many heroin users spend time in prison . People addicted to heroin often require prescribed medication when attempting to cease their drug use . The most commonly used detoxification agents in UK prisons are buprenorphine , dihydrocodeine and methadone . However , national guidelines do not state a detoxification drug of choice . Indeed , there is a paucity of research evaluating the most effective treatment for opiate detoxification in prisons . This study seeks to address the paucity by evaluating routinely used interventions amongst drug using prisoners within UK prisons . Methods / Design The Leeds Evaluation of Efficacy of Detoxification Study ( LEEDS ) Prisons Pilot Study will use r and omised controlled trial methodology to compare the open use of buprenorphine and dihydrocodeine for opiate detoxification , given in the context of routine care , within HMP Leeds . Prisoners who are eligible and give informed consent will be entered into the trial . The primary outcome measure will be abstinence status at five days post detoxification , as determined by a urine test . Secondary outcomes during the detoxification and then at one , three and six months post detoxification will be recorded BACKGROUND Platinum-containing two-drug combinations improve survival and cancer-related symptoms in patients with advanced non-small-cell lung cancer ( NSCLC ) . However , survival benefit is modest and platinum-containing regimens cause substantial toxic effects . We did a prospect i ve r and omised open-label phase III study to compare an experimental platinum-free , triplet , sequential regimen of vinorelbine plus gemcitabine followed by docetaxel with the st and ard platinum-containing , doublet regimen paclitaxel plus carboplatin in patients with advanced NSCLC . METHODS Between March , 2001 , and April , 2005 , patients with stage IIIB ( positive pleural effusion ) or IV NSCLC , performance status 0 to 1 , and adequate organ function , were r and omly assigned to experimental treatment or to st and ard treatment . R and omisation was done central ly by use of a dynamic balancing algorithm . Patients were stratified by weight loss , lactate dehydrogenase concentration , and disease stage . Patients in the experimental group were scheduled to receive intravenous vinorelbine ( 25 mg/m(2 ) ) plus gemcitabine ( 1000 mg/m(2 ) ) on days 1 and 8 every 21 days for three cycles , followed by intravenous docetaxel ( 60 mg/m(2 ) ) on day 1 every 21 days for three cycles . Patients in the st and ard group were scheduled to receive intravenous paclitaxel ( 225 mg/m(2 ) ) plus carboplatin ( area under the curve=6 ) for 3 h on day 1 , every 21 days for six cycles . The primary endpoint was overall survival , and secondary endpoints were progression-free survival , response , and toxic effects . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00079287 . FINDINGS Of the 401 patients enrolled and r and omised in the trial , five patients in the experimental group and three in the st and ard group were ineligible for analysis ; thus 196 patients in the experimental group and 197 in the st and ard group were included in analyses . Patient characteristics were well-balanced between the two groups with regard to major prognostic factors . Median overall survival was 13.6 months ( range 12.0 - 16.4 ) in the experimental group versus 14.1 months ( 11.9 - 17.5 ) in the st and ard group ( p=0.97 ) . 49 of 196 patients ( 25 % ) in the experimental group had a partial response compared with 73 of 197 patients ( 37 % ) in the st and ard group ( p=0.012 ) . There were no complete responses . Median progression-free survival was 5.5 months ( 95 % CI 4.9 - 6.3 ) in the experimental group compared with 5.8 months ( 5.3 - 6.1 ) in the st and ard group ( p=0.74 ) . The incidence of grade 3 and 4 neutropenia , neuropathy , arthralgia , and myalgia was lower in the experimental group than in the st and ard group , although the incidence of pulmonary toxic effects was higher . INTERPRETATION Although platinum-containing regimens remain the st and ard treatment for advanced NSCLC , non-platinum regimens could provide equivalent efficacy with a different toxicity profile Purpose To test efficacy and tolerability of non-platinum regimens for advanced non-small-cell lung cancer ( NSCLC ) . Methods Chemonaive patients with measurable stage IIIB/IV NSCLC treated with gemcitabine and cisplatin ( GC ) , or gemcitabine and docetaxel ( GD ) , maximumsix cycles in a phase IIB trial . Results A total of 108 patients were r and omized . Response rates ( GC vs. GD , respectively ) : complete 3.6/2.0 % , Partial 30.9/38.0 % . Median Overall Survival ( OS ) : 8.9 months in both groups ( P = 0.53 ) ; and median time to progression ( TTP ) : 6.2/5.5 months respectively ( P = 0.61 ) . Toxicities included ( GC vs. GD , respectively ) : grade 3–4 neutropenia 49.1/41.2 % ; grade 3 thrombocytopenia 30.9/3.9 % ; grade 3 anemia 14.5/3.9 % . Non-haematological toxicity was similar , except for nausea and vomiting , ( 16.3/2 % ) ; renal toxicity ( 3.7/0 % ) and hepatic toxicity ( 5.6/12.7 % ) . Conclusions With a higher overall response rate and lower toxicity , GD is a good first treatment option for advanced NSCLC PURPOSE we carried out a phase III r and omized trial to compare vinorelbine-cisplatin regimen to gemcitabine-cisplatin regimen , and to a sequential administration of gemcitabine-ifosfamide followed by vinorelbine-cisplatin or the opposite sequence of vinorelbine-cisplatin followed by ifosfamide-gemcitabine according to the ' worst drug rule ' hypothesis in patients with locally advanced unresectable stage IIIB or metastatic stage IV non-small cell lung cancer . The primary endpoint was survival parameters , while secondary endpoints included analysis of response rates and toxicity . PATIENTS AND METHODS patients were r and omized to receive : ( a ) gemcitabine 1000 mg/m(2 ) on days 1 , 8 and 15 plus ifosfamide 1500 mg/m(2 ) on days 8 - 12 with mesna uroprotection ( GI regimen ) followed by vinorelbine 25 mg/m(2 ) on days 1 and 8 plus cisplatin 100 mg/m(2 ) on day 1 ( GI -- > VC regimen ) ; ( b ) the opposite sequence ( VC -- > GI ) ; ( c ) vinorelbine plus cisplatin as above described ( VC regimen ) ; or ( d ) gemcitabine 1400 mg/m(2 ) on days 1 and 8 plus cisplatin 100 mg/m(2 ) on day 8 ( GC regimen ) . All regimens were given every 4 weeks . All patients were chemotherapy naive and had a ECOG PS 0 - 2 . RESULTS 400 patients were enrolled into the trial . Interim analysis after inclusion of 243 patients showed that ORR were 19 % in the GI -- > VC arm , 32 % in the inverse sequence arm ( CV -- > GI ) , 42 % in the VC arm , and 30 % in the GC arm . The VC arm was statistically superior over the GI -- > VC arm ( p = 0.0074 ) , but not over the other regimens . Median TTP was 3.1 months in the GI -- > VC arm versus 5.0 months in the VC -- > GI arm ( p = 0.014 ) . For these reasons the GI -- > VC and VC -- > GI arm were closed since the ' worst drug rule ' hypothesis was rejected . Accrual in the VC and GC arms continued up to 140 and 138 patients respectively . Final ORR were 44 % for the VC regimen ( 4 CR ) , and 34 % for the GC regimen ( 1 CR ) . This difference was statistically significant ( p = 0.032 ) . OS was 9.0 and 8.2 months , respectively , with no statistically significant difference . The 1-year survival rate was 24 and 20 % , respectively for VC and GC regimens . As expected the incidence of phlebitis was higher in the VC arm , while thrombocytopenia , flu-like syndrome and asthenia were more frequent in the GC arm . CONCLUSIONS the results of this trial indicate that the combination of vinorelbine and cisplatin and that of gemcitabine and cisplatin are equivalent in terms of median TTP and OS , although the vinorelbine-cisplatin regimen is associated with a higher ORR . Both regimens may be considered as reference treatments for future studies . Moreover , our data reject the ' worst drug rule ' hypothesis of sequential treatments in NSCCL at least with the combination used in this study Introduction : This r and omized phase II study investigated the efficacy and safety of a new taxane , larotaxel ( XRP9881 ) , in combination with either cisplatin or gemcitabine in the first-line treatment of patients with nonirradiable stage IIIB or stage IV non-small cell lung cancer to select the combination having the most promising antitumor activity . Methods : Patients received either larotaxel ( 50 mg/m2 ) as a 1-hour infusion , followed by a 1-hour infusion of cisplatin ( 75 mg/m2 ) , every 3 weeks ( arm A ) , or gemcitabine ( 800 mg/m2 ) as a 30 minute infusion , on days 1 and 8 , and larotaxel ( 60 mg/m2 ) as a 1-hour infusion , on day 8 ( following gemcitabine ) , every 3 weeks ( arm B ) . The primary end point was the objective response rate ( per- protocol population ) . Results : Thirty-two patients were r and omized to arm A and 30 to arm B. The response rate was higher in arm A compared with arm B in both the per- protocol ( 26.7 % versus 18.2 % ) and intention-to-treat ( 28.1 % versus 13.3 % ) population s. In the intention-to-treat population , median progression-free survival for arm A versus arm B was 4.7 versus 3.3 months and median overall survival was 8.6 versus 7.3 months , respectively . Fifty percent of patients in arm A and 66.7 % in arm B experienced at least one National Cancer Institute common toxicity criteria grade 3/4 adverse event and grade 3/4 neutropenia was observed in 46.9 % and 41.4 % of patients , respectively . Conclusions : Both larotaxel combinations were effective and manageable , however all measured efficacy parameters ( response rate , progression free survival , and survival ) seemed to favor the combination with cisplatin BACKGROUND The modest improvement in median survival of advanced non-small-cell lung cancer ( NSCLC ) by cisplatin-based chemotherapy has led to the current opinion that clinical benefit for the patient is at least as important an end-point as objective response rate ( ORR ) or survival . Clinical benefit response was the primary end-point of this prospect i ve r and omised trial in symptomatic , advanced stage IIIB/IV NSCLC , comparing single agent gemcitabine ( GEM ) to cisplatin-based chemotherapy . PATIENTS AND METHODS Patients received either GEM ( 1000 mg/m2 , days 1 , 8 and 15 ) or cisplatin ( 100 mg/M2 , day 1 ) plus Vindesine ( 3 mg/m2 , days 1 and 15 ) ( PV ) , both every four weeks . Clinical benefit was measured by a simple metric based on changes in a visual analogue symptom score list , the Karnofsky performance status and the weight . RESULTS One hundred sixty-nine patients were r and omised ( 84 GEM , 85 PV ) . Prognostic factors and baseline symptoms were well balanced between the two arms . Most of the the objective responders and about half of the patients with disease stabilisation experienced clinical benefit . Compared to PV , a significantly larger number of GEM-treated patients experienced a clinical benefit ( 48.1 vs. 28.9 % , P = 0.03 ) that lasted significantly longer ( median duration 16 vs. 10 weeks , P = 0.01 ) . No important differences in ORR , time-to-progression or median survival were observed . Grade 3 + 4 toxicity was significantly higher in the PV-group for leukopenia ( P = 0.0003 ) , neutropenia ( P < 0.0001 ) , nausea/vomiting ( P = 0.0006 ) , alopecia ( P < 0.0001 ) , and neurotoxicity ( P = 0.04 ) . Some severe pulmonary toxicity to GEM was noted . CONCLUSION Comparison of GEM with cisplatin-based therapy in symptomatic , advanced NSCLC demonstrates that GEM produces significantly a stronger and longer-lasting clinical benefit , probably due to its equal effectiveness in terms of ORR , time-to-progression or survival , combined with significantly less severe therapy-related toxicity BACKGROUND Vinorelbine prolongs survival and improves quality of life in elderly patients with advanced non-small-cell lung cancer ( NSCLC ) . Some studies have also suggested that gemcitabine is well tolerated and effective in such patients . We compared the effectiveness and toxicity of the combination of vinorelbine plus gemcitabine with those of each drug given alone in an open-label , r and omized phase III trial in elderly patients with advanced NSCLC . METHODS Patients aged 70 years and older , enrolled between December 1997 and November 2000 , were r and omly assigned to receive intravenous vinorelbine ( 30 mg/m(2 ) of body surface area ) , gemcitabine ( 1200 mg/m(2 ) ) , or vinorelbine ( 25 mg/m(2 ) ) plus gemcitabine ( 1000 mg/m(2 ) ) . All treatments were delivered on days 1 and 8 every 3 weeks for a maximum of six cycles . The primary endpoint was survival . Survival curves were drawn using the Kaplan-Meier method and analyzed by the Mantel-Haenszel test . Secondary endpoints were quality of life and toxicity . RESULTS Of 698 patients available for intention-to-treat analysis , 233 were assigned to receive vinorelbine , 233 to gemcitabine , and 232 to vinorelbine plus gemcitabine . Compared with each single drug , the combination treatment did not improve survival . The hazard ratio of death for patients receiving the combination treatment was 1.17 ( 95 % confidence interval [ CI ] = 0.95 to 1.44 ) that of patients receiving vinorelbine and 1.06 ( 95 % CI = 0.86 to 1.29 ) that of patients receiving gemcitabine . Although quality of life was similar across the three treatment arms , the combination treatment was more toxic than the two drugs given singly . CONCLUSION The combination of vinorelbine plus gemcitabine is not more effective than single-agent vinorelbine or gemcitabine in the treatment of elderly patients with advanced NSCLC Background : The FAST is a 2 × 2 factorial trial addressing two questions : ( 1 ) the role of replacing cisplatin ( P ) with a non-platinum agent , vinorelbine ( N ) , and ( 2 ) the role of adding a third agent , ifosfamide ( I ) , in a doublet based on gemcitabine ( G ) . Methods : A total of 433 stage IIIB – IV non-small cell lung cancer ( NSCLC ) patients were r and omised to one of four arms : gemcitabine – cisplatin ( GP ) , gemcitabine – vinorelbine , gemcitabine – ifosfamide-cisplatin or gemcitabine – ifosfamide – vinorelbine . Two comparisons were performed : N- vs P-containing regimens and I-triplets vs non-I doublets . Results : For N- vs P-containing regimens , adjusted overall survival was 9.7 vs 11.3 months ( P=0.044 ) , progression-free survival was 4.9 vs 6.4 months ( P=0.020 ) and response rate was 24 % vs 31 % ( P=0.124 ) , respectively . No statistically significant difference was observed between doublets and triplets . Grade 3–4 haematological toxicity was significantly more frequent in P-containing therapy ; grade 3–4 leucopenia was significantly more common in triplets . Concerning non-haematological toxicity , grade 3–4 nausea-vomiting was significantly increased in P-containing regimens . Conclusions : This trial provides evidence of a slight survival superiority of GP-containing regimens over platinum-free N-containing chemotherapy . This trial also confirms that the addition of a third chemotherapy agent ( I ) to a st and ard G-based doublet does not improve treatment outcome BACKGROUND Older patients , even if fit , are often considered incapable of tolerating platinum-based systemic therapy . We performed a retrospective analysis of Eastern Cooperative Oncology Group ( ECOG ) 5592 , a phase III r and omized trial of platinum-based chemotherapy regimens for non-small-cell lung cancer ( NSCLC ) , and compared outcomes in enrollees 70 years of age and older with those in younger patients . METHODS ECOG carried out a r and omized phase III trial of cisplatin plus either etoposide or paclitaxel in chemotherapy-naïve NSCLC patients with stages III(B ) or IV disease . Toxic effects , response rates , and survival rates were compared between age groups . All P values were two-sided . RESULTS A total of 574 patients enrolled from August 1993 through December 1994 were evaluable . Eighty-six ( 15 % ) were 70 years old or older . Older patients had a higher incidence of cardiovascular ( P = .009 ) and respiratory ( P = .04 ) comorbidities and nonanalgesic medication use ( P = .02 ) . Leukopenia ( P<.001 ) and neuropsychiatric toxicity ( P = .002 ) were more common in elderly men than in younger men . Elderly women lost more weight than younger women ( P = .006 ) . Other toxic effects were similar in older and younger patients . The proportions with clinical partial or complete response ( 21.5 % versus 23.3 % ; Fisher 's exact test , P = .66 ) , median time to progression ( 4.37 versus 4.30 months ; log-rank test , P = .29 ) , and survival distribution ( log-rank test , P = .29 ; median survival , 9.05 versus 8.53 months ; 1-year survival , 38 % versus 29 % ; and 2-year survival , 14 % versus 12 % ) were similar in patients younger than 70 years and 70 years old or older . Baseline quality -of-life and treatment- outcome indices were similar . Equivalent declines over time in functional well-being occurred in both groups . CONCLUSION Response rate , toxicity , and survival in fit , elderly NSCLC patients receiving platinum-based treatment appear to be similar to those in younger patients , although patients 70 years old or older have more comorbidities and can expect more leukopenia and neuropsychiatric toxicity . Advanced age alone should not preclude appropriate NSCLC treatment Purpose : To evaluate whether cisplatin-free chemotherapy ( docetaxel and gemcitabine [ DG ] ) provides a comparable alternative to cisplatin-based chemotherapy ( docetaxel and cisplatin [ DC ] ) as first-line treatment for patients with advanced non-small cell lung cancer ( NSCLC ) . Patients and Methods : Patients ( n = 133 ) with stage IIIB to IV NSCLC were r and omly assigned to receive DG ( docetaxel 60 mg/m2 , day 8 + gemcitabine 800 mg/m2 , days 1 and 8 , every 3 weeks ; n = 65 ) or DC ( docetaxel 60 mg/m2 , day 1 + cisplatin 80 mg/m2 , day 1 , every 3 weeks ; n = 68 ) . The primary end point of the study was overall response rate . No prophylactic use of human recombinant granulocyte colony stimulating factor was allowed . Results : The planned patient number was 150 . However , an unexpectedly high incidence of grade 3 interstitial lung disease ( 11.1 % ) was identified in the DG arm , so the study was closed early . The overall response rates of the DG and DC arms were 27 % and 23.5 % , respectively , which demonstrated that the DG treatment was not inferior to the DC arm . Gastrointestinal toxicities were less frequent in the DG arm than in DC arm . Interstitial lung disease was exclusively observed in seven of 63 patients in the DG arm ( 11.1 % ) . Median survival and 1-year survival rate were comparable between the two arms ( median survival , DG 13.7 months versus DC 11.4 months ; 1-year survival , DG 56.6 % versus DC 47.7 % ) . Conclusion : The DG regimen has a response rate and survival rate comparable to those of the DC regimen and can therefore be considered from an efficacy point of view to be comparable . However , the DG regimen may have induced pulmonary toxicity in 11 % of the patients exposed and therefore should be used cautiously among patients with advanced NSCLC BACKGROUND Docetaxel in combination with cisplatin or gemcitabine are active chemotherapy reigimes against non-small-cell lung cancer . We compared the efficacy and safety of a combination of cisplatin and docetaxel ( group 1 ) with that of gemcitabine and docetaxel ( group 2 ) in the treatment of advanced non-small-cell lung cancer in a prospect i ve , r and omised , multicentre trial . METHODS Patients with stage IIIB or IV lung cancer who had not had prior chemotherapy were allocated either to group 1 and treated with docetaxel ( 100 mg/m(2 ) , day 1 ) and cisplatin ( 80 mg/m(2 ) , day 2 ) or to group 2 and treated with gemcitabine ( 1100 mg/m(2 ) , days 1 and 8) and docetaxel ( 100 mg/m(2 ) , day 8) . All patients received recombinant human granulocyte colony-stimulating factor ( 150 mg/m(2 ) ) . All patients received recombinant human granulocyte colony-stimulating factor ( 150 mg/m(2 ) ) had appropriate st and ard premedication . Response and toxicity were assessed using WHO criteria . Analysis was by intention to treat . FINDINGS 441 patients were r and omly assigned to receive docetaxel/cisplatin ( group 1 , n=219 ) or gemcitabine/docetaxel ( group 2 , n=222 ) . 14 patients in group 1 and 21 patients in group 2 were not evaluable . Objective response rates were similar in the two groups : group 1 , 32.4 % ( 95 % CI 26.2 - 38.6 % ; 1.4 % complete response and 31 % partial response ) ; group 2 , 30.2 % ( 24.5 - 36.2 % ; 0.9 % complete response and 29.3 % partial response ) . The two groups did not differ in median duration of response , time to tumour progression , overall survival , or 1 year or 2 year survival rates . INTERPRETATION Both drug combinations had comparable activity in patients with advanced cancer who had not previously had chemotherapy ; however , gemcitabine and docetaxel had the most favourable toxicity profile Objective : This is a r and omized phase II study design ed to compare the toxicity profile of a non-platinum-based with a platinum-based regimen in the treatment of advanced non-small cell lung cancer . Methods : Eighty-nine chemotherapy-naïve patients were r and omized either to gemcitabine ( 1,000 mg/m2 , 30-min infusion on days 1 , 8 and 15 ) and oral etoposide ( 50 mg , days 1–14 ; GE group ) or gemcitabine at the same schedule and cisplatin ( 75 mg/m2 on day 15 ; GP group ) . The primary endpoint is toxicity , and secondary endpoints include response rate , survival outcome and quality of life ( QOL ) . Results : The incidence of WHO grade 3 or 4 anemia , neutropenia and thrombocytopenia was 29 , 44 and 22 % ( GE group ) , and 28 , 49 and 23 % ( GP group ) , respectively ( p = 0.75 , 0.95 and 0.87 , respectively ) . The rate of grade 2 or above nausea was numerically higher in the GP arm , but the difference was not statistically significant ( GE 15.5 % , GP 27.7 % , p = 0.20 ) . The rate of vomiting in the GE and GP arms was 20.0 and 20.5 % , respectively ( p = 0.96 ) . However , subjective changes in QOL scores on nausea and vomiting were significantly higher in the GP arm ( p = 0.001 ) . Other symptoms including sore mouth and hair loss were significantly higher in the GE arm ( p = 0.003 and 0.007 , respectively ) . There were also significant differences observed in emotional ( p = 0.014 ) , cognitive ( p = 0.028 ) and social functioning ( p = 0.034 ) in favor of GP . The differences in tumor response ( 35.5 and 46.5 % for GE and GP , respectively ) were not significantly different . Median time to disease progression ( 33.8 and 40.7 weeks , respectively ) and overall survival ( 41.4 and 57.3 weeks , respectively ) were of borderline significance in favor of the GP arm ( p = 0.055 ) . Conclusion : This toxicity profile of GE is similar to GP , but the apparent inferior efficacy may discourage further investigation BACKGROUND Paclitaxel ( Taxol ) plus carboplatin ( PC ) has shown activity in the treatment of advanced non-small-cell lung cancer ( NSCLC ) . Non-platinum-containing combination chemotherapy , such as paclitaxel plus gemcitabine ( PG ) , has also demonstrated reasonable efficacy . Our aim here was to evaluate the clinical efficacy and cost-effectiveness of PC versus PG in chemo-naive . advanced NSCLC patients . PATIENTS AND METHODS Ninety ( 68 male , 22 female ) patients were enrolled from August 1999 to August 2000 . The performance status was one in 29 patients and two in 16 patients of the PC group , and one in 24 patients and two in 21 patients of the PG group . Seventeen patients had stage IIIb disease and 28 patients stage IV disease in the PC group : 18 patients had stage IIIb disease and 27 patients stage IV disease in the PG group ( New International Staging System ) . Treatment consisted of P 175 mg/m2 and C at AUC = 7 ( predicted using measured clearances and the Calvert formula ) intravenous infusion ( i.v . ) on day 1 , or P 175 mg/m2 i.v . on day 1 and G 1000 mg/m2 i.v . on days 1 and 8 , every 3 weeks . RESULTS In all , 175 cycles of PC and 184 cycles of PG were given in the PC and PG groups , respectively . The median treatment cycle was four cycles in both groups . All the patients were assessable for toxicity and response measurement . There were three complete responses and 15 partial responses ( overall 40 % ) in the PC group , and no complete response , but 18 partial responses ( overall 40 % ) in the PG group . WHO grade s 3/4 leukopenia , anemia and thrombocytopenia occurred in six ( 13.3 % ) , seven ( 15.5 % ) and five patients ( 11.1 % ) in the PC group ; and in four ( 8.9 % ) , six ( 13.3 % ) and 0 patients in the PG group , respectively . Two patients in each group suffered from grade 3 peripheral neuropathy . Other non-hematological toxicities were mild and few . Median survival time was 14.1 months in the PC group and 12.6 months in the PG group . One-year survival was 50.7 % in the PC group and 53.3 % in the PG group . The PG group had a higher total expense and expended more days undergoing treatment than the PC group ( P = 0.034 and 0.069 , respectively ) . CONCLUSIONS Both PC and PG combination chemotherapy produce a similar efficacy in the treatment of NSCLC . However , PC is more cost-effective than PG PURPOSE We compared the efficacy of combination chemotherapy versus single-agent therapy in patients with advanced non-small-cell lung cancer . PATIENTS AND METHODS A total of 561 eligible patients were r and omly assigned to receive paclitaxel alone or in combination with carboplatin . RESULTS The response rate was 17 % in the paclitaxel arm and 30 % in the carboplatin-paclitaxel arm ( P < .0001 ) . Median failure-free survival was 2.5 months in the paclitaxel arm and 4.6 months in the carboplatin-paclitaxel arm ( P = .0002 ) . Median survival times were 6.7 months ( 95 % CI , 5.8 to 7.8 ) and 8.8 months ( 95 % CI , 8.0 to 9.9 ) , and 1-year survival rates were 32 % ( 95 % CI , 27 % to 38 % ) , and 37 % ( 95 % CI , 32 % to 43 % ) , respectively . The overall survival distributions were not statistically different : hazard ratio = 0.91 ( 95 % CI , 0.77 to 1.17 ; P = .25 ) . Hematological toxicity and nausea were more frequent in the combination arm , but febrile neutropenia and toxic deaths were equally low in both arms . There was no significant survival difference in elderly patients . Performance status 2 patients treated with combination chemotherapy had a better survival rate than those treated with single-agent therapy ( P = .019 ) . CONCLUSION Combination chemotherapy improves response rate and failure-free survival compared with single-agent therapy , but there was no statistically significant difference in the primary end point of overall survival . The results in elderly patients were similar to younger patients . Performance status 2 patients had a superior outcome when treated with combination chemotherapy Platinum-based chemotherapy is the st and ard treatment for patients with advanced non-small cell lung cancer ( NSCLC ) , but the evidence of its efficacy among ECOG performance status (PS)2 patients is weak because these patients are usually excluded from clinical trials ; concern exists about tolerability and feasibility of st and ard chemotherapy in these patients . No prospect i ve r and omized trial has tested the addition of cisplatin to single-agent chemotherapy in patients with advanced NSCLC and PS2 . CAPPA-2 was a multicenter , r and omized phase 3 study for first-line treatment of PS2 patients with advanced NSCLC . Patients , aged 18 - 70 , were eligible if they had stage IV or IIIB with malignant pleural effusion or metastatic supraclavicular nodes ( TNM VI edition ) and adequate organ function . Patients in st and ard arm received gemcitabine 1200 mg/m(2 ) days 1 and 8 . Patients in experimental arm received cisplatin 60 mg/m(2 ) day 1 plus gemcitabine 1000 mg/m(2 ) days 1 and 8 . All treatments were repeated every 3 weeks , up to 4 cycles , unless disease progression or unacceptable toxicity . Primary endpoint was overall survival ( OS ) . To have 80 % power of detecting hazard ratio ( HR ) 0.71 , corresponding to an increase in median OS from 4.8 to 6.8 months , 285 deaths were required . The study was stopped in June 2012 after the enrolment of 57 patients , due to the slow accrual and the report of positive results from a similar study . Median OS was 3.0 months with single-agent gemcitabine and 5.9 months with cisplatin plus gemcitabine ( HR 0.52 , 95 % CI 0.28 - 0.98 , p = 0.039 ) . Combination chemotherapy produced longer PFS ( median 1.7 vs. 3.3 months , HR 0.49 , 95 % CI 0.27 - 0.89 , p = 0.017 ) and higher response rate ( 4 % vs. 18 % , p = 0.19 ) , without substantial increase in toxicity . The addition of cisplatin to single-agent gemcitabine improves survival as first-line treatment of PS2 patients with advanced NSCLC BACKGROUND Epirubicin was effective for the treatment of non-small cell lung carcinoma ( NSCLC ) . This study compared the efficacy and safety of gemcitabine plus conventional-dose epirubicin ( GE ) with gemcitabine-cisplatin ( GC ) as first-line chemotherapy for stage IIIB/IV NSCLC and evaluated the predictive value of nuclear expression of excision repair cross-complementing group 1 ( ERCC1 ) and topoisomerase IIalpha ( TopoIIalpha ) on treatment outcome . PATIENTS AND METHODS Patients were r and omized to GE ( gemcitabine , 1000mg/m(2 ) on days 1 , 8 , and 15 and epirubicin , 70mg/m(2 ) on day 15 ) or GC ( gemcitabine , 1000mg/m(2 ) on days 1 , 8 , and 15 and cisplatin , 80mg/m(2 ) on day 15 ) . Treatment cycles were repeated every 4 weeks . Immunohistochemical study of ERCC1 and TopoIIalpha was done for patients with available tumor specimens . RESULTS The response rate was 31.0 % ( 95 % CI 16.4 - 45.5 % ) for GC ( n=41 ) and 37.2.0 % ( 95 % CI 22.2 - 52.3 % ) for GE ( n=39 ) . No significant differences in median time-to-treatment-failure ( TTF ) ( GC , 6.1 months ; GE , 6.2 months ) or overall survival ( GC , 13.2 months ; GE , 21.5 months ) were found between the two arms . Grade 3/4 neutropenia and febrile neutropenia were more common in GE . However , delay of protocol treatment due to leukopenia was similar between the two arms . Patients with expression of both ERCC1 and TopoIIalpha had a significantly shorter TTF ( median 2.4 months , 95 % CI 0.7 - 4.1 months ) than other patients ( median 8.8 months , 95 % CI 5.8 - 11.8 months ) ( p=0.04 ) . CONCLUSION GE regimen is effective and well-tolerated for NSCLC patients . Expression of both ERCC1 and TopoIIalpha may be associated with poor response to chemotherapy OBJECTIVE To explore a chemotherapeutic regimen suitable for non-small cell lung cancer ( NSCLC ) in elderly patients . METHODS A total of 68 elderly patients with NSCLC ( stage IIIb/IV ) were equally and r and omly divided into single-agent and combined groups . Patients in single-agent group received gemcitabine 1000 mg/m(2 ) at Days 1 and 8 for a 21-day cycle . Those in combined group received gemcitabine 1000 mg/m(2 ) at Days 1 and 8 in combination carboplatin AUC5 at Day 2 for a 21-day cycle . The drugs were intravenously administered . All patients received 3 cycles of treatment . RESULTS In single-agent and combined groups , CR 1 and 1 , PR 12 and 13 , response rates 38 % and 41 % were respectively observed . There was no statistically significant difference between two groups ( P > 0.05 ) . The 1-year and 2-year survival rates of single-agent and combined groups were 31 % vs 32 % and 12 % vs 14 % with a median survival of 9.9 and 9.8 months without a statistically significant difference ( P > 0.05 ) . The rates of leucopenia and thrombocytopenia ( III-IV degree ) were 47 % and 38 % in combined group and they were higher than 24 % and 15 % in single-agent group with a statistically significant difference ( P < 0.05 ) . The observer scale of lung cancer symptom scale showed that the post-treatment scores of appetite , fatigue and pain significantly improved in single-agent group while no improvement was observed in combined group . Also the scores of appetite , fatigue and pain of single-agent group were higher than those of combined group after chemotherapy ( P < 0.05 ) . CONCLUSION Single-agent gemcitabine regimen is more suitable for advanced NSCLC in elderly patients In the European Organization for Research and Treatment of Cancer r and omized phase III trial ( 08975 ) , 480 patients with advanced non-small cell lung cancer received the st and ard arm of cisplatin/paclitaxel or one of two experimental arms ; gemcitabine/cisplatin or gemcitabine/paclitaxel . Cisplatin was given at 80 mg/m(2 ) on day 1 , gemcitabine was administered at 1,250 mg/m(2 ) on days 1 and 8 , and paclitaxel at 175 mg/m(2 ) as a 3-hour infusion on day 1 , every 3 weeks . The cisplatin/paclitaxel and gemcitabine/cisplatin regimens were comparably active . The nonplatinum arm , gemcitabine/paclitaxel , was well tolerated , but had a trend toward lower median , 1-year , and progression-free survival compared with the st and ard arm . Further follow-up and analysis of quality of life may clarify this possible difference in treatment outcome Aims To evaluate the efficacy and treatment compliance in elderly patients with advanced non-small cell lung cancer ( NSCLC ) of two chemotherapeutic agents with mild toxicity , 153 previously untreated patients aged over 70 years were r and omized to receive lonidamine ( 450 mg daily p.o . until progression ) , vindesine ( 3 mg/m2/daily i.v . weekly for 4 weeks and then every 2 weeks until progression ) , the combination of the two drugs at the same dose and schedule , or supportive therapy only in a four-arm factorial r and omized trial . Methods 126 patients were included in the final analysis . Their median age was 75 years . Forty percent had stage IV disease and 60 % stage III . Most patients were males ( 85 % ) and the majority had squamous histology ( 68 % ) . Results Among 104 patients evaluable for response there were only 3 PRs ( 1/30 in the lonidamine arm and 2/33 in the lonidamine + vindesine arm ) . Overall , 8.7 % and 9.5 % of the patients , respectively , progressed or died early , before response evaluation ; another 9.4 % refused treatment continuation because of poor compliance with the study protocol . Eighty-five patients were fully evaluable for toxicity , which was generally mild . Leukopenia grade 1 - 3 was found in less than 30 % of patients treated with vindesine or vindesine + lonidamine . The most common complaints associated with lonidamine treatment were myalgia ( 70 % of patients ) , fatigue ( 55 % and 83 % of patients treated with lonidamine or lonidamine + vindesine , respectively ) and testicular pain in nearly 40 % of cases . The overall median survival was 170 days , with no significant impact on survival of either lonidamine or vindesine . Conclusions The low response rate and survival together with the poor treatment compliance , even in the presence of mild toxicity , do not support the usefulness of these “ gentle ” chemotherapies in elderly NSCLC patients . The st and ard management of advanced NSCLC in elderly patients remains to be defined . Specifically design ed studies to address this issue are warranted The authors compared the toxicity , response rate , and progression free survival of four chemotherapy regimens for patients with advanced ( Stage IIIB and IV ) nonsmall cell lung carcinoma A multicenter Italian Cooperative Study Group ( FONICAP ) conducted a prospect i ve , r and omized trial comparing cisplatin and etoposide ( VP-16 ) with single-agent etoposide . The national study accrued 216 patients with measurable or evaluable non-small cell lung cancer ( NSCLC ) with either unresectable stage III , or distant metastasis ( stage IV ) . One hundred patients were evaluable for response in the single-agent arm , and 93 in the two-drug combination arm . The overall response rates for the etoposide group and cisplatin/etoposide ( VP-16 ) group were 7 % and 26 % , respectively ( P less than 0.005 ) . Five patients ( 5.6 % ) in the combination arm and 1 ( 1 % ) in the single agent arm had a complete response . The overall median survival was 236 days for the two-drug arm and 178 days on the single-drug arm ( P = 0.2 ) . Treatment-related toxicity ( nausea and vomiting , leukopenia , anemia , hearing-loss , peripheral neuropathy , serum creatinine elevation ) was significantly more pronounced in the combined arm . The addition of cisplatin to etoposide gave a small non-statistically significant improvement in terms of performance status and thoracic symptoms BACKGROUND Platinum-based chemotherapy has been shown to be effective in improving survival and quality of life in advanced non-small-cell lung cancer ( NSCLC ) patients . The objective of this study was to identify patients more likely to benefit from chemotherapy in order to avoid the indiscriminate treatment of all patients . PATIENTS AND METHODS A multivariate analysis of survival was performed using the data base of the European r and omized phase III trial that compared vinorelbine ( navelbine ) ( NVB ) , vinorelbine-cisplatin ( NVB-P ) and vindesine-cisplatin ( VDS-P ) in 612 patients with inoperable NSCLC ( stage III or IV ) . Interactions between treatment and the prognostic factors singled out by the Cox procedure were specifically tested . RESULTS The performance status ( PS ) was the only significant interaction among the selected prognostic factors and treatment . Subgroup analysis showed that the advantage obtained with NVB-P predominantly concerned PS 0 - 1 patients , whose median survival lasted 43 weeks ( 95 % confidence interval ( 95 % CI ) : 39 - 50 weeks ) with a one-year survival rate of 38 % ( 95 % CI : 31%-46 % ) versus 36 weeks ( 95 % , CI : 30 - 40 weeks ) and 34 % ( 95 % CI : 27%-42 % ) for NVB alone , and 33 weeks ( 95 % CI : 30 - 39 weeks ) and 29 % ( 95 % CI : 22%-36 % ) for VDS-P. In sharp contrast , survival in PS 2 patients was similar ( median 18 weeks ) ( NVB-P 95 % CI : 11 - 34 weeks ; NVB 95 % CI : 11 - 35 weeks ; VDS-P 95 % CI : 14 - 32 weeks ) whatever the treatment . CONCLUSION PS 2 patients with advanced NSCLC might not benefit from cisplatin combination therapy BACKGROUND Third-generation platinum-based combinations are established as first-line treatment for advanced non-small cell lung cancer ( NSCLC ) . Non-platinum regimens could be an alternative if they show similar efficacy with better tolerability . This r and omized phase II trial compared the objective tumor response rate ( ORR ) of sequential gemcitabine plus vinorelbine followed by gemcitabine plus ifosfamide versus gemcitabine plus cisplatin . Secondary objectives included time to disease progression ( TTP ) , overall survival and toxicity . METHODS Chemo-naive patients with stages III and IV NSCLC and Karnofsky performance status > 70 were assigned to receive either ( a ) gemcitabine 1000mg/m(2 ) plus vinorelbine 25mg/m(2 ) on days 1 and 8 for 2 cycles , followed by gemcitabine 1000mg/m(2 ) on days 1 and 8 plus ifosfamide 2000mg/m(2 ) on day 1 ( GV-GI arm ) for 2 cycles or ( b ) gemcitabine 1250mg/m(2 ) on days 1 and 8 with cisplatin 70mg/m(2 ) on day 1 ( GC arm ) for 4 cycles . RESULTS Between July 2001 and January 2003 , 102 patients were enrolled ( 50 on the GV-GI arm and 52 on the GC arm ) . Patient characteristics were balanced between arms ( GV-GI arm : median age 59 years , 84 % male , 22 stage IIIB , 24 stage IV , 4 stage IIIA ; GC arm : median age 56 years , 87 % male , 27 stage IIIB , 23 stage IV , 2 stage IIIA ) . Of the 101 patients evaluable for response , ORR was significantly higher on the GC arm than on the GV-GI arm ( 25 % versus 6 % , respectively ; p=0.007 ) . No complete responses occurred . TTP was longer on the GC arm than on the GV-GI arm ( median 135 and 79 days , respectively ) , although this difference was not statistically significant ( p=0.065 ) . Survival was not significantly different between the arms ( median 293 and 197 days , respectively ; p=0.16 ) . Although significantly more thrombocytopenia was reported on the GC arm ( 22 % and 4 % , respectively ; p=0.02 ) , it did not lead to more transfusions ( 15 transfusions in 5 patients versus 14 transfusions in 6 patients , respectively ) . There was no significant difference in other safety parameters between treatment arms . CONCLUSIONS GC appears to produce better response in advanced NSCLC than GV-GI , with a trend towards longer TTP . Except for more thrombocytopenia with GC , similar toxicity profiles were observed Combined gemcitabine and carboplatin ( GC ) and combined gemcitabine and vinorelbine ( GV ) are active and well tolerated chemotherapeutic regimens for patients with advanced nonsmall cell lung cancer ( NSCLC ) . The authors conducted a r and omized Phase II study of GC versus GV to compare them in terms of efficacy and toxicity BACKGROUND In the attempt to optimize the efficacy of chemotherapy in advanced non-small cell lung cancer ( NSCLC ) several strategies need to be investigated including the use of non-platinum combinations and the sequential use of different agents . PATIENTS AND METHODS In a phase II r and omised study 165 patients with stage IIIB or IV NSCLC were assigned to receive docetaxel 40 mg/m(2 ) days 1 and 8 plus gemcitabine 1200 mg/m(2 ) days 1 and 8 every 21 days ( arm A , N=54 ) or docetaxel 50 mg/m(2 ) days 1 and 15 plus gemcitabine 1600 mg/m(2 ) days 1 and 15 every 28 days ( arm B , N=57 ) or gemcitabine 1200 mg/m(2 ) days 1 and 8 plus cisplatin 100mg/m(2 ) day 2 every 21 days for 3 cycles followed by docetaxel 75 mg/m(2 ) day 1 every 21 days for 3 cycles ( arm C , N=54 ) . The primary endpoint of the trial was overall response rate . Secondary end points included safety , progression-free and overall survival . RESULTS Response rate was 22.2 % , 23.2 % and 33.3 % after 3 cycles , whereas at the end of treatment was 24.1 % , 12.5 % and 27.8 % in arm A-C , respectively . Median time to progression was similar in all the 3 arms : 6.7 months in arm A ( 95 % CI : 4.8 - 9.7 ) , 5.6 in arm B ( 5.0 - 7.9 ) and 6.6 in arm C ( 5.7 - 9.1 ) . The median survival time was 10.7 months in arm A ( 95 % CI : 6.8 - 15.6 ) , 8.9 in arm B ( 7.4 - 12.5 ) and 14.6 in arm C ( 8.0 - 22.4 ) and 1-year survival rate was 46.3 % , 37.9 % and 53.9 % , respectively . Grade 3 - 4 haematological toxicities were more frequent in arm C while non-haematological were more common in the gemcitabine and docetaxel arms . CONCLUSIONS The results of this phase II r and omised clinical trial do not indicate a clear superior efficacy of one of the tested combinations according to the planned statistical design and none of these regimens is sufficiently active or less toxic to warrant further investigation in a phase III study PURPOSE We design ed a prospect i ve r and omized trial to compare vinorelbine and cisplatin ( NVB-P ) with vindesine and cisplatin ( VDS-P ) and to evaluate whether the best of these regimens affords a survival benefit compared with vinorelbine alone ( NVB ) , an outpatient regimen , in patients with non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Forty-five centers included 612 patients in this study : 206 on NVB-P , 200 on VDS-P , and 206 on NVB . Vinorelbine was administered at a dose of 30 mg/m2 weekly , cisplatin at 120 mg/m2 on days 1 and 29 and then every 6 weeks , and vindesine at 3 mg/m2 weekly for 6 weeks and then every other week . Treatment was continued until progression or toxicity . Four percent of the patients entered were ineligible and 59 % had metastatic disease . RESULTS An objective response rate was observed in 30 % of patients in the NVB-P arm versus 19 % in the VDS-P arm ( P = .02 ) and 14 % in the NVB arm ( P < .001 ) . The median duration of survival was 40 weeks in the NVB-P arm , compared with 32 weeks in the VDS-P arm and 31 weeks in the NVB arm . Comparison of survival among the three groups demonstrated an advantage for NVB-P compared with VDS-P ( P = .04 ) and NVB ( P = .01 ) . Neutropenia was significantly higher in the NVB-P group ( P < .001 ) , and neurotoxicity was more frequent with VDS-P ( P < .004 ) . CONCLUSION Since our results have demonstrated that NVB-P yields a longer survival duration and a higher response rate than VDS-P or NVB alone , with acceptable toxicity , this combination should be considered a relevant regimen in advanced NSCLC UNLABELLED Efficacy of first-line gefitinib for elderly epidermal growth factor receptor mutated patients with lung adenocarcinoma is uncertain . This study was aim ed to investigate efficacy of gefitinib for such population . The primary endpoint was response rate ( RR ) and at least 12 cases were needed . Overall RR was 59 % ( 95 % confidence interval , 33%-81 % ) and first-line gefitinib was effective for elderly patients . INTRODUCTION Feasibility of gefitinib therapy in elderly patients with non-small-cell lung cancer is uncertain . This phase II study aim ed to investigate the efficacy and usefulness of gefitinib therapy as a first-line treatment for elderly patients who have advanced lung adenocarcinoma with epidermal growth factor receptor ( EGFR ) mutations . PATIENTS AND METHODS We enrolled chemotherapy-naïve advanced lung adenocarcinoma patients aged 75 years or older . Patients were administered gefitinib ( 250 mg ) once daily until progression or unacceptable toxicity . The primary endpoint was response rate ( RR ) , and secondary endpoints were disease control rate ( DCR ; defined as complete response [ CR ] plus partial response [ PR ] plus stable disease [ SD ] ) , progression-free survival ( PFS ) , overall survival ( OS ) , and toxicity profile . RESULTS Between April 2008 and November 2009 , 17 lung adenocarcinoma patients were enrolled . Overall RR was 59 % ( 95 % confidence interval [ CI ] : 33 % to 81 % ) , with 2 patients achieving CR and 8 PR . SD was noted in 5 patients , and DCR was 88 % ( 95 % CI : 62 % to 98 % ) . Median PFS was 12.9 months ( 95 % CI : 2.2 to 23.6 months ) , and median OS had not yet been reached . Major grade 3 toxicities were skin rash ( 12 % ) and increased levels of aspartate aminotransferase or alanine aminotransferase ( 18 % ) . CONCLUSION First-line treatment with gefitinib was effective and well-tolerated in elderly patients with EGFR mutations PURPOSE To compare the activity and tolerability of docetaxel/gemcitabine ( DG ) and vinorelbine/cisplatin ( VC ) combinations in chemotherapy-naive non-small-cell lung cancer ( NSCLC ) patients . PATIENTS AND METHODS Patients with advanced NSCLC were r and omly assigned to receive either DG ( gemcitabine 1,000 mg/m(2 ) [ days 1 and 8 ] plus docetaxel 100 mg/m(2 ) [ day 8 ] ) or VC ( vinorelbine 30 mg/m(2 ) [ days 1 and 8 ] plus cisplatin 80 mg/m(2 ) [ day 8 ] ) and prophylactic recombinant human granulocyte colony-stimulating factor ( 150 microg/m(2 ) subcutaneously [ day 9 through 15 ] ) every 3 weeks . Results A total of 413 r and omly assigned patients were analyzed for response and toxicity ( DG , n = 197 ; VC , n = 192 ) . Median survival was 9.0 and 9.7 months ( P = .965 ) for DG and VC arms , respectively ; the corresponding 1-year survival rates were 34.3 % and 40.8 % , respectively . Overall response rate was 30 % ( 95 % CI , 23.9 % to 36.3 % ) and 39.2 % ( 95 % CI , 32.5 % to 45.9 % ; P = .053 ) for DG and VC , respectively . Toxicity was as follows ( DG v VC ) : grade 2 to 4 anemia , 34 % v 55 % ( P = .0001 ) ; grade 3 to 4 neutropenia , 16 % v 37 % ( P = .0001 ) ; febrile neutropenia , 6 % v 11 % ( P = .009 ) ; and grade 3 to 4 nausea and vomiting , 1 % v 15 % ( P = .003 ) . Nephrotoxicity occurred in 8 % and ototoxicity in 2 % of VC-treated patients . There were five and six treatment-related deaths in the DG and VC arms , respectively . Quality of life was improved in DG but not in VC patients . CONCLUSION Although the two regimens produced comparable overall survival , the DG regimen had a better toxicity profile . Therefore , DG could be used in the first-line setting of advanced NSCLC , especially for patients who can not tolerate cisplatin To compare the overall survival ( OS ) of patients with advanced non-small cell lung ( NSCLC ) treated with either docetaxel plus gemcitabine or single-agent docetaxel . Chemotherapy-naive patients with advanced/metastatic NSCLC were r and omly assigned to receive either DG [ n=157 ; gemcitabine 1100mg/m(2 ) on days 1 and 8 ] , docetaxel 75mg/m(2 ) on day 8 or D [ n=155 ; docetaxel 100mg/m(2 ) on day 1 ] every 3 weeks . A total of 312 patients were evaluable for toxicity and response . A predefined interim intention-to-treat analysis showed significantly longer median OS ( p=0.037 ) in favor of the DG regimen ( 9.4 months versus 8.3 months for DG and D regimens , respectively ) , result ing in the premature termination of the study . The DG regimen was also associated with a significantly higher response rate compared to D ( 26.8 % versus 11.6 % , p<0.001 ) . TTP were 3.5 and 2.3 months for the DG and D regimen , respectively ( p=0.054 ) . Although there were two treatment-related deaths in the DG arm , the toxicity profiles of the two regimens were comparable . The DG regimen was associated with a significantly better quality of life . The efficacy of the docetaxel plus gemcitabine combination is superior to single-agent docetaxel in chemonaive patients with advanced NSCLC PURPOSE To analyze the age-related enrollment of cancer patients onto registration trials of new drugs or new indications approved by the US Food and Drug Administration from 1995 to 2002 . PATIENTS AND METHODS This study involved retrospective analyses of demographic data of cancer patients enrolled onto registration trials . The data on 28,766 cancer patients from 55 registration trials were analyzed according to age distributions of > or = 65 , > or = 70 , and > or = 75 years . The rates of enrollment in each age group for each cancer were compared with the corresponding rates in the US cancer population . The age distributions of the US cancer population were derived from the Surveillance , Epidemiology , and End Results Program of the National Cancer Institute for the period 1995 to 1999 based on the 2000 US Census . RESULTS The proportions of the overall patient population s aged > or = 65 , > or = 70 , and > or = 75 years were 36 % , 20 % , and 9 % compared with 60 % , 46 % , and 31 % , respectively , in the US cancer population . Statistically significant under-representation of the elderly ( P < .001 ) was noted in registration trials for all cancer treatment except for breast cancer hormonal therapies . Patients aged > or = 70 years accounted for most of the under-representation . CONCLUSION Elderly were under-represented in the registration trials of new cancer therapies . Various strategies may be needed to evaluate cancer therapies for the elderly in prospect i ve clinical trials and to improve cancer care in the elderly population PURPOSE To compare the overall survival ( OS ) of patients with advanced non-small-cell lung cancer ( NSCLC ) treated with docetaxel plus cisplatin ( DC ) or docetaxel ( D ) alone . PATIENTS AND METHODS Chemotherapy-naïve patients with advanced/metastatic NSCLC were r and omly assigned to receive either DC ( n = 167 ; docetaxel 100 mg/m(2 ) on day 1 , cisplatin 80 mg/m(2 ) on day 2 , and recombinant human granulocyte colony-stimulating factor ( rhG-CSF ) 150 microg/m(2)/d on days 3 to 9 ) or D ( n = 152 ; 100 mg/m(2 ) on day 1 without rhG-CSF ) every 3 weeks . RESULTS The overall response rates were 36.5 % for DC ( three complete responses and 58 partial responses ) and 21.7 % for D ( one complete response and 32 partial responses ; P = .004 ) . The median OS was 10.5 months ( range , 0.5 to 41 months ) and 8.0 months ( range , 0.5 to 41 months ) for DC and D , respectively ( P = .200 ) . The 1- and 2-year survival rates were 44 % and 19 % for DC and 43 % and 15 % for D , respectively . Median times to tumor progression were 4.0 and 2.5 months for DC and D , respectively ( P = .580 ) . Grade 2/3 anemia was significantly higher with DC than with D ( 33 % v 16 % ; P = .0001 ) . Fifteen ( 9 % ) DC and 12 ( 8 % ) D patients developed febrile neutropenia . Grade 3/4 nausea/vomiting ( P = .0001 ) , diarrhea ( P = .007 ) , neurotoxicity ( P = .017 ) , and nephroroxicity ( P = .006 ) were significantly more common with DC than with D. There were five treatment-related deaths in the DC group and one in the D ( P = .098 ) . CONCLUSION DC regimen result ed in a higher response rate but without improvement in median time to tumor progression or OS compared with D. D could be a reasonable front-line chemotherapy for patients who can not tolerate cisplatin Introduction : Recent studies have demonstrated that first-line treatment with gefitinib , an epidermal growth factor receptor (EFGR)–targeted tyrosine kinase inhibitor , is significantly superior to st and ard chemotherapy for advanced non – small-cell lung cancer ( NSCLC ) harboring EGFR sensitive mutations . Meanwhile , the efficacy of gefitinib therapy among elderly population s diagnosed with EGFR-mutated NSCLC has not yet been eluci date d. The purpose of this study was to investigate the efficacy and feasibility of gefitinib for chemotherapy-naive patients aged 75 or older with NSCLC harboring EGFR mutations ; generally , these patients have no indication for treatment with platinum doublets . Methods : Chemotherapy-naive patients aged 75 years or older with performance status 0 to 1 and advanced NSCLC harboring EGFR mutations , as determined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method , were enrolled . The enrolled patients received 250 mg/day of gefitinib orally . Results : Between January 2008 and May 2009 , 31 patients were enrolled , all of whom were eligible . The median age was 80 ( range , 75–87 ) years . Twenty-five patients ( 81 % ) were women , and 30 patients ( 97 % ) had adenocarcinoma . The overall response rate was 74 % ( 95 % confidence interval , 58%–91 % ) , and the disease control rate was 90 % . The median progression-free survival was 12.3 months . The common adverse events were rash , diarrhea , and liver dysfunction . One treatment-related death because of interstitial lung disease occurred . Conclusions : This is the first study that verified safety and efficacy of first-line treatment with gefitinib in elderly patients having advanced NSCLC with EGFR mutation . Considering its strong antitumor activity and mild toxicity , first-line gefitinib may be preferable to st and ard chemotherapy for this population BACKGROUND To investigate whether the addition of intravenous carboplatin ( CBDCA ) to prolonged oral administration of etoposide improves treatment results over that obtained with the same etoposide given alone in patients with Stage IV non small-cell lung cancer ( NSCLC ) . MATERIAL AND METHODS Patients , 120 were r and omized to receive either 400 mg/m2 of CBDCA , day 1 and 50 mg/m2 of etoposide , days 1 - 21 ( Group I ) or the same etoposide alone ( Group II ) . Cycles were repeated every 4 weeks for up to 6 cycles or until tumor progression was noted . RESULTS Patients , 117 were fully evaluable for this report . Patients in Group I achieved better response rate than those in Group II ( 31 versus 20 % , P = 0.19 ) . They also had longer median survival time and higher 1- and 2-year survival rates than those in Group II ( 9 versus 5 months , respectively ; 38 and 12 % versus 24 and 5 % , respectively ; P = 0.015 ) . There were no treatment-related deaths . Leukopenia ( P = 0.047 ) and thrombocytopenia ( P = 0.000 ) were more frequent in Group I , but only 15 ( 26 % ) patients in Group and 7 ( 12 % ) patients in Group II experienced high- grade ( > or = 3 ) hematological toxicity . Apart from alopecia ( P = 0.000 ) , other non-hematological toxicity was not different between the two treatment Groups . CONCLUSION Results of this study showed improvement in survival for the two-drug regimen . Together with mild to moderate toxicity and low cost , they may warrant further studies comparing it with other approaches in patients with Stage IV NSCLC OBJECTIVE This phase III study was aim ed at evaluating whether the addition of gemcitabine ( G ) to vinorelbine ( V ) could improve the survival and quality of life ( QoL ) of elderly patients with advanced NSCLC . PATIENTS AND METHODS Patients with advanced NSCLC , aged > or=70 years , were r and omly allocated to receive V 30 mg/m(2 ) on days 1 and 8 every 3 weeks or G 1200 mg/m(2 ) plus V 30 mg/m(2 ) on days 1 and 8 every 3 weeks . Survival was the main end point of the study . The estimated sample size was 120 patients per arm , but an interim analysis of survival was planned on the first 60 patients per arm . RESULTS In May 1999 , an interim analysis was performed with the survival data of the first 120 eligible patients ( V(arm)=60 , G+V(arm)=60 ) . Forty-nine patients had stage IIIB disease and 71 patients stage IV disease , median potential follow-up of 14 months ( range ; 3 - 22 ) , 93 patients had died ( G+V(arm)=41 , V(arm)=52 ) . Median survival time ( MST ) was 29 weeks and projected 1-year survival was 30 % in the G+V(arm ) ; these values were 18 weeks and 13 % in the V(arm ) . At multivariate Cox analysis , the risk of death in the G+V(arm ) compared with V(arm ) was 0.48 ( 95 % C1=0.29 - 0.79 ; P<0.01 ) . Combination therapy was also associated with a clear delay in symptom and QoL deterioration . The ORR was 22 and 15 % in the G+V and V(arms ) , respectively . Toxicity was not irrelevant in both arms . CONCLUSIONS G+V treatment is associated with a significantly better survival than V alone in elderly NSCLC patients . The magnitude of the difference justifies the early closure of the study . The G+V regimen is now the SICOG reference regimen in this type of patients PURPOSE Older adults are vulnerable to chemotherapy toxicity ; however , there are limited data to identify those at risk . The goals of this study are to identify risk factors for chemotherapy toxicity in older adults and develop a risk stratification schema for chemotherapy toxicity . PATIENTS AND METHODS Patients age ≥ 65 years with cancer from seven institutions completed a prechemotherapy assessment that captured sociodemographics , tumor/treatment variables , laboratory test results , and geriatric assessment variables ( function , comorbidity , cognition , psychological state , social activity/support , and nutritional status ) . Patients were followed through the chemotherapy course to capture grade 3 ( severe ) , grade 4 ( life-threatening or disabling ) , and grade 5 ( death ) as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events . RESULTS In total , 500 patients with a mean age of 73 years ( range , 65 to 91 years ) with stage I to IV lung ( 29 % ) , GI ( 27 % ) , gynecologic ( 17 % ) , breast ( 11 % ) , genitourinary ( 10 % ) , or other ( 6 % ) cancer joined this prospect i ve study . Grade 3 to 5 toxicity occurred in 53 % of the patients ( 39 % grade 3 , 12 % grade 4 , 2 % grade 5 ) . A predictive model for grade 3 to 5 toxicity was developed that consisted of geriatric assessment variables , laboratory test values , and patient , tumor , and treatment characteristics . A scoring system in which the median risk score was 7 ( range , 0 to 19 ) and risk stratification schema ( risk score : percent incidence of grade 3 to 5 toxicity ) identified older adults at low ( 0 to 5 points ; 30 % ) , intermediate ( 6 to 9 points ; 52 % ) , or high risk ( 10 to 19 points ; 83 % ) of chemotherapy toxicity ( P < .001 ) . CONCLUSION A risk stratification schema can establish the risk of chemotherapy toxicity in older adults . Geriatric assessment variables independently predicted the risk of toxicity PURPOSE This multicenter phase II study was undertaken to investigate the efficacy and feasibility of gefitinib for patients with advanced non-small-cell lung cancer ( NSCLC ) harboring epidermal growth factor receptor ( EGFR ) mutations without indication for chemotherapy as a result of poor performance status ( PS ) . PATIENTS AND METHODS Chemotherapy-naïve patients with poor PS ( patients 20 to 74 years of age with Eastern Cooperative Oncology Group PS 3 to 4 , 75 to 79 years of age with PS 2 to 4 , and > or= 80 years of age with PS 1 to 4 ) who had EGFR mutations examined by the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method were enrolled and received gefitinib ( 250 mg/d ) alone . RESULTS Between February 2006 and May 2007 , 30 patients with NSCLC and poor PS , including 22 patients with PS 3 to 4 , were enrolled . The overall response rate was 66 % ( 90 % CI , 51 % to 80 % ) , and the disease control rate was 90 % . PS improvement rate was 79 % ( P < .00005 ) ; in particular , 68 % of the 22 patients improved from > or= PS 3 at baseline to < or= PS 1 . The median progression-free survival , median survival time , and 1-year survival rate were 6.5 months , 17.8 months , and 63 % , respectively . No treatment-related deaths were observed . CONCLUSION This is the first report indicating that EGFR mutation-positive patients with extremely poor PS benefit from first-line gefitinib . Because there previously has been no st and ard treatment for these patients with short life expectancy other than best supportive care , examination of EGFR mutations as a biomarker is recommended in this patient population 7509 Background : Tri-weekly D is one of the st and ard treatment regimens for elderly advanced NSCLC pts . To investigate whether the addition of a modified platinum agent might improve the survival in these patients , we conducted a phase III trial comparing weekly DP with tri-weekly D. METHODS Eligibility criteria were : chemotherapy-naïve ; unfit for bolus P administration ; stage III/IV or relapsed NSCLC ; age≥70 ; PS 0 - 1 . Pts were r and omized to receive either DP or D by the minimization method , balancing for site , age ( < 75/≥75 ) , and stage ( III/IV ) . DP comprised administration of D ( 20 mg/m2 ) and P ( 25 mg/m2 ) iv on days 1 , 8 , and 15 every 4 weeks . D comprised administration of D ( 60 mg/m2 ) iv on day 1 every 3 weeks . The primary endpoint was overall survival ( OS ) . The planned sample size was 190 pts in each arm , to provide an 80 % power to detect a 0.752 hazard ratio for DP to D in regard to the OS , and a 5 % one-sided alpha . RESULTS Between Oct 2008 and Sep 2010 , 276 pts were r and omized ( D/DP : 137/139 ) . The first planned interim analysis was performed on 221 assessable pts ( D/DP : 108/113 , < 75/≥75 : 22/78 % , male/female : 70/30 % , PS 0/1 : 35/65 % , III/IV or relapse : 32/68 % ) . Information time , defined as the proportion of interim events to planned events , was 24 % ( = 73/304 ) . The median survival times of the DP and D groups were 13.3 and 17.3 months , respectively ( hazard ratio [ 95 % CI ] : 1.557 [ 0.976 - 2.485 ] ) . The predictive probability that DP would be superior to D at the time of the final analysis was 0.996 % , which led to early termination of the trial . The major grade 3 - 4 toxicities were ( % D/DP ) : neutropenia 88/11 % , anemia 3/16 % , anorexia 1/10 % , febrile neutropenia 17/0 % , pneumonitis 3/2 % . Treatment-related death occurred in 3 pts of the DP arm . The proportion of pts with an improved symptom score ( FACT-L lung symptom subscale ) after 3 courses of treatment was higher in the D arm . CONCLUSIONS This study failed to demonstrate any advantage of the addition of weekly P to single-agent D in first line chemotherapy for elderly advanced NSCLC pts PURPOSE Platinum-containing chemotherapy regimens are the st and ard treatment for patients with advanced non-small-cell lung cancer ( NSCLC ) , although toxicity is common and may significantly affect the patient 's quality of life ( QoL ) . This trial aim ed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL , without influencing negatively on survival , compared with cisplatin-containing regimens . PATIENTS AND METHODS Patients with stage IIIB ( effusion and supraclavicular nodes ) or IV documented NSCLC who were younger than 70 years of age were r and omly assigned gemcitabine plus vinorelbine ( GemVin ) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin ( cisplatin-based ) . European Organization for Research and Treatment of Cancer scales were used for QoL analysis . RESULTS Five hundred one patients were r and omly assigned to treatment . The median age was 62 years . There were no significant differences in global QoL scores between the two arms after 2 months of treatment . However , worsening scores for appetite , vomiting , and alopecia were significantly more common in the cisplatin-based arm . Median survival was 38 v 32 weeks and median progression-free survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms , respectively . For the GemVin arm the hazard ratio for death was 1.15 ( 90 % confidence interval [ CI ] , 0.96 to 1.37 ) and the hazard ratio for progression was 1.29 ( 90 % CI , 1.10 to 1.52 ) . Grade 3 or 4 myelosuppression , vomiting , alopecia , and ototoxicity were significantly more frequent with cisplatin-based treatment . CONCLUSION Global QoL is not improved with GemVin , although advantages in some components of QoL were apparent . GemVin is less toxic than st and ard cisplatin-based chemotherapy . There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy . GemVin could be offered to advanced NSCLC patients who express concern about toxicity PURPOSE A phase II r and omized study was conducted to evaluate the efficacy and toxicity of gemcitabine ( GEM ) versus the combination of cisplatin and etoposide ( EP ) in Chinese patients with inoperable ( stage III or IV ) non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS From March 1995 to February 1996 , 53 patients were enrolled onto the study : 27 onto the GEM arm and 26 onto the EP arm . In the GEM arm , gemcitabine 1,250 mg/m2 was given as a 30-minute intravenous ( i.v . ) infusion on days 1 , 8 , and 15 of each 28-day cycle . In the EP arm , cisplatin 80 mg/m2 was given on day 1 and etoposide 80 mg/m2 was given on days 1 , 2 , and 3 of each 28-day cycle . RESULTS Twenty-six patients are assessable for treatment response on the GEM arm and 24 on the EP arm . Five patients ( 19.2 % ) on the GEM arm and five patients ( 20.8 % ) on the EP arm achieved a partial response ( PR ) . No complete responses were attained on either treatment arm . All patients enrolled onto the study were eligible for toxicity assessment . The main toxicities were myelosuppression and vomiting , which included World Health Organization ( WHO ) grade 3 or 4 leukopenia ( 3.7 % ) , thrombocytopenia ( 7.4 % ) , anemia ( 7.4 % ) , and nausea/vomiting ( 3.7 % ) on the GEM arm , and WHO grade 3 or 4 leukopenia ( 30.8 % ) , thrombocytopenia ( 7.7 % ) , anemia ( 15.4 % ) , and nausea/vomiting ( 34.6 % ) on the EP arm . The median survival time was 37 weeks on the GEM arm and 48 weeks on the EP arm . CONCLUSION Gemcitabine is a well-tolerated chemotherapeutic agent for NSCLC . The antitumor activity was promising , with a 19.2 % single-drug response rate , when compared with EP combination chemotherapy , which had a response rate of 20.8 % . The safety profile is better than that of EP treatment PURPOSE The purpose of the study was to assess the possible benefit of the combination vinorelbine (NVB)-cisplatin ( DDP ) in comparison with NVB alone in advanced non-small cell lung cancer ( NSCLC ) , not treated previously . It also involved confirmation of the efficacy of vinorelbine as monotherapy . PATIENTS AND METHODS In this phase III trial , 231 eligible patients were stratified by centre and r and omized to receive either NVB alone , 30 mg/m2/week or the combination of NVB 30 mg/m2/week and DDP 80 mg/m2/3 weeks . Patients were to be treated for a minimum of 6 weeks , with the first response assessment performed 9 weeks after the beginning of treatment . RESULTS The two groups differed in terms of objective response rates ( 16 % and 43 % , respectively , p = 0.0001 ) and median time to progression ( 10 weeks and 20 weeks , p = 0.0001 ) . However , the difference was not significant for median survival time ( 32 weeks , 33 weeks , p = 0.48 ) . The addition of DDP result ed in an increase in toxicity , in particular renal , hematologic , neurologic and emetic . This toxicity led to treatment discontinuation in 8 % and 21 % of patients , respectively . Respectively 3 % and 13 % of patients stopped treatment early during objective response ( toxicity or refusal ) . CONCLUSIONS The NVB-DDP combination increased objective response rates and time to progression in comparison with NVB alone , but did not influence the survival of patients . The activity of NVB in the treatment of advanced NSCLC was confirmed PURPOSE To study the prognostic value for overall survival of baseline assessment of functional status , comorbidity , and quality of life ( QoL ) in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy . PATIENTS AND METHODS Data from 566 patients enrolled onto the phase III r and omized Multicenter Italian Lung Cancer in the Elderly Study ( MILES ) study were analyzed . Functional status was measured as activities of daily living ( ADL ) and instrumental ADL ( IADL ) . The presence of comorbidity was assessed with a checklist of 33 items ; items 29 and 30 of the European Organisation for Research and Treatment of Cancer ( EORTC ) core question naire QLQ-C30 ( EORTC QLQ-C30 ) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency . For IADL and QoL , three categories were defined using first and third quartiles as cut points . Comorbidity was summarized using the Charlson scale . Analysis was performed by Cox model , and stratified by treatment arm . RESULTS Better values of baseline QoL ( P = .0003 ) and IADL ( P = .04 ) were significantly associated with better prognosis , whereas ADL ( P = .44 ) and Charlson score ( P = .66 ) had no prognostic value . Performance status 2 ( P = .006 ) and a higher number of metastatic sites ( P = .02 ) also predicted shorter overall survival . CONCLUSIONS Pretreatment global QoL and IADL scores , but not ADL and comorbidity , have significant prognostic value for survival of elderly patients with advanced non-small-cell lung cancer who were treated with chemotherapy . Using these scores in clinical practice might improve prognostic prediction for treatment planning PURPOSE To compare the survival benefit obtained with cisplatin plus gemcitabine , a cisplatin-based triplet , and nonplatinum sequential doublets in advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Stage IIIB to IV NSCLC patients were r and omly assigned to receive cisplatin 100 mg/m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8 , every 3 weeks for six cycles ( CG ) ; cisplatin 100 mg/m2 day 1 plus gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 days 1 and 8 , every 3 weeks for six cycles ( CGV ) ; or gemcitabine 1,000 mg/m2 plus vinorelbine 30 mg/m2 days 1 and 8 , every 3 weeks for three cycles , followed by vinorelbine 30 mg/m2 days 1 and 8 plus ifosfamide 3 g/m2 day 1 , every 3 weeks for three cycles ( GV-VI ) . RESULTS Five hundred fifty-seven patients were assigned to treatment ( 182 CG , 188 CGV , 187 GV-VI ) . Response rates were significantly inferior for the nonplatinum sequential doublet ( CG , 42 % ; CGV , 41 % ; GV-VI , 27 % ; CG v GV-VI , P = .003 ) . No differences in median survival or time to progression were observed . Toxicity was higher for the triplet : grade 3 to 4 neutropenia ( GC , 32 % ; CGV , 57 % ; GV-VI , 27 % ; P < .05 ) ; neutropenic fever ( CG , 4 % ; CGV , 19 % ; GV-VI , 5 % ; P < .0001 ) ; grade 3 to 4 thrombocytopenia ( CG , 19 % ; CGV , 23 % ; GV-VI , 3 % ; P = .0001 ) ; and grade 3 to 4 emesis ( GC , 22 % ; GCV , 32 % ; GV-VI , 6 % ; P < .0001 ) . CONCLUSION On the basis of these results , CG remains a st and ard regimen for first-line treatment of advanced NSCLC AIM While meta-analyses and clinical trials show improved survival in advanced NSCLC treated with platinum-containing chemotherapy , there are few data concerning front-line platinum-free ifosfamide-based regimens . We aim ed to compare cisplatin-based chemotherapy to ifosfamide-gemcitabine ( IG ) with pre-defined second-line docetaxel . PATIENTS AND METHODS 693 Untreated advanced inoperable NSCLC cases were r and omised to either GIP ( gemcitabine , ifosfamide , cisplatin ) , DP ( docetaxel , cisplatin ) or IG . Primary outcome was overall survival . RESULTS Median age of the patients was 58 years with a predominance of males ( 75 % ) , adenocarcinoma ( 56 % ) , Karnofsky PS 80 - 100 ( 77 % ) and stage-IV disease ( 81 % ) . Median survival times were 8.7 , 8.8 and 8.3 months for IG , GIP and DP ( p=0.79 ) . GIP presented with ( p<0.05 ) greater neutropenia , thrombopenia , vomiting , while greater cardiotoxicity , diarrhea , peripheral neuropathy were observed for DP and encephalopathy for IG . CONCLUSION In advanced NSCLC , cisplatin-based CT is not superior to a platinum-free regimen ( ifosfamide-gemcitabine ) with a favourable toxicity profile PURPOSE To compare single-agent pemetrexed ( P ) versus the combination of carboplatin and pemetrexed ( CP ) in first-line therapy for patients with advanced non-small-cell lung cancer ( NSCLC ) with an Eastern Cooperative Oncology Group ( ECOG ) performance status ( PS ) of 2 . PATIENTS AND METHODS In a multicenter phase III r and omized trial , patients with advanced NSCLC , ECOG PS of 2 , any histology at first and later amended to nonsquamous only , no prior chemotherapy , and adequate organ function were r and omly assigned to P alone ( 500 mg/m(2 ) ) or CP ( area under the curve of 5 and 500 mg/m(2 ) , respectively ) administered every 3 weeks for a total of four cycles . The primary end point was overall survival ( OS ) . RESULTS A total of 205 eligible patients were enrolled from eight centers in Brazil and one in the United States from April 2008 to July 2011 . The response rates were 10.3 % for P and 23.8 % for CP ( P = .032 ) . In the intent-to-treat population , the median PFS was 2.8 months for P and 5.8 months for CP ( hazard ratio [ HR ] , 0.46 ; 95 % CI , 0.35 to 0.63 ; P < .001 ) , and the median OS was 5.3 months for P and 9.3 months for CP ( HR , 0.62 ; 95 % CI , 0.46 to 0.83 ; P = .001 ) . One-year survival rates were 21.9 % and 40.1 % , respectively . Similar results were seen when patients with squamous disease were excluded from the analysis . Anemia ( grade 3 , 3.9 % ; grade 4 , 11.7 % ) and neutropenia ( grade 3 , 1 % ; grade 4 , 6.8 % ) were more frequent with CP . There were four treatment-related deaths in the CP arm . CONCLUSION Combination chemotherapy with CP significantly improves survival in patients with advanced NSCLC and ECOG PS of 2 PURPOSE To evaluate whether cisplatin-based chemotherapy ( gemcitabine , vinorelbine , and cisplatin [ GVP ] ) prolongs overall survival in comparison to cisplatin-free chemotherapy ( gemcitabine and vinorelbine [ GV ] ) as first-line treatment in patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Between September 1999 and June 2001 , 300 patients with NSCLC stage IIIB with malignant pleural effusion or stage IV disease were r and omly assigned to receive GV ( gemcitabine 1000 mg/m(2 ) + vinorelbine 25 mg/m(2 ) on days 1 and 8 every 3 weeks ) or GVP ( gemcitabine 1000 mg/m(2 ) + vinorelbine 25 mg/m(2 ) on days 1 and 8 + cisplatin 75 mg/m(2 ) on day 2 every 3 weeks ) . Primary end point of the study was overall survival . RESULTS Two hundred eighty-seven patients ( GV , 143 patients ; GVP , 144 patients ) were eligible for analysis . At the time of analysis , April 15 , 2002 , 209 patients ( GV , 103 patients ; GVP , 106 patients ) of 287 patients had died ( 73 % ) . No statistically significant difference was observed for overall survival ( P = .73 ; median survival , 35.9 versus 32.4 weeks ; 1-year survival rate , 33.6 % versus 27.5 % ) as well as for event-free survival ( P = .35 ; median time-to-event , 19.3 versus 22.3 weeks ) between GV and GVP . Two hundred fourteen patients were assessable for best response . The overall response rates were 13.0 % for GV versus 28.3 % for GVP ( P = .004 ; complete responders , 0 % versus 3.8 % ; partial responders , 13.0 % versus 24.5 % ) . Hematologic and nonhematologic toxicity was significantly lower in the GV treatment arm compared with GVP . No statistically significant difference in quality of life was observed . CONCLUSION In this phase III study , the cisplatin-based GVP regimen showed no survival benefit as first-line chemotherapy in advanced NSCLC when compared with the cisplatin-free GV regimen , which was substantially better tolerated PURPOSE Our aim here was to determine whether or not the addition of cisplatin into vinorelbine ( V ) treatment is an appropriate regimen for physically fit chemo-naïve non-small cell lung cancer ( NSCLC ) patients aged 70 or older . PATIENTS AND METHODS Patients were r and omized into vinorelbine ( V ) or vinorelbine plus cisplatin ( VP ) treatment arms . Treatment consisted of vinorelbine 25 mg/m(2 ) intravenous infusion ( i.v . ) on days 1 and 8 every 3 weeks ( V arm ) , or vinorelbine 22.5 mg/m(2 ) i.v . on days 1 and 8 plus cisplatin 50 mg/m(2 ) i.v . on day 1 every 3 weeks ( VP arm ) . RESULTS Sixty-five patients were enrolled from May 2005 to December 2006 , including 31 who received V treatment and 34 who received VP treatment . Objective response rates were 16.1 % in V and 32.4 % in VP ( p=0.009 ) . Control rates were 51.6 % in V and 82.4 % in VP ( p=0.008 ) . Myelosuppression was more common and severe in the VP arm . Any grade of anemia and neutropenia was significantly higher in the VP arm ( p=0.001 and 0.009 , respectively ) . Fatigue sensation was more common and severe in the VP arm ( p=0.032 ) . Median time to disease progression was 3.1 months in the V arm and 5.2 months in the VP arm ( p=0.0303 ) . The 1-year survival rate was 50.9 % in the V arm and 47.2 % in the VP arm . CONCLUSIONS Adding cisplatin to vinorelbine treatment is feasible in elderly patients , and has a better response rate and longer median time to disease progression . However , both statistically significantly higher toxicity and no survival advantage for the combination treatment was observed PURPOSE To compare the therapeutic efficacy of paclitaxel plus cisplatin ( arm A ) versus gemcitabine plus cisplatin ( arm B ) and arm A versus paclitaxel plus gemcitabine ( arm C ) in chemotherapy-naive patients with advanced non-small-cell lung cancer ( NSCLC ) . MATERIAL S AND METHODS Patients were r and omly assigned to receive either paclitaxel 175 mg/m2 ( 3-hour infusion , day 1 ) or gemcitabine 1,250 mg/m2 ( days 1 and 8) both combined with cisplatin 80 mg/m2 ( day 1 ) or paclitaxel 175 mg/m2 ( 3-hour infusion , day 1 ) combined with gemcitabine 1,250 mg/m2 ( days 1 and 8) . Primary end point was comparison of overall survival for B versus A and C versus A. Secondary end points included response rate and duration , progression-free survival , toxicities , quality of life [ QoL ] , and cost of treatment . RESULTS Four hundred eighty patients ( arm A , 159 ; arm B , 160 ; arm C , 161 patients ) were enrolled ; all baseline characteristics were balanced . Median survival times were as follows : arm A , 8.1 months ; arm B , 8.9 months ; arm C , 6.7 months . Response rates were 31.8 % for arm A , 36.6 % for arm B , and 27.7 % for arm C. Other than myelosuppression ( B v A , P < .005 ) , no statistically or clinical ly significant differences were observed for secondary end points . The average treatment costs were 25 % higher in arm C as compared with arms A and B. CONCLUSION Gemcitabine plus cisplatin and paclitaxel plus gemcitabine do not increase overall survival in patients with advanced NSCLC as compared with paclitaxel plus cisplatin . Treatment was well tolerated , and most QoL parameters were similar , but costs associated with the nonplatinum arm were highest PURPOSE To evaluate whether the addition of gemcitabine ( G ) to vinorelbine ( V ) improves survival and quality of life ( QoL ) among elderly patients with advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS Patients with NSCLC aged > /= 70 years with advanced disease were r and omly allocated to receive V 30 mg/m(2 ) on days 1 and 8 every 3 weeks or G 1,200 mg/m(2 ) + V 30 mg/m(2 ) on days 1 and 8 every 3 weeks . The estimated sample size was 120 patients per arm , but an interim analysis of survival was planned based on the first 60 patients per arm . RESULTS In May 1999 , the survival data were analyzed of 120 eligible patients ( V group = 60 ; G + V group = 60 ) who had been r and omized from June 1997 to February 1999 . Forty-nine patients had stage IIIB disease , and 71 had stage IV . At a median potential follow-up of 14 months ( range , 3 to 22 months ) , 93 patients had died ( G + V group = 41 ; V group = 52 ) . In the G + V group , median survival time was 29 weeks and projected 1-year survival was 30 % ; these values were 18 weeks and 13 % in the V group . According to multivariate Cox analysis , the risk of death in the G + V arm compared with the V arm was 0.48 ( 95 % confidence interval , 0 . 29 to 0.79 ; P < .01 ) . Combination therapy was also associated with a clear delay in symptom and QoL deterioration . The overall response rates were 22 % and 15 % in the G + V and V groups , respectively . CONCLUSION In elderly patients with NSCLC , G + V treatment is associated with significantly better survival than is V alone BACKGROUND Platinum-based chemotherapy is the cornerstone of treatment of advanced non-small-cell lung cancer ( NSCLC ) patients , but the efficacy of adding cisplatin to single-agent chemotherapy remains to be demonstrated in prospect i ve phase III trials dedicated to elderly patients . Furthermore , the superiority of cisplatin/pemetrexed over cisplatin/gemcitabine in non-squamous NSCLC has not been confirmed prospect ively . We present the rationale and design of two open-label , multicenter , r and omized phase III trials for elderly patients with advanced NSCLC∶ Multicenter Italian Lung cancer in the Elderly Study (MILES)-3 and MILES-4 . The aim is to evaluate the efficacy of adding cisplatin to single-agent chemotherapy ( both trials ) and the efficacy of pemetrexed versus gemcitabine in non-squamous tumors ( MILES-4 ) . PATIENTS AND METHODS Both trials are dedicated to first-line therapy of patients older than 70 years with advanced NSCLC , ECOG performance status 0 - 1 . In the MILES-3 trial , patients are r and omized in a 1∶1 ratio to gemcitabine or cisplatin/gemcitabine . In the MILES-4 study patients with non-squamous histology are r and omized , in a factorial design with 1∶1∶1∶1 ratio , to four arms : gemcitabine ( A ) , cisplatin/gemcitabine ( B ) , pemetrexed ( C ) , cisplatin/pemetrexed ( D ) . Two comparisons are planned∶ A+C vs B+D to test the role of cisplatin ; A+B vs C+D to test the role of pemetrexed . Primary endpoint of both trials is overall survival . Secondary and exploratory endpoints include progression-free survival , response rate , toxicity , and quality of life . CONCLUSIONS MILES-3 and MILES-4 results will add important evidence about the role of cisplatin-based doublets and pemetrexed in the first-line therapy of elderly patients with advanced NSCLC PURPOSE This r and omized phase III trial of advanced or metastatic non-small-cell lung cancer ( NSCLC ) was design ed to compare a st and ard treatment such as carboplatin (CRP)-paclitaxel ( PCT ) with a new combination , vinorelbine (VRL)-PCT-two agents acting in microtubules . PATIENTS AND METHODS Three hundred and sixty patients ( stage IIIa , IIIb and IV ) were included and evaluated for response rate , survival and toxicity . Arm A patients were treated with the control combination of CRP 6 AUC and PCT 175 mg/m(2 ) repeated every 3 weeks for six cycles , and arm B with the investigational combination of VRL 25 mg/m(2 ) and PCT 135 mg/m(2 ) repeated every 2 weeks for nine cycles . The patients were well balanced with respect to gender , disease stage and performance status . Arm A received 849 cycles ( mean 4.59 per patient ) and arm B 951 cycles ( mean 5.39 per patient ) . RESULTS Complete and partial response rates were 45.95 % and 42.86 % for arms A and B , respectively . Median survival was 11 and 10 months , 1-year survival 42.7 % and 37.85 % and 2-year survival 10.12 % and 19 % for arms A and B , respectively . Toxicity was similar in all patients , except for neutropenia , which was significantly greater in arm B. CONCLUSIONS PCT combined with VRL produces similar ( non-significant ) response rates , survival and toxicity ( except for neutropenia , as noted above ) to st and ard CRP-PCT treatment in untreated advanced-stage NSCLC |
13,634 | 17,589,331 | The most consistent finding in de novo renal , hepatic , and cardiac transplant recipients is a higher mean cyclosporine dose in the early postoperative period in C2 monitored patients .
There is no clear evidence that this leads to impaired renal function .
In the majority of studies , the monitoring strategy had no significant effect on the rate of acute rejection .
In stable transplant recipients , the majority of studies show a reduction in mean cyclosporine dose with adoption of C2 monitoring .
No obvious clinical benefit was derived from this reduction in dose .
In de novo transplant patients , there is little evidence from prospect i ve studies to support the theoretical benefits of C2 monitoring .
Potential dose reductions in stable patients may reduce costs , but no short-term clinical benefit is seen . | BACKGROUND Monitoring of cyclosporine microemulsion ( Neoral ) using 2-hour postdose ( C2 ) levels is alleged to improve clinical outcomes , but the efficacy of this strategy is uncertain . | Cyclosporine ( CsA ) blood concentrations measured 2 h after Neoral ® administration ( c 2 ) are a sensitive predictor of clinical outcome in organ transplantation , as suggested by a recent prospect i ve clinical trial in liver transplant patients ( 1 ) . c 2 is now recommended as the target exposure index for the therapeutic drug monitoring ( TDM ) of CsA (2)(3)(4)(5)(6)(7)(8 ) . The aim of this study was to investigate , for different types of grafts , the concentration – time relationships around c 2 to evaluate the concentration error as a function of the sampling-time error and to identify the sampling-time range compatible with acceptable performance of this c 2 TDM strategy . Data obtained from three different clinical trials were studied retrospectively . Each patient gave written informed consent , and each trial was approved by a local ethics committee (9)(10)(11 ) . The three population s were as follows Background . Cyclosporine monitoring using the 2-hr postdose sample , C2 , has been shown to have advantages in monitoring de novo renal transplant recipients . The purpose of this study was to assess cyclosporine exposure , using C2 , in stable renal transplant patients previously monitored by C0 to determine the effect of dose reduction on patients with C2 more than 10 % above target and the course of those with C2 at and more than 10 % below target , whose dose was not modified . Methods . One hundred and seventy-five patients , three or more months after transplantation , had C2 assessed . The relationship of C2 to C0 and of both to renal function was analyzed by linear regression . Blood pressure , serum creatinine level , and lipids were followed for a mean of 15±2.6 months . Results . Eighty-five patients had values more than 10 % above target , 42 were within 10 % of target , and 48 were more than 10 % below target . Cyclosporine dose was reduced in all patients above target . In this group , serum creatinine level was stable overall , but fell significantly in 46 ( 54 % ) of 85 from 153±55 to 132±49 & mgr;M. Blood pressure also fell in that group from 135/82 to 131/77 . Serum creatinine level was stable in the remaining two groups of patients . Conclusions . These data suggest that dose reduction in many overexposed patients leads to improvements in renal function and blood pressure . Further study is required to confirm the long-term benefits of this strategy Background . A prospect i ve , open-label , study was conducted at 29 centers in 9 countries , involving 307 de novo liver transplant patients to compare the clinical usefulness of monitoring 2-hr post-dose cyclosporine ( CsA ) levels ( C2 ) with conventional trough cyclosporine blood levels ( pre-dose ) ( C0 ) . Methods . Neoral oral therapy was initiated at 15 mg/kg/day and dose adjusted according to predetermined C2 or C0 target level ranges . The primary efficacy variable was treatment failure at 3 months , where evaluation was based on a composite endpoint of biopsy-proven rejection , treatment for rejection , graft loss , death , or premature withdrawal/discontinuation from the study . Results . Baseline characteristics were similar between groups . Graft loss at 12 weeks ( retransplantation or death ) occurred in 6.8 % C2 and in 7.0 % C0 patients . Overall incidence of treated acute rejection was lower for C2 ( 23.6 % ) than C0 patients ( 31.6 % ) ( P = 0.144 , Cochran-Mantel-Haenszel [ CMH ] test ) . In hepatitis C virus (HCV)-negative patients , the incidence of rejection in the C2 group was significantly less than in the C0 group ( 21.2 % vs. 33.0%;P < 0.05 ) , whereas in HCV-positive patients , the rejection rate was similar in both groups ( 26.7 % for C2 group vs. 27.3 % for C0 group : P = 0.81 ) . C2 patients ( n=16 ) who reached minimum target CsA levels by day 3 had a notably low incidence of rejection ( 12.5 % ) , whereas there was no difference in the incidence of rejection in C0 patients , irrespective of time to reach target level . For biopsy-proven acute rejections ( 21.6 % for C2 vs. 30.4 % for C0 ) , the incidence of moderate and severe histological diagnosis was significantly lower in the C2 group than in the C0 group ( 47 % vs. 73%;P = 0.01 ) . Safety profiles were similar between the two groups , with few patient withdrawals due to adverse events ( 9.5 % for C2 ; 7.0 % for C0 ) . Conclusions . Using C2 monitoring , the overall incidence of acute cellular rejection was lower compared with the C0 group , and the histological severity of acute rejections was shown to be significantly milder for the C2 group , indicative of good long-term prognosis . These data demonstrate that the use of C2 monitoring is superior to C0 and results in a reduction in the incidence and severity of acute cellular rejection without detrimental effect on the drug safety profile Background . The clinical utility of C2 monitoring of cyclosporine A microemulsion ( CsA-ME ) was evaluated in a prospect i ve study of 110 patients more than 12 months posttransplant who demonstrated stable graft function and were receiving CsA-ME and steroids . Methods . Patients were converted to C2 monitoring with the CsA-ME dose adjusted to a target C2 range of 800 to 1,000 ng/mL and followed for 40 + 11 months . Results . At the time of conversion , 57 % of patients exceeded the C2 target , 20 % of patients were below the C2 target , and 23 % of patients were within the C2 target range . The mean dose of CsA-ME decreased from 258 + 88 to 202 + 76 mg/day ( P<0.0001 ) , and the mean C2 level decreased from 1,052 + 292 ng/mL to 896 + 233 ng/mL ( P<0.0002 ) . There were no episodes of rejection . At last follow-up , 7.3 % of patients had developed chronic renal allograft dysfunction . Use of antihypertensive agents decreased significantly ( P=0.0004 ) , and mean total cholesterol decreased from 6.4 + 1.3 to 5.8 + 1.1 ( P=0.0009 ) after adoption of C2 monitoring . Conclusion . These findings suggest that conversion of maintenance renal transplant recipients from C0 to C2 monitoring of CsA-ME offers the clinical benefits of better control of hypertension and dyslipidemia , with effective protection against chronic renal allograft dysfunction . A target C2 range of 800 to 1,000 ng/mL in maintenance patients receiving CsA-ME dual therapy seems appropriate The registry of r and omized trials in organ transplantation reported between 1 January and 30 June 2004 and an evaluation of the quality of the trial methodology was published in an earlier issue ( 1 ) . In an editorial accompanying this registry of trials , it was noted that the methodology of many trials was less than adequate ( 2 ) . In this issue , we are publishing an analysis of the trials published between 1 July and 31 December 2004 , namely 44 trials described in 58 publications . In the future , the registry of trials published for the first and second six months of each year will appear in March and July respectively in the following year . The methodology has been evaluated again on the basis of the Jadad score , together with two other components required in a good trial , namely an adequate description of the concealment of allocation of the intervention and an analysis based on the intention to treat . These were described in some detail in the initial registry publication ( 1 ) . There was little difference in the overall quality of trial methodology published in the second six months of 2004 . The quality of the methodology of the trials over the whole year is summarized in Table 1 . A Jadad score equal to or greater than 3 is generally regarded as a good quality trial . As can be seen , only 40 % of r and omized trials could be regarded of adequate quality based on the Jadad score . Furthermore , with respect to two other key components of a good trial , in only 31 % of trials was there concealment of allocation and in only 44 % was the analysis based on intention to treat . This has to be regarded as rather disappointing and there is a need for better planning and reporting of r and omized trials in the field of transplantation . As in the first report , we did correspond with the authors not only to obtain agreement with our analysis of their paper but also to seek further information , which was also forthcoming . It has also generated an interesting dialog with a number of authors who have drawn to our attention that often there was editorial pressure to reduce the length of the manuscript , and quite often it was the description of the trial methodology that suffered . Where the authors have provided additional information , this has again been included in this report . As indicated in the initial introduction , we have begun to examine the quality of reporting of outcomes especially in the light of an analysis of outcome reporting bias by Chan and Altman ( 3 ) . Their conclusion was “ incomplete reporting of outcomes within published articles of r and omized trials is common and is associated with statistical non significance . The medical literature therefore represents a selective and biased subset of study outcomes , and trial protocol s should be made publicly available . ” Thus , in this second registry of r and omized trials in solid organ transplantation , we have assessed the reporting of a number of items included in the Consoli date d St and ards of Reporting Trials ( CONSORT ) statement ( 4 ) . Several medical journals have endorsed the CONSORT statement , including the New Engl and Journal of Medicine , The Lancet , and JAMA . Furthermore , a number of publications have recommended the use of these guidelines in transplantation trials ( 2 , 5–7 ) Background . C2 monitoring of cyclosporine ( CsA ) has been promoted as improving the results of organ transplantation . No r and omized , controlled studies in de novo kidney transplant recipients are available . Methods . Between June 2003 and August 2004 , 160 consecutive cadaveric kidney recipients allocated to CsA , mycophenolate and steroids were r and omized to either C0 or C2 monitoring of CsA for the first 3 weeks posttransplant . Both levels were measured , keeping the other level blinded until 3 weeks . Altogether , 1451 double measurements were done . The target C0 was 200–300 & mgr;g/L and C2 1500–2000 & mgr;g/L. From the fourth week on , only C0 monitoring was used . Median follow up time was 505 days . Results . The overall 3-month rejection rate was 7.5 % in Group C0 vs. 10.8 % in Group C2 and the one-year graft survival rates were 92.5 % vs. 94.6 % ( NS ) . Rate of delayed graft function was similar in the groups . Plasma creatinine tended to be higher in group C2 at 3 weeks , but not thereafter . During the first three weeks posttransplant , the mean CsA dose was 57 % , mean C2 levels were 55 % , and mean C0 levels were 98 % higher in group C2 than in group C0 ( P<0.00001 ) . Conclusion . This pilot study showed no advantages of C2 monitoring but led to significantly higher CsA doses and blood levels than C0 monitoring Pescovitz , MD , Barbeito , R for the Simulect US01 Study Group . Two‐hour post dose cyclosporin level is a better predictor than trough level of acute rejection of renal allografts . Clin Transplant 2002 : 16 : 378–382 . © Blackwell Munksgaard , BACKGROUND Cyclosporine monitoring using 2-hour post-dose sample s ( C2 ) is thought to be more efficacious than using pre-dose levels ( C0 ) in managing immunosuppression for transplant patients . We evaluated the effect of C2 monitoring on cyclosporine dose and clinical parameters in stable heart transplant patients . METHODS 125 stable heart transplant patients were r and omized to C0 or C2 monitoring of cyclosporine levels for a period of six months . All patients had both C0 and C2 sample s taken , and clinicians were blinded to one of the sample s depending on r and omization . The primary endpoint was the relative change in cyclosporine ( Neoral ) dose during the study period and secondary endpoints were change in creatine clearance , mortality , infection , and acute rejection . RESULTS There was a significant decrease in the cyclosporine dose for the C2 group as compared with the C0 group ( -11 mg/day and -26 mg/day respectively , p = 0.0025 ) . No proven rejection episodes occurred in either group and there was no significant difference in the incidence of infection ( C0 6 , C2 10 ; p = 0.14 ) , the change in renal function ( change in creatine clearance C(0 ) + 0.54 ml/min ; C2 -0.16 ml/min ; p = 0.61 ) , the number of blood tests or dose adjustments between groups over the study period . Analysis of the blinded sample s revealed that the reduction of cyclosporine dose in the C2 group could not be accounted for by reduced immunosuppression . CONCLUSION C2 monitoring allows a significant cyclosporine dose reduction without compromising patient outcome in stable heart transplant patients . Further studies are required to ascertain whether this dose reduction can be translated into clinical benefit BACKGROUND We reported that cyclosporine 2-hr postdose levels ( C2 ) correlate better with the AUC0 - 4 hr than trough levels ( C0 ) in heart transplant patients receiving Neoral . METHODS We compared Neoral dose adjustment with C0 ( group 1 : 100 - 200 ng/ml ) vs. C2 ( group 2 : 700 - 1000 ng/ml ; group 3 : 300 - 600 ng/ml ) in 35 stable adult patients > 1 year after liver transplantation . The AUC0 - 4hr was calculated , and simultaneous blood sample s were obtained to measure calcineurin inhibition . Clinical benefit was defined as the absence of rejection and no increase in serum creatinine at the 7-month follow-up . RESULTS C2 correlated better with the AUC0 - 4 hr than C0 ( r=0.92 vs. r=0.40 ) . Neoral dose increased by 17 % and 39 % in groups 1 and 2 , and decreased by 18 % in group 3 ( P=0.002 vs. group 1 and P=0.0004 vs. group 2 ) . Serum creatinine increased by 2.1 % and 16 % in groups 1 and 2 , and decreased by 5.1 % in group 3 ( P=0.006 vs. group 2 ) . A clinical benefit was observed in 37.5 % , 23 % , and 82 % of patients in groups 1 , 2 , and 3 ( P=0.03 vs. group 1 and P=0.01 vs. group 2 ) . Calcineurin inhibition was similar in all groups at 2-hr ( 44+/-17 % , 39+/-30 % , and 44+/-35 % ) , in spite of different Neoral doses ( 2.9+/-0.9 , 4.0+/-1.8 , and 2.6+/-1.3 mg/kg/day ) and C2 ( 857+/-226 , 922+/-274 , and 588+/-274 ng/ml ) . CONCLUSIONS C2 correlated better with the AUC0 - 4 hr than C0 . Neoral dose monitoring with a C2 range of 300 - 600 ng/ml result ed in a lower dose and greater clinical benefit compared to C0 or a higher C2 in stable liver transplant patients . The correlation between calcineurin inhibition and clinical events deserves further research Neoral dosing is traditionally based on cyclosporine ( CyA ) trough levels ( C(0 ) ) . Four-h area under the curve ( AUC(0 - 4 ) ) for Neoral in the early posttransplantation period was shown previously to have a better correlation to acute rejection ( AR ) and CyA nephrotoxicity ( CyANT ) , compared with C(0 ) . An AUC(0 - 4 ) range of 4400 to 5500 microg/h per L during the first week was associated with the lowest AR and CyANT . This article describes a prospect i ve study to assess the feasibility , safety , and efficacy of dosing Neoral solely by AUC(0 - 4 ) monitoring , regardless of C(0 ) , in the first 3 mo after kidney transplantation . Fifty-nine kidney transplant recipients received Neoral-based triple immunosuppression . AUC(0 - 4 ) was measured on days 3 , 5 , 7 , 10 , and 14 and weeks 3 , 4 , 6 , and 8 , then monthly . Target AUC(0 - 4 ) was 4400 to 5500 microg/h per L. Dose was adjusted by percentage difference from target AUC(0 - 4 ) . Ninety-four percent of AUC were performed on the scheduled day or close to it . No patients had CyANT while AUC(0 - 4 ) was in target range . Four patients had reversible CyANT with AUC(0 - 4 ) > 5500 . Only 1 of 33 patients ( 3 % ) who achieved and maintained AUC(0 - 4 ) > 4400 by day 3 posttransplantation had AR , whereas 10 of 22 ( 45 % ) of those with day 3 to 5 AUC(0 - 4 ) < 4400 had AR ( P : = 0.0002 ) . In logistic regression analysis , higher early AUC(0 - 4 ) was the only significant variable associated with lower serum creatinine at 3 mo . Neoral dose monitoring by AUC(0 - 4 ) is a potentially valuable tool for optimizing Neoral immunosuppression . Attainment of a target range of 4400 to 5500 microg/h per L for AUC(0 - 4 ) early after transplantation has been demonstrated to reduce significantly the risk of AR and CyANT BACKGROUND Clinical ly , cyclosporine ( CSA , Neoral ) is titrated to concentrations , and not to pharmacological effect . METHODS Intracellular interleukin- ( IL ) 2 was measured in phorbol myristic acid-ionomycin-stimulated peripheral lymphocytes by flow cytometry , after isolation from 14 renal transplant recipients receiving CSA+prednisone , and double-blind rapamycin ( rapamycin : placebo=4:1 ) . RESULTS The proportion ( % ) of CD4+IL-2 + lymphocytes corresponding to CSA levels ( mean+/-SD ng/ml ) measured preoperatively ( TO = O ) , and on postoperative day 8 , before ( 356+/-63 ) , and 2 hr after the morning dose ( Cmax=1567+/-669 ) , decreased from 39+/-16 to 15+/-8 and 3+/-1.6 , respectively . Reciprocally , unresponsive lymphocytes ( % CD4+IL-2- ) increased with increasing CSA levels and predicted an EC50 of 249 ng/ml ( CSA concentration at which CD4+IL-2- cells increased by 50 % over baseline ) in an Emax pharmacodynamic model . CONCLUSIONS Clinical ly , the pharmacological effect of CSA is quantifiable , and lies in the upper end of the predicted range . In our Neoral-treated sample population , Cmax was associated with the least variable " cyclosporine effect . " Such information could potentially individualize immunosuppression , and lead to rational dosing strategies BACKGROUND Dosing of the microemulsion formulation of cyclosporine ( Neoral ) is conventionally based on trough levels ( C(0 ) ) . However , experience in renal transplantation has shown that cyclosporine exposure during the absorption phase ( AUC(0 - 4 ) ) is critical for optimizing immunosuppression , and that cyclosporine ( CsA ) concentration at 2 hours post-dose ( C(2 ) ) shows the closest correlation with AUC(0 - 4 ) . This study evaluated whether C(2 ) values correlate more closely with AUC(0 - 4 ) than C(0 ) in lung transplant patients . METHODS Pharmacokinetic data were collected prospect ively from 20 clinical ly stable adult lung allograft recipients receiving CsA , mycophenolate mofetil and steroids . Indications for transplantation were emphysema ( n = 15 ) , idiopathic fibrosis ( n = 2 ) , primary pulmonary hypertension ( n = 1 ) , cystic fibrosis ( n = 1 ) and lymphangioleiomyomatosis LAM ( n = 1 ) . Blood sample s were collected at 0 , 1 , 2 , 3 and 4 hours after administration of CsA , and then AUC(0 - 4 ) was calculated . The Correlation between cyclosporine concentration at each time-point and AUC(0 - 4 ) was also calculated . RESULTS C(2 ) showed the closest correlation with AUC(0 - 4 ) ( r(2 ) = 0.85 ) . C(0 ) had the poorest correlation of all time-points ( r(2 ) = 0.64 ) . Two patients with radiologic signs of gastroparesis had no peak cyclosporine levels at all and were excluded from the correlation analysis . Mean AUC(0 - 4 ) was 3,700 ng . h/ml during Year 1 post-transplant , 2,400 ng . h/ml during Years 1 to 3 , and 1,500 ng . h/ml thereafter . Mean C(2 ) values were 1.2 microg/ml during Year 1 , 0.8 microg/ml during Years 1 to 3 , and 0.5 microg/ml thereafter . CONCLUSIONS C(2 ) is the single time-point that correlates most closely with AUC(0 - 4 ) in lung transplant recipients without gastroparesis . It remains to be demonstrated whether monitoring CsA based on C(2 ) levels results in a lower incidence of rejection without additional toxicity BACKGROUND Evidence suggests that optimal immunosuppressive drug exposure must be achieved early posttransplant to minimize the risk of acute graft rejection . This study was design ed to examine the absorption profile of Neoral during the first 2 weeks after renal transplantation , to develop simple sparse-sampling pharmacokinetic methods to predict exposure , and to explore the target range for optimal clinical immunosuppression under conditions of normal clinical practice . METHODS The prospect i ve multicenter study was conducted in six Canadian renal transplant centers in patients receiving Neoral-based immunosuppression . Full ( 8-point ) pharmacokinetic studies were performed on days 3 , 7 , and 14 posttransplant in a nested subset of patients , and the occurrence and severity of acute rejection , infection or other adverse effects , routine laboratory parameters , and vital signs were assessed on days 3 , 7 , 14 , and 28 . RESULTS A total of 38 adult kidney graft recipients were studied , of whom a nested subset of 16 patients had complete 12-hr pharmacokinetic ( PK ) data on all 3 sampling days . Mean area under the time-concentration curve over the entire 12-hr dosage interval ( AUC[0 - 12 ] ) was 9249+/-3236 microg.hr/L by day 3 and did not change significantly throughout the study , although dose-corrected AUC[0 - 12 ] rose by 20 % from 1924+/-671 microg.hr/L on day 3 to 2316+/-697 microg.hr/L on day 14 ( P=0.067 ) . Mean AUC[0 - 4 ] was 4566+/-1463 microg.hr/L by day 3 and also did not change significantly , although the dose-adjusted AUC[0 - 4 ] rose by 31 % from 952+/-317 microg.hr/L on day 3 to 1250+/-697 microg.hr/L on day 14 ( P=0.009 ) . AUC[0 - 4 ] represented 52 % of the AUC[0 - 12 ] values across the three PK study days and closely predicted this latter value ( R2=0.803 day 3 , R2=0.972 day 14 ) . Cyclosporine ( CsA ) concentration profiles became more uniform throughout the first 14 days posttransplant , with a reduction in Tmax from 2.45 to 1.48 hr ( P<0.005 ) and a significant decrease in coefficient of variation for AUC[0 - 12 ] ( 35 % vs. 21 % , P<0.005 ) and for Tmax ( 47.4 % vs. 33.1 % , P<0.005 ) . Predosage trough level ( C0 ) was a poor predictor of drug exposure , with R2 values less than 0.5 for AUC[0 - 4 ] and 0.7 for AUC[0 - 12 ] at all time points . Sparse sample modeling identified three 3-point sparse-sampling strategies that predicted AUC[0 - 12 ] and AUC[0 - 4 ] with R2 values approaching or exceeding 0.9 on all three study days ; C2 or C3 seemed to be the most important single predictor , with R2 values > 0.80 . Ten of the 36 treated patients ( 27.8 % ) experienced 13 episodes of acute rejection by 28 days posttransplant . Longitudinal logistic regression showed no association between C0 and rejection , but lower AUC[0 - 12 ] values were marginally ( P=0.099 ) and lower AUC[0 - 4 ] values were significantly ( P=0.046 ) associated with increased risk of rejection . CsA exposure on day 7 ( n=29 ) was significantly lower in patients who experienced acute rejection in the second week than in those who were rejection free whether measured by AUC[0 - 12 ] ( 7976+/-1476 vs. 10,239+/-2759 microg.hr/L ; P=0.048 ) , AUC[0 - 4 ] ( 4027+/-412 vs. 5623+/-1389 microg.hr/L ; P<0.0001 ) , C2 ( 1116+/-183 vs. 1852+/-522 microg/L ; P<0.0001 ) , or Cmax ( 1415+/-323 vs. 2084+/-450 microg/L ; P=0.005 ) , and rejection was significantly less common in patients with an AUC[0 - 4 ] > 4,500 microg.hr/L ( 7 % vs. 40 % ; P=0.041 ) or a C2 level>1500 microg/L ( 0 % vs. 58 % ; P<0.001 ) on day 7 ( sensitivity , 100 % ; specificity , 75 % ; positive predictive value , 58 % ; negative predictive value , 100 % ) . There was no evident relationship between CsA exposure and renal toxicity within this patient sample . CONCLUSIONS Absorption of CsA is highly heterogeneous immediately posttransplant , although the pharmacokinetic profile normalizes , interpatient variability decreases , and CsA absorption increases throughout the first 2 weeks permitting a reduction in Neoral dose to achieve constant exposure . Trough ( C0 ) levels do not accurately predict CsA exposure or rejection risk and should be replaced by sparse or single point ( C2 ) sampling methods , which offer a high predictive value to optimize the use of this drug and reduce rejection risk . Acute rejection is significantly more common with low CsA exposure during the first week posttransplant , and levels above the threshold of approximately AUC[0 - 4 ] 4500 microg.hr/L or C2 1500 microg/L are desirable to minimize the risk of rejection To assess the importance of cyclosporine pharmacokinetics on graft outcome and acute rejection episodes , pretransplant and a total of 1868 posttransplant whole‐blood cyclosporine pharmacokinetic profiles were performed in 160 consecutive kidney transplant recipients . The following posttransplant pharmacokinetic risk factors were associated with a poorer graft survival and a higher incidence of acute rejection : F , < 25 % ; clearance , > 325 ml/min ; steady‐state cyclosporine concentrations , < 350 ng/ml during intravenous infusion ; or average cyclosporine concentrations , < 400 ng/ml during the first oral study . Although the discrimination between rejecting and nonrejecting patients was greatest for cyclosporine concentrations obtained at 24 hours after drug administration , measurements at 6 and 14 hours , as well as average concentrations , were all highly predictive . Because of the strong association between the cyclosporine concentrations and outcome , an equation is described to provide initial oral dose prediction . Furthermore , this association suggests that improved cyclosporine pharmacokinetic monitoring may aid in improving outcome after kidney transplantation BACKGROUND Despite two decades of use , there are limited data on the best way to administer and monitor cyclosporine ( CsA ) for liver transplantation . The present study was undertaken ( 1 ) to determine whether treatment with a new formulation of CsA , Neoral , would improve the results of liver transplantation ; and ( 2 ) to study the relationships between pharmacokinetic parameters and clinical outcomes after transplantation . METHODS A double-blind , r and omized , comparison of S and immune ( SIM ) with Neoral ( NEO ) was conducted at five Canadian centers in 188 consecutive adults undergoing primary orthotopic liver transplantation . Patients were induced with intravenous CsA then switched to NEO or SIM . Dose adjustments were made daily , or as needed , to reach a target trough CsA level of 350 ng/ml in both groups . Pharmacokinetic studies were performed on days 5 , 10 , 15 , and 16 weeks after transplantation . RESULTS The NEO group was slightly younger , with a median age of 50 years ( range : 23 - 70 ) versus 55 years ( range : 24 - 71 ) for SIM ( P = 0.007 ) ; otherwise the two groups were well balanced . The NEO group stopped intravenous CsA earlier ( 5.8+/-2.6 days vs. 8.7+/-4.7 days , P<0.0001 ) . This group required a lower median daily oral dose ( 7.5 mg/kg vs. 9.0 mg/kg , P<0.01 ) to maintain comparable trough CsA levels . Five SIM patients , but no NEO patients , discontinued the study due to the inability to reach target trough levels of CsA within the prescribed time ( P<0.05 ) . At 4 months , there were no differences between the two groups with respect to patient survival ( 93 % NEO vs. 91 % SIM ) , graft survival ( 90 % NEO vs. 86 % SIM ) , and rejection-free survival ( 54.1 % NEO , 51.8 % SIM ) . The incidence of serious adverse events was also similar and did not correlate with CsA pharmacokinetic profiles . The NEO group had a higher area under the drug concentration curve for the first 6 hr after the dosing interval ( AUC0 - 6 ) and peak CsA levels ( Cmax ) . There was a strong correlation between freedom from graft rejection during the first month after transplantation and ( a ) AUC0 - 6 and ( b ) Cmax at days 5 and 10 after transplantation , but only in the NEO group did this reach statistical significance . In contrast , there was a poor correlation between trough CsA and graft rejection . In patients on NEO , the concentration of CsA 2 hr after dosing ( C2 ) closely reflected AUC0 - 6 ( r2 = 0.93 ) , whereas there was a poorer correlation in patients on SIM ( r2 = 0.73 ) CONCLUSIONS Cmax and /or AUC0 - 6 may provide better markers than trough levels for monitoring CsA-based immune suppression after orthotopic liver transplantation . Prospect i ve studies are underway to determine whether dosing to C2 , which provides a good estimation of Cmax , can be used to take full advantage of NEO 's improved absorption profile THE INRODUCTION of CsA has been a major advance in transplantation . Subsequently , the development of the new formulation , Neoral microemulsion , has helped to overcome the problems associated with S and immune , including poor bioavailability , dependence on bile for absorption , and need for intravenous administration in the early postoperative period . The use of Neoral has result ed in better absorption and bioavailability , leading to less toxicity and a marked reduction in the incidence of acute cellular rejection . A second major advance has been the introduction of a new tool for monitoring levels of Neoral . Classical monitoring with C0 trough levels ( predose ) has been demonstrated to be inadequate due to high intrapatient and interpatient pharmacokinetic variability and poor correlation with the true drug exposure ( AUC and Cmax ) . In addition , recent review s of studies correlating pharmacokinetics with clinical outcome confirmed that C0 levels did not always correlate with the incidence of acute rejection and toxicity . By contrast , a single blood level measurement , made 2 hours after dosing ( C2 or Cmax ) , has been shown to be a significantly more accurate predictor of drug exposure in liver transplantation recipients . Therefore , C2 level is the best marker of Neoral absorption ( the best surrogate of AUC and Cmax ) , and is currently considered the best way to monitor Neoral cyclosporine levels . However , because sampling of C2 must be performed 2 hours ( 15 minutes ) after intake , the most important problem associated with this method of drug monitoring is implementation in daily clinical practice . The purpose of this study was to evaluate the feasibility , efficacy , and safety of C2 monitoring of Neoral as compared with st and ard C0 levels . Feasibility was assessed in relation to problems with timing of sampling , and implementation in the ICU , ward , and laboratory . Efficacy was evaluated in terms of rate of rejection . The safety profile was compiled based on incidence of renal dysfunction The steady-state pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine ( S and immune Neoral ) were compared with the commercial formulation ( S and immune ) in 55 clinical ly stable renal allograft recipients . In study period I ( 2 weeks ' duration ) , patients entered the study on a stable , individualized twice-daily dosage regimen of the commercial formulation . In period II ( 2 weeks ) , they were changed over to the microemulsion formulation at the same dose as at study entry . In period III ( 2 weeks ) , dose titration was subsequently allowed if necessary to provide comparable steady-state trough concentrations as at study entry . The commercial formulation was reinstituted during period IV ( 2 weeks ) . Safety and tolerability were assessed at weekly clinic visits , and the steady-state pharmacokinetics of cyclosporine in whole blood were characterized at the end of each study period . A milligram-to-milligram dose conversion was adequate when making the initial change between formulations in order to maintain steady-state trough concentrations in the target therapeutic range . Concomitant with this conversion , the steady-state peak concentration and area under the curve increased on average by 69 % and 30 % , respectively , due to absorption-related differences between the formulations . These increases were not associated with an increase in adverse experiences or changes in blood pressure or clinical laboratory parameters over the first four weeks after the change-over . Trough concentrations were more stable and were more strongly correlated with systemic exposure ( area under the curve ) during treatment with the microemulsion formulation . Intraindividual coefficients of variation in steady-state peak concentration , time to attain the peak , area under the curve , and percent peak-trough fluctuation ranged from 18 % to 74 % from the commercial formulation . Variability from the microemulsion formulation was significantly less , ranging from 10 % to 22 % BACKGROUND Cyclosporine 2-hour post-dose ( C2 ) monitoring is predictive of outcomes in solid-organ transplants . The purpose of this study was to determine C2 levels at various time points after heart transplantation and determine whether trough ( C0 ) or C2 better predicts clinical outcomes . METHODS This was a 2-phase prospect i ve study with paired determinations of cyclosporine levels at C0 and C2 in 58 heart transplant patients ( 46 men ; mean age , 56 years ) . Phase I ( 6-month follow-up ) : cyclosporine monitored according to C0 levels ( C2 blinded ) . Phase II ( 6-month follow-up ) : cyclosporine monitored according to C2 levels ( C0 blinded ) . Clinical outcomes assessed were severe infections , rejection score , and renal dysfunction . RESULTS No differences were observed in renal function between the phases . In Phase I , 8 infections ( 4 severe ) and in Phase II , 6 infections ( 2 severe ) were detected . During Phase I , the C0 levels did not correlate ( p = .96 ) with the presence ( 195 + /- 121 ng/ml ) or not ( 197 + /- 100 ng/ml ) of rejection . During Phase II , C0 levels did not correlate ( p = .88 ) with the presence ( 204 + /- 85 ng/ml ) or not ( 209 + /- 138 ng/ml ) of rejection . During Phase I , C2 levels did correlate ( p = 0.022 ) with the presence ( 777 + /- 326 ng/ml ) or not ( 1,015 + /- 422 ng/ml ) of rejection . During Phase II , higher C2 levels showed a significant correlation ( p = 0.03 ) with no rejection ( 967 + /- 470 ng/ml vs 765 + /- 297 ng/ml , no rejection vs rejection , respectively ) . CONCLUSION High C2 levels were associated with less episodes of acute cellular rejection in patients post-heart transplantation . Monitoring with C2 levels is feasible and safe in terms of preservation of renal function and infection rates Sequential cyclosporine pharmacokinetic assessment s were performed at four centres within the context of a double-blind , multicenter clinical trial comparing the safety and tolerability of the conventional formulation with cyclosporine for microemulsion in de novo renal transplant patients . The initial average daily oral dose was 9.3 mg/kg given in two divided doses every 12 hr with subsequent dose reductions individually titrated to maintain trough concentrations within the target therapeutic range . Pharmacokinetic profiles were assessed at week 2 , once between weeks 4 - 6 , and at week 12 in 12 patients on the conventional formulation and 9 patients on the microemulsion . Over the study duration , cyclosporine daily doses were comparable in both study arms and were reduced in parallel from 9.2 to 6.9 to 4.7 mg/kg/day at the three successive pharmacokinetic visits . Dose-normalized peak and area-under-the-curve ( AUC ) increased between the week 2 and week 4 - 6 assessment s for both formulations . Thereafter , these parameters continued to increase for the conventional formulation but exhibited a high degree of within-in patient stability for the microemulsion between week 4 - 6 and week 12 . Between-formulation comparisons indicated that the rate and extent of cyclosporine absorption from the microemulsion were significantly higher over the study duration . Specifically , at week 2 , 4 - 6 and 12 , dose-normalized AUC was 49 % , 63 % , and 32 % higher for the microemulsion . Intrasubject coefficients of variability for pharmacokinetic parameters of the conventional formulation ranged from 26.3 % to 68.2 % . Corresponding values for the microemulsion were reduced by approximately half , ranging from 13.1 % to 38.7 % . The correlation between predose trough concentration and AUC was stronger for the microemulsion ( r(2)0.819 vs. 0.635 ) over the full range of systemic exposures attained throughout the study . These results provide initial evidence that , as doses are reduced with time posttransplant , the cyclosporine dose-exposure relationship from the microemulsion may stabilize earlier than that from the conventional formulation , allowing increased pharmacokinetic control over cyclosporine use in this critical posttransplant period OBJECTIVE To evaluate the safety and reliability of cyclosporine microemulsion ( CsA-ME ) C(2 ) monitoring and to determine the target level of C(2 ) in Chinese adult liver transplant recipients . METHODS 53 Chinese adult liver transplant recipients were r and omly divided into three groups ( group C(0 ) , n = 17 ; group high level C(2 ) , n = 18 ; group low level C(2 ) , n = 18 ) . Blood chemistry reflecting heart , liver and renal function and CsA level were examined at certain interval during follow-up . The change of immune status and episodes of rejection were also observed closely . RESULTS The group low level C(2 ) had the lowest CsA oral dose ( 2.51 + /- 0.37 mg/kg/d ) , and had significant difference compared with the other groups ( P < 0.01 ) . The best liver , heart and renal function was observed in group low level C(2 ) . The CD(4)(+)/CD(8)(+ ) ratio of group low level C(2 ) was 1.04 + /- 0.68 , which had no significant difference with C(0 ) group . The rejection incidence of the three groups had no significant difference . group low level C(2 ) had highest clinical benefit ratio ( 72.22 % ) , while the clinical benefit of group high level C(2 ) is the lowest ( 11.11 % ) . CONCLUSIONS With rational target level , C(2 ) monitoring can show us the proper oral dose of CsA which can decrease the side effects remarkably without rejection episodes increasing . The target level of C(2 ) in Chinese adult liver transplant recipients might be : 600 - 800 ng/ml 1 to 6 months posttransplant , 400 - 600 ng/ml 7 - 12 months posttransplant Background . The role and burden of cyclosporine ( CsA ) nephrotoxicity in long-term progressive kidney graft dysfunction is poorly documented . Methods . The authors evaluated 888 prospect i ve protocol kidney biopsy specimens from 99 patients taken regularly until 10 years after transplantation for evidence of CsA nephrotoxicity . Results . The most sensitive histologic marker of CsA nephrotoxicity was arteriolar hyalinosis , predicted by CsA dose and functional CsA nephrotoxicity . Striped fibrosis was associated with early initiation of CsA and the need for posttransplant dialysis ( both P<0.05 ) . The 10-year cumulative Kaplan-Meier prevalence of arteriolar hyalinosis , striped fibrosis , and tubular microcalcification was 100 % , 88.0 % , and 79.2 % of kidneys , respectively . Beyond 1 year , 53.9 % had two or more lesions of CsA nephrotoxicity . Structural CsA nephrotoxicity occurred in two phases , with different clinical and histologic characteristics . The acute phase occurred with a median onset 6 months after transplantation , was usually reversible , and was associated with functional CsA nephrotoxicity ( P<0.05 ) , high CsA levels ( P<0.05 ) , and mild arteriolar hyalinosis ( P<0.001 ) . The chronic phase of CsA nephrotoxicity persisted over several biopsies , occurred at a median onset of 3 years , and was associated with lower CsA doses and trough levels ( both P<0.05 ) . It was largely irreversible and accompanied by severe arteriolar hyalinosis and progressive glomerulosclerosis ( both P<0.001 ) . A threshold CsA dose of 5 mg/kg/day predicted worsening of arteriolar hyalinosis on sequential histology . Conclusions . Pathologic changes of CsA nephrotoxicity were virtually universal by 10 years and exacerbated chronic allograft nephropathy . CsA is unsuitable as a universal , long-term immunosuppressive agent for kidney transplantation . Strategies to ameliorate or avoid nephrotoxicity are thus urgently needed To assess the safety profile of Neoral dose adjustment using cyclosporine ( CsA ) trough levels ( C0 ) compared with levels obtained 2 h after the morning dose ( C2 ) , 30 stable adult heart transplant patients 1 yr or more after surgery were converted from S and immune to Neoral . After a baseline visit ( before conversion ) , initial follow-up included two visits ( 2 and 4 - 6 wk after conversion ) . After the first visit , patients were r and omized to Group I ( C0 : 100 - 200 ng/ml ) or Group II ( C2 : 200 - 400 ng/ml ) . Abbreviated pharmacokinetics were obtained for the estimation of the AUC0 - 4 h. Renal function was assessed by serum creatinine and the cimetidine-modified creatinine clearance . C2 correlated better than C0 with the AUC0 - 4 h ( r = 0.91 vs. 0.63 ) . Initial Neoral dose ( mg/kg/d ) was similar in both groups ( 2.8 + /- 0.5 and 2.8 + /- 0.8 ) , and was lower in Group II at the second visit ( 2.0 + /- 0.7 vs. 3.0 + /- 0.6 , p = 0.0001 ) . C2 levels decreased in Group II from 912 + /- 438 to 555 + /- 271 ng/ml ( p = 0.01 ) , without evidence of acute rejection on endomyocardial biopsies . After the second visit,-both groups were monitored with C2 , and the range was increased to 300 - 600 ng/ml . At the last visit ( additional follow-up of 5 + /- 1 months ) , Neoral dose ( mg/kg/d ) was reduced to 2.0 + /- 0.3 in Group I ( p < 0.001 ) and 1.8 + /- 0.4 in Group II . Serum creatinine was lower in Group II at the second visit ( 138 + /- 59 vs. 168 + /- 37 mumol/L , p = 0.01 ) and was similar in both groups at the last visit . Neoral dose reduction based on C2 levels was not associated with acute rejection . The better correlation with the AUC0 - 4 h suggests that C2 may be more reliable than C0 for Neoral dose adjustment BACKGROUND Monitoring immunosuppression with cyclosporine microemulsion formulation ( CsA-MEF ) by using 2-hour CsA blood levels ( C2 ) has been strongly recommended after kidney transplantation . The aim of our study was to evaluate the impact of C2 monitoring on the clinical outcome early after transplantation in a single-center setting . METHODS Nonsensitized , consecutive , de novo cadaveric kidney-transplant recipients were treated with CsA-MEF , mycophenolate mofetil , and steroids . Patients receiving transplants after January 2002 ( n=89 ) were prospect ively monitored by C2 levels ( target : 1,500+/-200 ng/mL [ fluorescence-polarization immunoassay ] ) . They were retrospectively compared with the patients receiving transplants during 2001 ( n=88 ) who had been monitored by C0 levels ( target : 250+/-50 ng/mL ) . RESULTS In the intention-to-treat analysis , 40 ( 45.4 % ) patients in the C0 group and 25 ( 28.1 % ) patients in the C2 group received treatment for rejection ( P=0.017 ) . The incidence of histologically verified rejection of Banff grade I or higher was 20.45 % in the C0 group and 13.48 % in the C2 group ( P=0.235 ) . In the per- protocol analysis , incidence of treated rejection was 24.7 % , and incidence of histologically verified rejection of Banff grade I or higher was 12.35 % in the C2 group ( P=0.004 and 0.160 , respectively , vs. C0 ) . Mean CsA-MEF doses were 1.7 to 2 times higher in the C2 group than in the C0 group throughout follow-up ( P=0.019 ) . In the C2 group , target C2 levels were achieved on average 4 days after transplantation , and there was no significant difference in C2 levels between patients who rejected and patients who did not reject . CONCLUSION Kidney-transplant recipients monitored by C2 levels receive significantly higher doses of CsA-MEF and have a lower incidence of early acute allograft rejection than patients monitored by C0 levels . In C2 monitored patients , C2 levels are not predictive for the incidence of early allograft rejection Background . Targeting 2-hr postdose cyclosporine ( C2 ) levels to 1,000 to 1,700 mg/dL during the first 6 months after renal transplantation is recommended for triple immunosuppressive regimens . This trial determines whether lower C2 levels could be targeted safely in de novo kidney transplant recipients under a quadruple regimen compared with a similar cohort monitored with trough ( C0 ) levels . Methods . This single-center , sequential , cohort- design ed trial included patients who received Thymoglobulin , corticosteroids , an antimetabolite , and cyclosporine monitored by C2 ( n=50 ) or C0 ( n=50 ) . Cyclosporine was tapered to maintain the C2 between 1,000 and 1,200 ng/mL months 0 to 3 and between 600 and 1,000 ng/mL thereafter and C0 between 250 and 350 ng/mL months 0 to 3 and between 100 and 250 ng/mL thereafter . Results . Baseline patient and donor characteristics were similar . There were no differences in graft survival ( 100 % C2 vs. 100 % C0 ) , acute rejection ( 4 % C2 vs. 6 % C0 ) , allograft function , or adverse events at 6 months . C2 levels were lower than the suggested guidelines throughout the study ( 33 % lower at 1 month and 48 % lower at 6 months ) . Lower cyclosporine doses were achieved in the C2 arm compared with the C0 arm by 1 month and were sustained throughout the trial , which translated into an average cyclosporine cost savings of $ 773 in the C2 arm during the 6-month period ( P<0.001 ) . Conclusion . With a quadruple immunosuppressive regimen and lower C2 targets than recommended for triple therapy , safe and effective cyclosporine minimization was achieved . Lower cyclosporine doses were achieved in C2-monitored patients compared with C0-monitored patients , translating into lower immunosuppressive costs Cyclosporine therapeutic drug monitoring based on 2-hour postdose concentration ( C2 ) compared with conventional trough concentration ( C0 ) can improve clinical outcomes for de novo renal and liver transplant patients . However , in heart transplant patients , published studies are limited . To determine the clinical significance of C2 compared with C0 following orthotopic heart transplantation , the authors measured CsA at C0 and C2 and estimated CsA area under the curve ( AUC ) using Bayesian estimation and 4 sparse sample algorithms in a cross section of 31 adult patients receiving triple-drug immunosuppression with CsA , mycophenolate mofetil ( MMF ) , and prednisone . CsA was measured using a vali date d HPLC method . Endomyocardial biopsies were grade d based on the ISHLT system . Mean ± SD values for CsA dose , C0 , and C2 were 4.8 ± 1.4 mg/kg/d , 240 ± 62 μg/L , and 1319 ± 469 μg/L , respectively . Correlation with AUC , using different estimation algorithms , was better for C2 ( r2 = 0.79 - 0.99 ) than for C0 ( r2 = 0.11 - 0.52 ) . The mean ± SD values for C0 ( μg/L ) and C2 ( μg/L ) for rejectors ( n = 3 ) were 215 ± 68 and 949 ± 204 versus 242 ± 62 and 1359 ± 474 for the nonrejectors ( P = 0.66 and 0.12 , respectively ) . Fisher exact test P values using the median as threshold value for C0 and C2 ( 234 μg/L and 1251 μg/L , respectively ) were 0.6 and 0.1 . Analysis of the data revealed that C0 values in rejectors have wider variability than C2 . There were no rejectors among the 16 patients exceeding the C2 median value ; for C0 , however , there was not an easily identifiable threshold value . There is a trend for a significant relationship between C2 and the incidence of rejection , but the number of rejectors was too small to reach statistical significance . A prospect i ve concentration-control de novo study design is recommended as the most appropriate way to fully evaluate the potential utility of C2 monitoring in heart transplant patients |
13,635 | 24,028,709 | The use of mTOR inhibitors is associated with a significant increase in the risk of developing all- grade and high- grade anemia and thrombocytopenia compared with placebo/control arms | BACKGROUND Mammalian target of rapamycin ( mTOR ) inhibitors , temsirolimus and everolimus , are currently approved for the treatment of several malignancies .
Hematological toxicities have been reported with these drugs , but overall incidence and relative risk remains undefined .
We perform an up-to- date meta- analysis to determine the incidence and risk of hematologic toxicities associated with mTOR inhibitors . | Purpose : Loss of PTEN , which is common in glioblastoma multiforme ( GBM ) , results in activation of the mammalian target of rapapmycin ( mTOR ) , thereby increasing mRNA translation of a number of key proteins required for cell-cycle progression . CCI-779 is an inhibitor of mTOR . The primary objectives of this study were to determine the efficacy of CCI-779 in patients with recurrent GBM and to further assess the toxicity of the drug . Experimental Design : CCI-779 was administered weekly at a dose of 250 mg intravenously for patients on enzyme-inducing anti-epileptic drugs ( EIAEDs ) . Patients not on EIAEDs were initially treated at 250 mg ; however , the dose was reduced to 170 mg because of intolerable side effects . Treatment was continued until unacceptable toxicity , tumor progression , or patient withdrawal . The primary endpoint was 6-month progression-free survival . Results : Forty-three patients were enrolled ; 29 were not on EIAEDs . The expected toxicity profile of increased lipids , lymphopenia , and stomatitis was seen . There were no grade IV hematological toxicities and no toxic deaths . One patient was progression free at 6 months . Of the patients assessable for response , there were 2 partial responses and 20 with stabilization of disease . The median time to progression was 9 weeks . Conclusions : CCI-779 was well tolerated at this dose schedule ; however , there was no evidence of efficacy in patients with recurrent GBM . Despite initial disease stabilization in approximately 50 % of patients , the durability of response was short . Because of the low toxicity profile , CCI-779 may merit exploration in combination with other modalities St and ard cytotoxic treatments for neuroendocrine tumours have been associated with limited activity and remarkable toxicity . A phase II study was design ed to evaluate the efficacy , safety and pharmacodynamics of temsirolimus in patients with advanced neuroendocrine carcinoma ( NEC ) . Thirty-seven patients with advanced progressive NEC received intravenous weekly doses of 25 mg of temsirolimus . Patients were evaluated for tumour response , time to progression ( TTP ) , overall survival ( OS ) and adverse events ( AE ) . Twenty-two archival specimens , as well as 13 paired tumour biopsies obtained pretreatment and after 2 weeks of temsirolimus were assessed for potential predictive and correlative markers . The intent-to-treat response rate was 5.6 % ( 95 % CI 0.6–18.7 % ) , median TTP 6 months and 1-year OS rate 71.5 % . The most frequent drug-related AE of all grade s as percentage of patients were : fatigue ( 78 % ) , hyperglycaemia ( 69 % ) and rash/desquamation ( 64 % ) . Temsirolimus effectively inhibited the phosphorylation of S6 ( P=0.02 ) . Higher baseline levels of pmTOR ( phosphorylated mammalian target of rapamycin ) ( P=0.01 ) predicted for a better response . Increases in pAKT ( P=0.041 ) and decreases in pmTOR ( P=0.048 ) after treatment were associated with an increased TTP . Temsirolimus appears to have little activity and does not warrant further single-agent evaluation in advanced NEC . Pharmacodynamic analysis revealed effective mTOR pathway downregulation Hypothesis : To study the progression-free survival ( PFS ) and toxicity with 25- or 250-mg doses of temsirolimus ( CCI-779 ) after induction chemotherapy in patients with extensive small-cell lung cancer . Methods : Patients with either stable or responding disease to four to six cycles of cisplatin or carboplatin plus etoposide or irinotecan were r and omized between 4 and 8 weeks after completion of induction therapy to receive either 25 or 250 mg of temsirolimus intravenously every week until disease progression . Results : Eighty-seven patients entered between January 2002 and December 2003 , of whom 85 were eligible : 44 received 25 mg ( arm A ) , and 41 received 250 mg ( arm B ) . The overall median follow-up time for all eligible patients was 34.6 months . Median age was 59 years ( range , 39–80 ) ; 42 ( 49.4 % ) were male and 43 ( 50.6 % ) female ; 12.9 % had brain metastases . The overall median and 1-year PFS were 2.2 months ( 95 % confidence interval [ CI ] : 1.8 , 2.9 ) and 4.7 % ( 95 % CI : 0.2 % , 9.2 % ) , respectively . The median PFS ( 95 % CI ) for arm A was 1.9 months ( 1.6 , 2.3 ) ; for arm B , it was 2.5 months ( 1.9 , 3.4 ; p = 0.24 ) . The median overall survival from r and omization was 8 months ( 95 % CI : 6.5 , 9.5 ) . Among the 86 patients with reported toxicities , 36 ( 42 % ) had grade 3 toxicities , the most common of which were thrombocytopenia , hypophosphatemia , and fatigue , and an additional 12 ( 14 % ) had grade 4 toxicities , the most common of which was neutropenia . No patients experienced lethal toxicities . Conclusion : Temsirolimus ( CCI 779 ) , given at 25 or 250 mg weekly , seemed not to increase the PFS in this patient population PURPOSE Cross-talk between the estrogen receptor ( ER ) and the phosphoinositide-3-kinase (PI3K)/Akt/mammalian target of rapamycin ( mTOR ) pathways is a mechanism of resistance to endocrine therapy , and blockade of both pathways enhances antitumor activity in pre clinical models . This study explored whether sensitivity to letrozole was enhanced with the oral mTOR inhibitor , everolimus ( RAD001 ) . PATIENTS AND METHODS Two hundred seventy postmenopausal women with operable ER-positive breast cancer were r and omly assigned to receive 4 months of neoadjuvant treatment with letrozole ( 2.5 mg/day ) and either everolimus ( 10 mg/day ) or placebo . The primary end point was clinical response by palpation . M and atory biopsies were obtained at baseline and after 2 weeks of treatment ( ie , day 15 ) . Sample s were assessed for PI3 K mutation status ( PIK3CA ) and for pharmacodynamic changes of Ki67 , phospho-S6 , cyclin D1 , and progesterone receptor ( PgR ) by immunohistochemistry . RESULTS Response rate by clinical palpation in the everolimus arm was higher than that with letrozole alone ( ie , placebo ; 68.1 % v 59.1 % ) , which was statistically significant at the preplanned , one-sided , alpha = 0.1 level ( P = .062 ) . Marked reductions in progesterone receptor and cyclin D1 expression occurred in both treatment arms , and dramatic downregulation of phospho-S6 occurred only in the everolimus arm . An antiproliferative response , as defined by a reduction in Ki67 expression to natural logarithm of percentage positive Ki67 of less than 1 at day 15 , occurred in 52 ( 57 % ) of 91 patients in the everolimus arm and in 25 ( 30 % ) of 82 patients in the placebo arm ( P < .01 ) . The safety profile was consistent with historical results of everolimus monotherapy ; grade s 3 to 4 adverse events occurred in 22.6 % of patients who received everolimus and in 3.8 % of patients who received placebo . CONCLUSION Everolimus significantly increased letrozole efficacy in neoadjuvant therapy of patients with ER-positive breast cancer BACKGROUND Everolimus ( RAD001 ) is an orally administered inhibitor of the mammalian target of rapamycin ( mTOR ) , a therapeutic target for metastatic renal cell carcinoma . We did a phase III , r and omised , double-blind , placebo-controlled trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular endothelial growth factor-targeted therapy . METHODS Patients with metastatic renal cell carcinoma which had progressed on sunitinib , sorafenib , or both , were r and omly assigned in a two to one ratio to receive everolimus 10 mg once daily ( n=272 ) or placebo ( n=138 ) , in conjunction with best supportive care . R and omisation was done central ly via an interactive voice response system using a vali date d computer system , and was stratified by Memorial Sloan-Kettering Cancer Center prognostic score and previous anticancer therapy , with a permuted block size of six . The primary endpoint was progression-free survival , assessed via a blinded , independent central review . The study was design ed to be terminated after 290 events of progression . Analysis was by intention to treat . This study is registered with Clinical Trials.gov , number NCT00410124 . FINDINGS All r and omised patients were included in efficacy analyses . The results of the second interim analysis indicated a significant difference in efficacy between arms and the trial was thus halted early after 191 progression events had been observed ( 101 [ 37 % ] events in the everolimus group , 90 [ 65 % ] in the placebo group ; hazard ratio 0.30 , 95 % CI 0.22 - 0.40 , p<0.0001 ; median progression-free survival 4.0 [ 95 % CI 3.7 - 5.5 ] vs 1.9 [ 1.8 - 1.9 ] months ) . Stomatitis ( 107 [ 40 % ] patients in the everolimus group vs 11 [ 8 % ] in the placebo group ) , rash ( 66 [ 25 % ] vs six [ 4 % ] ) , and fatigue ( 53 [ 20 % ] vs 22 [ 16 % ] ) were the most commonly reported adverse events , but were mostly mild or moderate in severity . Pneumonitis ( any grade ) was detected in 22 ( 8 % ) patients in the everolimus group , of whom eight had pneumonitis of grade 3 severity . INTERPRETATION Treatment with everolimus prolongs progression-free survival relative to placebo in patients with metastatic renal cell carcinoma that had progressed on other targeted therapies BACKGROUND Interferon alfa is widely used for metastatic renal-cell carcinoma but has limited efficacy and tolerability . Temsirolimus , a specific inhibitor of the mammalian target of rapamycin kinase , may benefit patients with this disease . METHODS In this multicenter , phase 3 trial , we r and omly assigned 626 patients with previously untreated , poor-prognosis metastatic renal-cell carcinoma to receive 25 mg of intravenous temsirolimus weekly , 3 million U of interferon alfa ( with an increase to 18 million U ) subcutaneously three times weekly , or combination therapy with 15 mg of temsirolimus weekly plus 6 million U of interferon alfa three times weekly . The primary end point was overall survival in comparisons of the temsirolimus group and the combination-therapy group with the interferon group . RESULTS Patients who received temsirolimus alone had longer overall survival ( hazard ratio for death , 0.73 ; 95 % confidence interval [ CI ] , 0.58 to 0.92 ; P=0.008 ) and progression-free survival ( P<0.001 ) than did patients who received interferon alone . Overall survival in the combination-therapy group did not differ significantly from that in the interferon group ( hazard ratio , 0.96 ; 95 % CI , 0.76 to 1.20 ; P=0.70 ) . Median overall survival times in the interferon group , the temsirolimus group , and the combination-therapy group were 7.3 , 10.9 , and 8.4 months , respectively . Rash , peripheral edema , hyperglycemia , and hyperlipidemia were more common in the temsirolimus group , whereas asthenia was more common in the interferon group . There were fewer patients with serious adverse events in the temsirolimus group than in the interferon group ( P=0.02 ) . CONCLUSIONS As compared with interferon alfa , temsirolimus improved overall survival among patients with metastatic renal-cell carcinoma and a poor prognosis . The addition of temsirolimus to interferon did not improve survival . ( Clinical Trials.gov number , NCT00065468 [ Clinical Trials.gov ] . ) The primary goal of this trial was to evaluate the confirmed response rate of temsirolimus ( CCI‐779 ) , a mammalian target of rapamycin in patients with advanced soft tissue sarcomas ( STS ) PURPOSE To evaluate the efficacy , safety , and pharmacokinetics of multiple doses of CCI-779 , a novel mammalian target of rapamycin kinase inhibitor , in patients with advanced refractory renal cell carcinoma ( RCC ) . PATIENTS AND METHODS Patients ( n = 111 ) were r and omly assigned to receive 25 , 75 , or 250 mg CCI-779 weekly as a 30-minute intravenous infusion . Patients were evaluated for tumor response , time to tumor progression , survival , and adverse events . Blood sample s were collected to determine CCI-779 pharmacokinetics . RESULTS CCI-779 produced an objective response rate of 7 % ( one complete response and seven partial responses ) and minor responses in 26 % of these advanced RCC patients . Median time to tumor progression was 5.8 months and median survival was 15.0 months . The most frequently occurring CCI-779-related adverse events of all grade s were maculopapular rash ( 76 % ) , mucositis ( 70 % ) , asthenia ( 50 % ) , and nausea ( 43 % ) . The most frequently occurring grade 3 or 4 adverse events were hyperglycemia ( 17 % ) , hypophosphatemia ( 13 % ) , anemia ( 9 % ) , and hypertriglyceridemia ( 6 % ) . Neither toxicity nor efficacy was significantly influenced by CCI-779 dose level . Patients were retrospectively classified into good- , intermediate- , or poor-risk groups on the basis of criteria used by Motzer et al for a first-line metastatic RCC population treated with interferon alfa . Within each risk group , the median survivals of patients at each dose level were similar . CONCLUSION In patients with advanced RCC , CCI-779 showed antitumor activity and encouraging survival and was generally well tolerated over the three dose levels tested BACKGROUND Angiomyolipomas are slow-growing tumours associated with constitutive activation of mammalian target of rapamycin ( mTOR ) , and are common in patients with tuberous sclerosis complex and sporadic lymphangioleiomyomatosis . The insidious growth of these tumours predisposes patients to serious complications including retroperitoneal haemorrhage and impaired renal function . Everolimus , a rapamycin derivative , inhibits the mTOR pathway by acting on the mTOR complex 1 . We compared the angiomyolipoma response rate on everolimus with placebo in patients with tuberous sclerosis or sporadic lymphanioleiomyomatosis-associated angiomyolipomata . METHODS In this double-blind , placebo-controlled , phase 3 trial , patients aged 18 years or older with at least one angiomyolipoma 3 cm or larger in its longest diameter ( defined by radiological assessment ) and a definite diagnosis of tuberous sclerosis or sporadic lymphangioleiomyomatosis were r and omly assigned , in a 2:1 fashion with the use of an interactive web response system , to receive oral everolimus 10 mg per day or placebo . The primary efficacy endpoint was the proportion of patients with confirmed angiomyolipoma response of at least a 50 % reduction in total volume of target angiomyolipomas relative to baseline . This study is registered with Clinical Trials.gov number NCT00790400 . RESULTS 118 patients ( median age 31·0 years ; IQR 18·0–61·0 ) from 24 centres in 11 countries were r and omly assigned to receive everolimus ( n=79 ) or placebo ( n=39 ) . At the data cutoff , double-blind treatment was ongoing for 98 patients ; two main reasons for discontination were disease progression ( nine placebo patients ) followed by adverse events ( two everolimus patients ; four placebo patients ) . The angiomyolipoma response rate was 42 % ( 33 of 79 [ 95 % CI 31–53 % ] ) for everolimus and 0 % ( 0 of 39 [ 0–9 % ] ) for placebo ( response rate difference 42 % [ 24–58 % ] ; one-sided Cochran-Mantel-Haenszel test p<0·0001 ) . The most common adverse events in the everolimus and placebo groups were stomatitis ( 48 % [ 38 of 79 ] , 8 % [ 3 of 39 ] , respectively ) , nasopharyngitis ( 24 % [ 19 of 79 ] and 31 % [ 12 of 39 ] ) , and acne-like skin lesions ( 22 % [ 17 of 79 ] and 5 % [ 2 of 39 ] ) . INTERPRETATION Everolimus reduced angiomyolipoma volume with an acceptable safety profile , suggesting it could be a potential treatment for angiomyolipomas associated with tuberous sclerosis . FUNDING Novartis Pharmaceuticals Dysregulation of phosphatase and tensin homolog ( PTEN ) and the gene that encodes the p110α catalytic subunit of phosphatidylinositol‐3‐kinase ( PI3 K ) , PIK3CA , are the most common mutations in endometrial carcinoma ( EC ) . Loss of PTEN or activation of PIK3CA results in constitutive activation of AKT , which leads to up‐regulation of mammalian target of rapamycin ( mTOR ) . Everolimus is an oral rapamycin analog that acts by selectively inhibiting mTOR OBJECTIVE Temsirolimus , an inhibitor of the mammalian target of rapamycin , is approved for treatment of patients with advanced renal cell carcinoma in the USA and Europe . Temsirolimus was not yet evaluated in East Asian patients . METHODS This non-r and omized Phase II study enrolled 82 patients with advanced renal cell carcinoma [ 20 ( 24 % ) Japanese , 30 ( 37 % ) Korean and 32 ( 39 % ) Chinese patients ; median age ( range ) : 55 ( 26 - 83 ) years ] . Most ( 71 % ) received prior systemic therapy for metastatic disease ; two-thirds were intermediate risk . Six Japanese patients received intravenous temsirolimus 20 mg/m(2 ) weekly for tolerability assessment ( Group A ) ; the remaining 76 received a 25 mg flat dose weekly ( Group B ) . Temsirolimus was dosed once weekly . Primary efficacy end point was the Response Evaluation Criteria in Solid Tumors-defined clinical benefit rate in the intent-to-treat population . RESULTS In the entire population , regardless of treatment group , the clinical benefit rate was 48 % ( 95 % confidence interval : 36 , 59 ) . Objective response rate was 11 % ( 95 % confidence interval : 5 , 20 ) , median progression-free survival was 7.3 months ( 95 % confidence interval : 4.0 , 9.2 ) and median time to treatment failure was 5.4 months ( 95 % confidence interval : 3.5 , 7.4 ) . No patient in Group A demonstrated dose-limiting toxicity . The most frequent Grade 3 or 4 drug-related adverse events were anemia , hyperglycemia , hypophosphatemia and stomatitis ( 5 % each ) . Serious adverse events reported in ≥ 5 % of patients were pneumonia ( 9 % ) and interstitial lung disease ( 7 % ) . Temsirolimus and its major metabolite , sirolimus , were long-lived throughout the dosage interval , with no evidence of accumulation . CONCLUSION Temsirolimus was well tolerated and showed promising activity in Japanese , Korean and Chinese patients with advanced renal cell carcinoma Purpose : Mammalian target of rapamycin ( mTOR ) is a promising target in small cell lung cancer ( SCLC ) . We design ed a phase II study of everolimus , an mTOR inhibitor , in previously treated , relapsed SCLC . Experimental Design : Patients were treated with everolimus 10 mg orally daily until disease progression . The primary endpoint was disease control rate ( DCR ) at 6 weeks . PI3K/Akt signaling pathway biomarkers were evaluated on baseline tumor tissue . Results : A total of 40 patients were treated : 23 had 1 prior regimen/sensitive relapse , 4 had 1 prior regimen/refractory , and 13 had 2 prior regimens . Twenty-eight patients received 2 or more cycles of everolimus , 7 received 1 cycle , and 5 did not complete the first cycle . Best response in 35 evaluable patients : 1 ( 3 % ) partial response ( in sensitive relapse ) , 8 ( 23 % ) stable disease , and 26 ( 74 % ) progression ; DCR at 6 weeks was 26 % ( 95 % CI = 11–40 ) . Median survival was 6.7 months and median time to progression was 1.3 months . Grade 3 toxicities included thrombocytopenia ( n = 2 ) , neutropenia ( n = 2 ) , infection ( n = 2 ) , pneumonitis ( n = 1 ) , fatigue ( n = 1 ) , elevated transaminases ( n = 1 ) , diarrhea ( n = 2 ) , and acute renal failure ( n = 1 ) . High phosphorylated AKT expression was modestly associated with overall survival ( HR = 2.07 ; 95 % CI = 0.97–4.43 ) . Baseline S6 kinase protein expression was significantly higher in patients with disease control versus patients with progression ( P = 0.0093 ) . Conclusions : Everolimus was well tolerated but had limited single-agent antitumor activity in unselected previously treated patients with relapsed SCLC . Further evaluation in combination regimens for patients with sensitive relapse may be considered . Clin Cancer Res ; 16(23 ) ; 5900–7 . © 2010 AACR Long-term beta blockade for perhaps a year or so following discharge after an MI is now of proven value , and for many such patients mortality reductions of about 25 % can be achieved . No important differences are clearly apparent among the benefits of different beta blockers , although some are more convenient than others ( or have slightly fewer side effects ) , and it appears that those with appreciable intrinsic sympathomimetic activity may confer less benefit . If monitored , the side effects of long-term therapy are not a major problem , as when they occur they are easily reversible by changing the beta blocker or by discontinuation of treatment . By contrast , although very early IV short-term beta blockade can definitely limit infa rct size , more reliable information about the effects of such treatment on mortality will not be available until a large trial ( ISIS ) reports later this year , with data on some thous and s of patients entered within less than 4 hours of the onset of pain . Our aim has been not only to review the 65-odd r and omized beta blocker trials but also to demonstrate that when many r and omized trials have all applied one general approach to treatment , it is often not appropriate to base inference on individual trial results . Although there will usually be important differences from one trial to another ( in eligibility , treatment , end-point assessment , and so on ) , physicians who wish to decide whether to adopt a particular treatment policy should try to make their decision in the light of an overview of all these related r and omized trials and not just a few particular trial results . Although most trials are too small to be individually reliable , this defect of size may be rectified by an overview of many trials , as long as appropriate statistical methods are used . Fortunately , robust statistical methods exist -- based on direct , unweighted summation of one O-E value from each trial -- that are simple for physicians to use and underst and yet provide full statistical sensitivity . These methods allow combination of information from different trials while avoiding the unjustified direct comparison of patients in one trial with patients in another . ( Moreover , they can be extended of such data that there is no real need for the introduction of any more complex statistical methods that might be more difficult for physicians to trust . ) Their robustness , sensitivity , and avoidance of unnecessary complexity make these particular methods an important tool in trial overviews PURPOSE Temsirolimus , a specific inhibitor of the mammalian target of rapamycin kinase , has shown clinical activity in mantle cell lymphoma ( MCL ) . We evaluated two dose regimens of temsirolimus in comparison with investigator 's choice single-agent therapy in relapsed or refractory disease . PATIENTS AND METHODS In this multicenter , open-label , phase III study , 162 patients with relapsed or refractory MCL were r and omly assigned ( 1:1:1 ) to receive one of two temsirolimus regimens : 175 mg weekly for 3 weeks followed by either 75 mg ( 175/75-mg ) or 25 mg ( 175/25-mg ) weekly , or investigator 's choice therapy from prospect ively approved options . The primary end point was progression-free survival ( PFS ) by independent assessment . RESULTS Median PFS was 4.8 , 3.4 , and 1.9 months for the temsirolimus 175/75-mg , 175/25-mg , and investigator 's choice groups , respectively . Patients treated with temsirolimus 175/75-mg had significantly longer PFS than those treated with investigator 's choice therapy ( P = .0009 ; hazard ratio = 0.44 ) ; those treated with temsirolimus 175/25-mg showed a trend toward longer PFS ( P = .0618 ; hazard ratio = 0.65 ) . Objective response rate was significantly higher in the 175/75-mg group ( 22 % ) compared with the investigator 's choice group ( 2 % ; P = .0019 ) . Median overall survival for the temsirolimus 175/75-mg group and the investigator 's choice group was 12.8 months and 9.7 months , respectively ( P = .3519 ) . The most frequent grade 3 or 4 adverse events in the temsirolimus groups were thrombocytopenia , anemia , neutropenia , and asthenia . CONCLUSION Temsirolimus 175 mg weekly for 3 weeks followed by 75 mg weekly significantly improved PFS and objective response rate compared with investigator 's choice therapy in patients with relapsed or refractory MCL |
13,636 | 25,668,347 | Higher consumption of beta-glucan fibre is associated with lower SBP and DBP . | OBJECTIVE To determine the effect of different types of dietary fibre on SBP and DBP . | Aims We aim ed to assess the effects of psyllium supplementation on insulin sensitivity and other parameters of the metabolic syndrome in an at risk adolescent population . Methods This study encompassed a participant-blinded , r and omized , placebo-controlled , crossover trial . Subjects were 47 healthy adolescent males aged 15–16 years , recruited from secondary schools in lower socio-economic areas with high rates of obesity . Participants received 6 g/day of psyllium or placebo for 6 weeks , with a two-week washout before crossing over . Fasting lipid profiles , ambulatory blood pressure , auxological data , body composition , activity levels , and three-day food records were collected at baseline and after each 6-week intervention . Insulin sensitivity was measured by the Matsuda method using glucose and insulin values from an oral glucose tolerance test . Results 45 subjects completed the study , and compliance was very high : 87 % of participants took > 80 % of prescribed capsules . At baseline , 44 % of subjects were overweight or obese . 28 % had decreased insulin sensitivity , but none had impaired glucose tolerance . Fibre supplementation led to a 4 % reduction in and roid fat to gynoid fat ratio ( p = 0.019 ) , as well as a 0.12 mmol/l ( 6 % ) reduction in LDL cholesterol ( p = 0.042 ) . No associated adverse events were recorded . Conclusions Dietary supplementation with 6 g/day of psyllium over 6 weeks improves fat distribution and lipid profile ( parameters of the metabolic syndrome ) in an at risk population of adolescent males . Trial Registration Australian New Zeal and Clinical Trials Registry The results of epidemiologic studies suggest that increased intake of dietary fiber is associated with lower levels of arterial blood pressure ( BP ) . However , there is little information available addressing the possibility that increased oat consumption may reduce arterial BP in individuals with elevated arterial BP . To test this hypothesis , middle-aged and older men ( n = 36 ; body mass index , 25 - 35 kg/m(2 ) ; aged 50 - 75 y ) with elevated BP ( systolic BP 130 - 159 mmHg and /or diastolic BP 85 - 99 mmHg ) were r and omly assigned to consume an additional 14 g/d of dietary fiber in the form of oat ( 5.5 g beta-glucan , n = 18 ) or wheat cereals ( no beta-glucan , n = 18 ) for 12 wk . Casual resting arterial BP was measured at baseline and after 4 , 8 and 12 wk of intervention . The 24-h ambulatory arterial BP was measured at baseline and after 12 wk of intervention . There were no differences in casual resting or 24-h ambulatory BP at baseline in the two groups . Casual systolic BP ( SBP ) did not change as a result of the 12-wk intervention in the oat ( 138 plus minus 2 vs. 135 plus minus 3 mmHg ) or wheat ( 142 plus minus 2 vs. 140 plus minus 3 mmHg ) groups , respectively ( all P > 0.05 ) . Casual diastolic BP ( DBP ) also did not change in the oat ( 89 plus minus 2 vs. 88 plus minus 2 mmHg ) or wheat ( 90 plus minus 2 vs. 91 plus minus 2 mmHg ) group during this period ( all P > 0.05 ) . Further , 24-h , daytime and nighttime SBP and DBP did not decrease with the intervention . Therefore , the results of the present study suggest that any cardioprotective benefit of regular oat consumption may not be conferred via an arterial BP-lowering effect Soluble-fiber breakfast cereals were examined for their cholesterol-lowering ability in 58 male patients with mild to moderate hypercholesterolemia in a r and omized , double-blind , placebo-controlled study . Patients followed a step 1 diet for a minimum of 6 wk , then were r and omly assigned to groups incorporating either corn flakes or one of two soluble-fiber cereals ( pectin enriched or psyllium enriched ) in the diet for an additional 6 wk . During the diet-only phase , total cholesterol dropped 3.8 % . During the cereal-plus-diet phase , total and LDL cholesterol values of the pectin-enriched cereal group dropped an additional 2.1 % ( P = 0.243 ) and 3.9 % ( P = 0.16 ) , respectively , and they dropped 5.9 % ( P = 0.005 ) and 5.7 % ( P = 0.034 ) , respectively , in the psyllium-enriched cereal group . During the cereal-plus-diet phase , no significant effects on HDL cholesterol , triglyceride , or body weight were found within or between any cereal groups . These results support use of soluble-fiber cereals as an effective and well-tolerated part of a prudent diet in the treatment of mild to moderate hypercholesterolemia High intakes of whole grain foods are inversely related to the incidence of coronary heart diseases and type 2 diabetes , but the mechanisms remain unclear . Our study aim ed to evaluate the effects of a diet rich in whole grains compared with a diet containing the same amount of refined grains on insulin sensitivity and markers of lipid peroxidation and inflammation . In a r and omized crossover study , 22 women and 8 men ( BMI 28 + /- 2 ) were given either whole-grain or refined-grain products ( 3 bread slices , 2 crisp bread slices , 1 portion muesli , and 1 portion pasta ) to include in their habitual daily diet for two 6-wk periods . Peripheral insulin sensitivity was determined by euglycemic hyperinsulinemic clamp tests . 8-Iso-prostagl and in F(2alpha ) ( 8-iso PGF(2alpha ) ) , an F(2)-isoprostane , was measured in the urine as a marker of lipid peroxidation , and highly sensitive C-reactive protein and IL-6 were analyzed in plasma as markers of inflammation . Peripheral insulin sensitivity [ mg glucose . kg body wt(-1 ) . min(-1 ) per unit plasma insulin ( mU/L ) x 100 ] did not improve when subjects consumed whole-grain products ( 6.8 + /- 3.0 at baseline and 6.5 + /- 2.7 after 6 wk ) or refined products ( 6.4 + /- 2.9 and 6.9 + /- 3.2 , respectively ) and there were no differences between the 2 periods . Whole-grain consumption also did not affect 8-iso-PGF(2alpha ) in urine , IL-6 and C-reactive protein in plasma , blood pressure , or serum lipid concentrations . In conclusion , substitution of whole grains ( mainly based on milled wheat ) for refined-grain products in the habitual daily diet of healthy moderately overweight adults for 6-wk did not affect insulin sensitivity or markers of lipid peroxidation and inflammation Hypertension , dyslipidemia and overweight contribute substantially to cardiovascular disease risk . One of the most effective methods for improving high blood pressure and lipid profiles is loss of excess weight . Other recommendations for reducing cardiovascular risk include changes in dietary micronutrient , macronutrient and fiber intakes . To better define a diet for reduction in cardiovascular risk , 43 adults ( body mass index 26.4 + /- 3.3 , range 20.5 - 33.9 kg/m(2 ) ) participated in an 8-wk study to determine the effects of two diets on weight , blood pressure , lipids and insulin sensitivity . For 2 wk , weight was maintained and all subjects consumed a control diet . For the next 6 wk , subjects consumed one of two hypocaloric diets ( maintenance energy minus 4.2 MJ/d ) : the control diet ( n = 21 ) or a diet containing oats [ 45 g/(4.2 MJ dietary energy . d ) , n = 22 ] . There was no significant difference between groups in changes in weight loss ( control -4.0 + /- 1.1 kg , oats -3.9 + /- 1.6 kg , P = 0.8 ) . The oats diet result ed in greater decreases in mean systolic blood pressure ( oats -6 + /- 7 mm Hg , control -1 + /- 10 mm Hg , P = 0.026 ) , whereas diastolic blood pressure change did not differ between the two groups ( oats -4 + /- 6 mm Hg , control -3 + /- 5 mm Hg , P = 0.8 ) . The oat diet result ed in significantly greater decreases in total cholesterol ( oats -0.87 + /- 0.47 mmol/L , control -0.34 + /- 0.5 mmol/L , P = 0.003 ) and LDL cholesterol ( oats -0.6 + /- 0.41 mmol/L , control -0.2 + /- 0.41mmol/L , P = 0.008 ) . In summary , a hypocaloric diet containing oats consumed over 6 wk result ed in greater improvements in systolic blood pressure and lipid profile than did a hypocaloric diet without oats OBJECTIVE The present study compared the feasibility of two simple messages ( a high-fiber diet or a low saturated fat diet ) to a combination message ( high fiber/low saturated fat ) on their potential to affect dietary quality and metabolic health . METHODS Thirty-six subjects were r and omized to one of three intervention conditions and received individual dietary counseling sessions . Study assessment s occurred at baseline , 3 mo , and 6 mo . RESULTS The sample was 84 % female and 94 % Caucasian . Mean body mass index was 31kg/m(2 ) . At the 6-mo assessment phase , we retained all 12 patients in the high-fiber diet condition , 10 of 12 in the low saturated fat condition , and 9 of 12 in the combination condition . Participants reported that the dietary fiber intervention was easier to maintain compared with the other two intervention conditions ( 83 % for high dietary fiber versus 60 % for low saturated fat versus 33 % for the combination , P=0.008 ) . Overall dietary quality improved in all three conditions during the study ( P=0.01 ) . In addition to increasing fiber , the high-fiber condition decreased their saturated fat intake , even though a reduction in saturated fat was not a part of that intervention condition . Participants in all three conditions lost an average of 9 lb from baseline weight ( P<0.001 ) . CONCLUSION A simple dietary message is feasible and can improve overall dietary quality . Results support the need for a larger r and omized controlled trial that is powered to detect the efficacy of a simplified dietary recommendation for dietary quality and metabolic health BACKGROUND Acute studies with alginate-based preloads suggested that these strong gelling fibers may induce increased feelings of satiety and reduce energy intakes . However , the long-term efficacy and safety of alginate supplementation on body weight regulation are lacking . OBJECTIVE The primary aim of the study was to investigate the effects in subjects of alginate supplementation in conjunction with energy restriction ( -300 kcal/d ) on loss of body weight and fat and , second , on metabolic risk markers in comparison with in a placebo group . DESIGN In a parallel , double-blind , placebo-controlled study , we r and omly assigned 96 obese subjects to either an energy-restricted diet plus a placebo preload supplement or an energy-restricted diet plus an alginate-based preload supplement ( 15 g fiber ) . The preload was administered as a beverage 3 times/d before main meals for a period of 12 wk . RESULTS No differences in loss of body weight and fat between groups were shown in the intension-to-treat ( ITT ) analysis ( P > 0.1 ) . However , in the completer analysis ( n = 80 ) , we showed a greater weight loss with alginate ( 6.78 ± 3.67 kg ) than with the placebo ( 5.04 ± 3.40 kg ) ( P = 0.03 ) , which was mainly attributed to a reduction in the percentage of body fat ( P = 0.03 ) . In the ITT analysis , a larger decrease in systolic and diastolic blood pressure was shown in the placebo group than in the alginate group ( P < 0.05 ) . Plasma concentrations of glucose , insulin , C-reactive protein , and ghrelin , HOMA-IR , and lipid metabolism did not differ between treatment groups in the ITT analysis ( P > 0.1 ) . CONCLUSION These results suggest that alginate supplementation as an adjunct to energy restriction may improve weight loss in obese subjects who complete a 12-wk dietary intervention OBJECTIVE : To investigate whether fibre supplementation is effective in weight-reduced subjects for maintenance of weight-loss in the long-term . DESIGN : Longitudinal , r and omly assigned intervention study with supplementation of 20 g of water soluble fibre ( guar gum ) daily for 14 months after an energy-restricted period of two months ( VLCD ) . SUBJECTS : Thirty-one female , obese subjects ( age : 41.4±7.4 y : BMI 33.2±3.7 kg/m−2 ) ; 20 subjects were supplemented with fibre and 11 subjects served as the control group . MEASUREMENTS : Body weight ( BW ) , blood lipids and blood pressure , anthropometry , and eating behaviour were measured before the VLCD ( 0 ) , after VLCD ( 2 ) , and at 4 , 10 and 16 months . RESULTS : The fibre group with at least 80 % compliance ( group A ) and the control group showed the same weight regain response after VLCD . The fibre consuming group with 50–80 % compliance ( group B ) differed with respect to relapse . The rate and amount of BW regain was significantly higher for group B. After 14 months group B had returned to baseline levels , whereas group A and the control group showed a tendency to a lower BW than at baseline ( P=0.09 ) . No effect of fibre supplementation was found on blood lipids , blood pressure and energy intake . Eating behaviour characteristics changed during the intervention and might explain differences in weight maintenance . CONCLUSIONS : No effect of 14 months fibre supplementation was found on weight maintenance in weight‐reduced subjects . Guar gum intake did not result in reduction of blood pressure or cholesterol , or in suppression of energy intake We conducted a 6-month r and omized , double-blind , parallel trial in which subjects consumed their usual diet plus arabinogalactan , a functional fiber isolated from either larch or tamarack . Healthy human subjects ( 28 men , 26 women ) ages 18 to 55 years old consumed 8.4 g/day larch arabinogalactan ( n=18 ) , tamarack arabinogalactan ( n=19 ) , or a placebo of rice starch ( n=17 ) . Serum cholesterol , low-density lipoprotein cholesterol , high-density lipoprotein cholesterol , triglycerides , apolipoprotein B , apolipoprotein A-I , glucose , and insulin were measured monthly . Three-day food records , body weight , blood pressure , and gastrointestinal symptom surveys were obtained monthly . Serum lipids seemed to decrease at month 2 , but there were no statistically significant differences among diets for any measured endpoint . Arabinogalactan is a recognized soluble fiber and is currently being used in products because it is not viscous , is easily incorporated into foods and beverages , and is well accepted by consumers OBJECTIVE : To investigate whether supplementation of carbohydrate , chromium , dietary fibre and caffeine is effective for maintenance of weight-loss in the long-term . DESIGN : A longitudinal , double-blind , r and omly assigned intervention study of 16 months with supplementation of either 50 g of carbohydrates ( CHO ) , 200 µg chromium-picolinate ( Cr-Pic ) , 20 g of soluble fibre plus 100 mg caffeine ( CHO+ ) or 50 g of plain CHO , for 16 months besides a very low energy diet ( VLED ) during the first two months . SUBJECTS : Thirtythree female obese subjects ( age , 34.8±7.0 y ; body weight ( BW ) : 85.5±10.0 kg ; body mass index ( BMI ) 31.2±3.7 kg.m−2 ) participated , 13 subjects were supplemented with CHO+ , 11 subjects were supplemented with CHO and 9 subjects served as a control group . MEASUREMENTS : BW , body composition , energy intake and blood parameters were measured before the VLED ( 0 ) , after the VLED at 2 months ( 2 ) , and at 4 , 10 and 16 months . RESULTS : The amount and course of relapse of BW was equal for the supplemented and control groups . The average regain at 16 months ( the weight gained as a percentage of the total weight loss during the VLED ) was 66.1±81.2 % , and was not different between the groups . No differences in body composition were found between the groups at 16 months . The CHO supplements result ed in significantly elevated energy percentage ( En % ) intake of CHO daily , in both supplemented groups , although this did not result in less regain . Pearson correlation analysis for all subjects revealed that the more fat consumed , the more regain was found at 16 months ( r= 0.41 , P<0.05 ) . A high CHO consumption was correlated with less regain ( r=−0.40 , P=0.05 ) . Furthermore , chromium intake did not result in significant changes in blood parameters and body composition . CONCLUSION : Although additional supplementation of CHO , chromium , dietary fibre and caffeine intake did not affect BW , the En % CHO daily was increased significantly . Our results indicate that a high En % intake of CHO and a low En % intake of fat daily is beneficial for prevention of weight regain Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Endothelial dysfunction and increased arterial stiffness occur early in the pathogenesis of the metabolic syndrome and they are both powerful independent predictors of cardiovascular risk . A high-fibre diet has been correlated with lower BMI and a lower incidence of hyperlipidaemia , CVD , hypertension and diabetes . The present r and omised , parallel- design study compared the effects of fibre intake from a healthy diet v. fibre supplement diets on blood pressure ( BP ) and vascular function over 12 weeks . Overweight and obese adults were r and omised to one of three groups : control ( with placebo ) , fibre supplement ( FIB ) or healthy eating group with placebo ( HLT ) . Systolic blood pressure ( SBP ) was lower in the FIB group compared with the control group at week 6 , but not at week 12 . However , SBP was lower in the HLT group compared with control group at week 12 . At week 6 , the FIB group presented lower diastolic blood pressure and augmentation index compared with the control group , but this result did not persist to the end of the study . The present study did not show any improvements in BP or vascular function in overweight and obese individuals with psyllium fibre supplementation over 12 weeks of intervention . However , a healthy diet provided the greatest improvements in BP in overweight and obese subjects . Further research with hypertensive individuals is necessary to eluci date whether increased fibre consumption in the form of psyllium supplementation may provide a safe and acceptable means to reduce BP , vascular function and the risk of developing CVD BACKGROUND It is known that obesity , sodium intake , and alcohol consumption factors influence blood pressure . In this clinical trial , Dietary Approaches to Stop Hypertension , we assessed the effects of dietary patterns on blood pressure . METHODS We enrolled 459 adults with systolic blood pressures of less than 160 mm Hg and diastolic blood pressures of 80 to 95 mm Hg . For three weeks , the subjects were fed a control diet that was low in fruits , vegetables , and dairy products , with a fat content typical of the average diet in the United States . They were then r and omly assigned to receive for eight weeks the control diet , a diet rich in fruits and vegetables , or a " combination " diet rich in fruits , vegetables , and low-fat dairy products and with reduced saturated and total fat . Sodium intake and body weight were maintained at constant levels . RESULTS At base line , the mean ( + /-SD ) systolic and diastolic blood pressures were 131.3+/-10.8 mm Hg and 84.7+/-4.7 mm Hg , respectively . The combination diet reduced systolic and diastolic blood pressure by 5.5 and 3.0 mm Hg more , respectively , than the control diet ( P<0.001 for each ) ; the fruits- and -vegetables diet reduced systolic blood pressure by 2.8 mm Hg more ( P<0.001 ) and diastolic blood pressure by 1.1 mm Hg more than the control diet ( P=0.07 ) . Among the 133 subjects with hypertension ( systolic pressure , > or = 140 mm Hg ; diastolic pressure , > or = 90 mm Hg ; or both ) , the combination diet reduced systolic and diastolic blood pressure by 11.4 and 5.5 mm Hg more , respectively , than the control diet ( P<0.001 for each ) ; among the 326 subjects without hypertension , the corresponding reductions were 3.5 mm Hg ( P<0.001 ) and 2.1 mm Hg ( P=0.003 ) . CONCLUSIONS A diet rich in fruits , vegetables , and low-fat dairy foods and with reduced saturated and total fat can substantially lower blood pressure . This diet offers an additional nutritional approach to preventing and treating hypertension Objective A proprietary natural fiber complex ( Litramine IQP G-002AS ) derived from Opuntia ficus-indica , and st and ardized on lipophilic activity , was previously shown in pre clinical and human studies to reduce dietary fat absorption through gastrointestinal ( GI ) fat binding . Here , we investigated the efficacy and safety of IQP G-002AS in body weight reduction . Design and Methods One hundred twenty-five overweight and obese adults participated in the study . Subjects were advised on physical activity , and received nutritional counseling , including hypocaloric diet plans ( 30 % energy from fat and 500 kcal deficit/day ) . After a 2-week placebo run-in phase , subjects were r and omized to receive either 3 g/day of IQP G-002AS ( IQ ) or a placebo . The primary endpoint was change in body weight from baseline ; secondary endpoints included additional obesity measures and safety parameters . Results One hundred twenty-three subjects completed the 12-week treatment phase ( intention-to-treat ( ITT ) population : 30 male and 93 female ; mean BMI : 29.6 ± 2.8 kg/m2 and age : 45.4 ± 11.3 years ) . The mean body weight change from baseline was 3.8 ± 1.8 kg in IQ vs. 1.4 ± 2.6 kg in placebo ( P < 0.001 ) . More IQ subjects lost at least 5 % of their initial body weight compared to placebo ( P = 0.027 ) . Compared with placebo , IQ also showed significantly greater reduction in BMI , body fat composition , and waist circumference . IQ was well tolerated with no adverse reactions reported . Conclusions These results suggest that the natural fiber complex Litramine IQP G-002AS is effective in promoting weight loss Several regulatory bodies have approved a health cl aim on the cholesterol-lowering effects of oat β-glucan at levels of 3·0 g/d . The present study aim ed to test whether 1·5 g/d β-glucan provided as ready-to-eat oat flakes was as effective in lowering cholesterol as 3·0 g/d from oats porridge . A 6-week r and omised controlled trial was conducted in eighty-seven mildly hypercholesterolaemic ( ≥ 5 mmol/l and < 7·5 mmol/l ) men and women assigned to one of three diet arms ( 25 % energy ( E% ) protein ; 45 E% carbohydrate ; 30 E% fat , at energy requirements for weight maintenance ) : ( 1 ) minimal β-glucan ( control ) ; ( 2 ) low-dose oat β-glucan ( 1·5 g β-glucan ; oats low - OL ) or ( 3 ) higher dose oat β-glucan ( 3·0 g β-glucan ; oats high - OH ) . Changes in total cholesterol and LDL-cholesterol ( LDL-C ) from baseline were assessed using a linear mixed model and repeated- measures ANOVA , adjusted for weight change . Total cholesterol reduced significantly in all groups ( - 7·8 ( sd 13·8 ) % , - 7·2 ( sd 12·4 ) % and - 5·5 ( sd 9·3 ) % in the OH , OL and control groups ) , as did LDL-C ( - 8·4 ( sd 18·5 ) % , - 8·5 ( sd 18·5 ) % and - 5·5 ( sd 12·4 ) % in the OH , OL and control groups ) , but between-group differences were not significant . In responders only ( n 60 ) , β-glucan groups had higher reductions in LDL-C ( - 18·3 ( sd 11·1 ) % and - 18·1 ( sd 9·2 ) % in the OH and OL groups ) compared with controls ( - 11·7 ( sd 7·9 ) % ; P = 0·044 ) . Intakes of oat β-glucan were as effective at doses of 1·5 g/d compared with 3 g/d when provided in different food formats that delivered similar amounts of soluble β-glucan Fifty-two ( 41 females , 11 males ) overweight patients , mean body mass index ( BMI ) = 29.3 , were treated for 6 months in a r and omized , double-blind , placebo-controlled , parallel group design . The treatment consisted of an energy restricted diet and a dietary fibre supplement amounting to 7 g/day . After treatment the weight reduction in the fibre-treated group , 5.5 + /- 0.7 kg , was significantly higher than that of the placebo group , 3.0 + /- 0.5 kg ( P = 0.005 ) . Both groups were normotensive and comparable commencing treatment , 126.5/75.6 + /- 2.0/1.3 mm Hg versus 126.7/78.7 + /- 2.5/1.6 mm Hg . The treatment changed blood pressure non-significantly . Hunger feelings using visual analogue scales ( VAS ) were significantly reduced from 139.8 + /- 8.2 cm to 118.3 + /- 7.0 cm in the fibre-treated group , whereas a significant increase from 129.5 + /- 6.9 cm to 146.9 + /- 8.8 cm ( P less than 0.02 ) was seen in the placebo group . Side-effects were predominantly gastrointestinal and equally distributed in the two groups . It is concluded that a dietary fibre supplement is of value in the management of overweight , enhancing weight loss and decreasing hunger feelings Objective To examine the effect of dietary fiber intake on blood pressure ( BP ) . Design R and omized , double-blind , placebo-controlled trial . Setting and participants A total of 110 trial participants aged 30 to 65 years who had untreated , but higher than optimal BP or stage-1 hypertension were recruited from the community in New Orleans , Louisiana , USA . Interventions Study participants were r and omly assigned to receive 8 g/day of water-soluble fiber from oat bran or a control intervention . Main outcome measures Nine BP measurements were obtained by trained observers using r and om-zero sphygmomanometers , over three clinical visits , at the baseline and termination visits of the trial . An average of the nine measurements was used to determine mean BP at the baseline and termination visits . Results The net changes [ 95 % confidence interval , ( CI ) ] in systolic blood pressure were −1.8 mmHg ( −4.3 to 0.8 , P = 0.17 ) following 12 weeks , −2.2 mmHg ( −5.3 to 1.0 , P = 0.18 ) following 6 weeks , and −2.0 mmHg ( −4.4 to 0.3 , P = 0.09 ) for an average of the 6- and 12-week visits . The corresponding net changes ( 95 % CI ) in diastolic blood pressure were −1.2 mmHg ( −3.0 to 0.5 , P = 0.17 ) following 12 weeks , −0.8 mmHg ( −3.1 to 1.4 , P = 0.47 ) following 6 weeks , and −1.0 mmHg ( −2.6 to 0.5 , P = 0.19 ) for an average of the 6- and 12-week visits . Conclusions Our findings suggest that a diet rich in fiber may have a moderate BP-lowering effect and indicate the need for further investigation of this important question Observational studies show inverse associations between intake of whole grain and adiposity and cardiovascular risk ; however , only a few dietary intervention trials have investigated the effect of whole-grain consumption on health outcomes . We studied the effect of replacing refined wheat ( RW ) with whole-grain wheat ( WW ) for 12 wk on body weight and composition after a 2-wk run-in period of consumption of RW-containing food intake . In this open-label r and omized trial , 79 overweight or obese postmenopausal women were r and omized to an energy-restricted diet ( deficit of ~1250 kJ/d ) with RW or WW foods providing 2 MJ/d . Body weight and composition , blood pressure , and concentration of circulating risk markers were measured at wk 0 , 6 , and 12 . Fecal output and energy excretion were assessed during run-in and wk 12 . Plasma alkylresorcinol analysis indicated good compliance with the intervention diets . Body weight decreased significantly from baseline in both the RW ( -2.7 ± 1.9 kg ) and WW ( -3.6 ± 3.2 kg ) groups , but the decreases did not differ between the groups ( P = 0.11 ) . The reduction in body fat percentage was greater in the WW group ( -3.0 % ) than in the RW group ( -2.1 % ) ( P = 0.04 ) . Serum total and LDL cholesterol increased by ~5 % ( P < 0.01 ) in the RW group but did not change in the WW group ; hence , the changes differed between the groups ( P = 0.02 ) . In conclusion , consumption of whole-grain products result ed in a greater reduction in the percentage fat mass , whereas body weight changes did not differ between the RW and WW groups . Serum total and LDL cholesterol , two important risk factors of cardiovascular disease , increased with RW but not WW consumption , which may suggest a cardioprotective role for whole grain Carbohydrate-restricted diets ( CRDs ) promote weight loss , reductions in plasma triacylglycerol ( TAG ) levels , and increases in high-density lipoprotein cholesterol ( HDL-C ) levels but may cause undesirable low-density lipoprotein cholesterol ( LDL-C ) responses in some people . The objective of the present study was to determine the effect of adding soluble fiber to a CRD on plasma LDL-C and other traditionally measured markers of cardiovascular disease . Using a parallel-arm , double-blind , placebo-controlled design , 30 overweight and obese men ( body mass index , 25 - 35 kg/m(2 ) ) were r and omly assigned to supplement a CRD with soluble fiber ( Konjac-mannan , 3g/d ) ( n = 15 ) or placebo ( n = 15 ) . Plasma lipids , anthropometrics , body composition , blood pressure , and nutrient intake were evaluated at baseline and at 6 and 12 weeks . Compliance was excellent as assessed by 7-day weighed dietary records and ketonuria . Both groups experienced decreases in ( P < .01 ) body weight , percent body fat , systolic blood pressure , waist circumference , and plasma glucose levels . After 12 weeks , HDL-C and TAG improved significantly in the fiber ( 10 % and -34 % ) and placebo ( 14 % , -43 % ) groups . LDL-C decreased by 17.6 % ( P < .01 ) at week 6 and 14.1 % ( P < .01 ) at week 12 in the fiber group . Conversely , LDL-C reductions were significant in the placebo group only after 12 weeks ( -6.0 % , P < .05 ) . We conclude that although clearly effective at lowering LDL-C , adding soluble fiber to a CRD during active and significant weight loss provides no additional benefits to the diet alone . Furthermore , a CRD led to clinical ly important positive alterations in cardiovascular disease risk factors Objective : Barley fiber rich in beta-glucans lowers serum lipids , but is difficult to incorporate into products acceptable to consumers . We investigated the physiological effects of two concentrated barley β-glucans on cardiovascular disease ( CVD ) endpoints and body weight in human subjects . Methods : Hypercholesterolemic men and women ( n = 90 ) were r and omly assigned to one of two treatments : low molecular weight ( low-MW ) or high molecular weight ( high-MW ) concentrated barley β-glucan consumed as a daily supplement containing 6 grams beta-glucan/day . Fasting blood sample s were collected at baseline and week 6 and analyzed for total cholesterol , HDL cholesterol , LDL cholesterol , triglycerides , glucose , insulin , homocysteine and C-reactive protein ( CRP ) . Dietary intakes , body weights , blood pressure , hunger ratings , and gastrointestinal symptoms were measured at baseline and 6 weeks . Results : The only difference between treatments in lipid outcomes at week 6 was a reduction of the cholesterol/HDL ratio in the low-MW group and a small increase in the high-MW group . No changes were found in blood pressure , glucose , insulin , and gastrointestinal symptoms . Body weight decreased from baseline to 6 weeks in the high-MW group while body weight increased in the low-MW group . Levels of hunger decreased slightly in the low-MW group and decreased significantly in the high-MW group ( P = 0.02 ) Conclusion : Overall , supplementation with isolated barley β-glucans of different molecular weights had small effects on cardiovascular disease markers . Molecular weight of the barley fiber did alter effects on body weight with the high-MW fiber significantly decreasing body weight Objectives : To determine the effects of a vegetarian diet on daytime ambulatory ( Accutracker ) blood pressures and heart rates , and to relate these to the estimated peak in plasma glucose to determine whether low-glycaemic-index diets reduce sympathetic activity in response to differences in postpr and ial glucose and insulin . Design : The subjects were matched for age and body mass index and r and omly assigned to one of two parallel diet groups . Setting : Clinical . Participants : Twenty-one normotensive non-vegetarian male hospital workers volunteered for the study and 20 completed it . Intervention : After 2 weeks of baseline measurement the subjects followed an omnivorous or a lacto-ovovegetarian diet for 6 weeks . Main outcome measures : Daytime ambulatory blood pressures and heart rate , and postbreakfast catecholamines , insulin and glucose . Results : Ambulatory systolic blood pressure and heart rates were lower in the vegetarian group during the working day . The prepr and ial rise in diastolic pressure was attenuated on the vegetarian diet . There were no differences in plasma catecholamine , glucose or insulin levels sample d after breakfast on the two dietary regimes . Conclusions : The blood pressure-lowering effect of a lacto-ovovegetarian diet , which occurs throughout the working day , is associated with lower heart rates , suggesting a central nervous or cardiac mechanism . The possibility that the lower glycaemic index of a lacto-ovovegetarian diet has some effect needs to be investigated further in relation to major meal-times and studied in both normotensive and hypertensive subjects The associations of diastolic blood pressure ( DBP ) with stroke and with coronary heart disease ( CHD ) were investigated in nine major prospect i ve observational studies : total 420,000 individuals , 843 strokes , and 4856 CHD events , 6 - 25 ( mean 10 ) years of follow-up . The combined results demonstrate positive , continuous , and apparently independent associations , with no significant heterogeneity of effect among different studies . Within the range of DBP studied ( about 70 - 110 mm Hg ) , there was no evidence of any " threshold " below which lower levels of DBP were not associated with lower risks of stroke and of CHD . Previous analyses have described the uncorrected associations of DBP measured just at " baseline " with subsequent disease rates . But , because of the diluting effects of r and om fluctuations in DBP , these substantially underestimate the true associations of the usual DBP ( ie , an individual 's long-term average DBP ) with disease . After correction for this " regression dilution " bias , prolonged differences in usual DBP of 5 , 7.5 , and 10 mm Hg were respectively associated with at least 34 % , 46 % , and 56 % less stroke and at least 21 % , 29 % , and 37 % less CHD . These associations are about 60 % greater than in previous uncorrected analyses . ( This regression dilution bias is quite general , so analogous corrections to the relations of cholesterol to CHD or of various other risk factors to CHD or to other diseases would likewise increase their estimated strengths . ) The DBP results suggest that for the large majority of individuals , whether conventionally " hypertensive " or " normotensive " , a lower blood pressure should eventually confer a lower risk of vascular disease Clinical studies have shown that the consumption of coffee mannooligosaccharides ( MOS ) decreases body fat , suggesting that MOS consumption may be useful for weight management . This study was undertaken to determine whether consumption of coffee MOS improves body composition when consumed as part of a weight-maintaining diet . In this double-blind , r and omized , placebo-controlled study , 54 men and women , age 19 - 65 y and with BMI of 27 - 33 kg/m(2 ) , consumed study beverages twice daily , for 12 wk . Beverages were identical except for the presence ( MOS group ) or absence ( placebo group ) of MOS ( 4 g/d ) . Body composition was assessed at baseline and endpoint using magnetic resonance imaging ( MRI ) . Body weight , blood pressure , and assessment s of feelings of appetite and satiety were taken weekly . Fifty men and women completed both baseline and endpoint MRI scans . There was a significant beverage x time interaction on total body volume ( P = 0.026 ) , total adipose tissue ( TAT ) ( P = 0.046 ) , and total subcutaneous adipose tissue ( P = 0.032 ) in men but not women . Men consuming the MOS beverage had a greater percent change in total body volume ( P = 0.043 ) and tended to have greater percent changes in subcutaneous ( P = 0.069 ) and TAT ( P = 0.098 ) compared with the placebo group . Consumption of a MOS-containing beverage , as part of a free-living weight-maintaining diet , leads to reductions in total body volume , relative to placebo , in men . More research is needed to further investigate the mechanism by which MOS may act to improve body composition and to eluci date the influence of gender Objectives To determine whether low-glycemic index ( GI ) diets have clinical utility in overweight patients with non-insulin-dependent diabetes mellitus ( NIDDM ) . Research Design and Methods Six patients with NIDDM were studied on both high- and low-GI diets of 6-wk duration with metabolic diets with a r and omized crossover design . Both diets were of similar composition ( 57 % carbohydrate , 23 % fat , and 34 g/day dietary fiber ) , but the low-GI diet had a GI of 58 compared with 86 for the high-GI diet . Results Small and similar amounts of weight were lost on both diets : 2.5 kg on high-GI diet and 1.8 kg on low-GI diet . On the low-GI diet , the mean level of serum fructosamine , as an index of overall blood glucose control , was lower than on the high-GI diet by 8 % ( P < 0.05 ) , and total serum cholesterol was lower by 7 % ( P < 0.01 ) . Conclusions In overweight patients with NIDDM , reducing diet GI improves overall blood glucose and lipid control Objective To evaluate the performance of the QRISK2 - 2011 score for predicting the 10 year risk of cardiovascular disease in an independent UK cohort of patients from general practice and to compare it with earlier versions of the model and a National Institute for Health and Clinical Excellence version of the Framingham equation . Design Prospect i ve cohort study to vali date a cardiovascular risk score with routinely collected data between June 1994 and June 2008 . Setting 364 practice s from the United Kingdom contributing to The Health Improvement Network ( THIN ) data base . Participants Two million patients aged 30 to 84 years ( 11.8 million person years ) with 93 564 cardiovascular events . Main outcome measure First diagnosis of cardiovascular disease ( myocardial infa rct ion , angina , coronary heart disease , stroke , and transient ischaemic attack ) recorded in general practice records . Results Results from this independent and external validation of QRISK2 - 2011 indicate good performance data when compared with the NICE version of the Framingham equation . QRISK2 - 2011 had better ability to identify those at high risk of developing cardiovascular disease than did the NICE Framingham equation . QRISK2 - 2011 is well calibrated , with reasonable agreement between observed and predicted outcomes , whereas the NICE Framingham equation seems to consistently over-predict risk in men by about 5 % and shows poor calibration in women . Conclusions QRISK2 - 2011 seems to be a useful model , with good discriminative and calibration properties when compared with the NICE version of the Framingham equation . Furthermore , based on current high risk thresholds , concerns exist on the clinical usefulness of the NICE version of the Framingham equation for identifying women at high risk of developing cardiovascular disease . At current thresholds the NICE version of the Framingham equation has no clinical benefit in either men or women Previous studies have shown that supplementation of the diet with oat bran may lower serum cholesterol levels . However , it is not known whether oat-bran diets lower serum cholesterol levels by replacing fatty foods in the diet or by a direct effect of the dietary fiber contained in oat bran . To determine which is the case , we compared the effect of isocaloric supplements of high-fiber oat bran ( 87 g per day ) and a low-fiber refined-wheat product on the serum lipoprotein cholesterol levels of 20 healthy subjects , 23 to 49 years old . After a one-week base-line period during which they consumed their usual diets , the subjects were given each type of supplement for six-week periods in a double-blind , crossover trial . Mean serum cholesterol levels ( + /- SD ) were not significantly different during the high-fiber and low-fiber periods : total cholesterol , 4.44 + /- 0.73 and 4.46 + /- 0.64 mmol per liter ( 172 + /- 28 and 172 + /- 25 mg per deciliter ) ; low-density lipoprotein , 2.69 + /- 0.63 and 2.77 + /- 0.59 mmol per liter ( 104 + /- 24 and 107 + /- 23 mg per deciliter ) ; and high-density lipoprotein , 1.40 + /- 0.39 and 1.32 + /- 0.39 mmol per liter ( 54.2 + /- 15.0 and 50.9 + /- 15.2 mg per deciliter ) , respectively . However , both types of supplements lowered the mean base-line serum cholesterol level , 4.80 + /- 0.80 mmol per liter ( 186 + /- 31 mg per deciliter ) , by 7 to 8 percent ( 95 percent confidence interval for high fiber , 11 to 4 percent , and for low fiber , 11 to 3 percent ) . The subjects ate less saturated fat and cholesterol and more polyunsaturated fat during both periods of supplementation than at base line . Those changes in dietary fats were sufficient to explain all of the reduction in serum cholesterol levels caused by the high-fiber and low-fiber diets . The average blood pressure was 112/68 mm Hg at base line and did not change during either dietary period . We conclude that oat bran has little cholesterol-lowering effect and that high-fiber and low-fiber dietary grain supplements reduce serum cholesterol levels about equally , probably because they replace dietary fats OBJECTIVE Evidence supports the role of dietary fiber in improving metabolic health . PolyGlycopleX ( PGX ) , a viscous functional polysaccharide improves lipidemia and glycemia in healthy adults . Our objective was to examine the effects of PGX on risk factors associated with the metabolic syndrome in Japanese adults with abdominal obesity . DESIGN AND METHODS Sixty four subjects assigned to 14 weeks of 15 g day(-1 ) of PGX or placebo were assessed in a r and omized , double-blind , placebo-controlled , parallel group trial . At week 0 and 14 , primary outcome measures were serum lipids , abdominal adiposity , glucose tolerance and blood pressure . RESULTS Total and LDL cholesterol were reduced at week 14 with PGX but not placebo ( P < 0.05 ) . The reduction in waist circumference at week 14 was greater with PGX versus placebo ( P < 0.05 ) . In females , abdominal visceral fat was decreased to a greater extent with PGX versus placebo ( P < 0.05 ) . While glucose tolerance worsened with placebo over time , PGX reduced glucose total area under the curve from week 0 to 6 ( P = 0.039 ) . Serum concentrations of resistin and IL6 increased slightly in placebo and decreased slightly with PGX . CONCLUSIONS PGX is a functional fiber that shows promise in reducing risk factors related to the metabolic syndrome in Japanese adults with abdominal obesity Chitosan is a deacetylated product of chitin . Microcrystalline form of chitosan has a large adsorption area cl aim ed to decrease gastrointestinal absorption of cholesterol . However , the long-term effect of chitosan on plasma lipids is variable , the averaged influence being negligible or lacking in mildly-to-moderately hypercholesterolaemic ( 4.8 - 6.8 mmol/l ) subjects . We evaluated whether this variation and inefficacy depend on apolipoprotein E genotype . 130 middle-aged , otherwise healthy men ( n=55 ) and women ( n=75 ) were r and omized into two treatment groups for a 7 month trial . During a 1 month run-in period all participants received placebo . Subsequently , one half first took placebo twice daily for 3 months and then 1.2 g chitosan twice daily for 3 months , and the other half vice versa in a cross-over way . Altogether 84 participants completed the study . Plasma lipids and glucose were determined at the end of each phase of the study , and all subjects undergone to the cross-over phases were apolipoprotein E genotyped . Chitosan altered plasma total , low- and high density cholesterol , triglycerides , and blood glucose in neither apolipoprotein E epsilon 4 allele carriers ( n=29 ) nor non-carriers ( n=55 ) , compared to placebo . In conclusions , chitosan is ineffective to decrease plasma lipids in apolipoprotein E epsilon 4 carrier and non-carrier phenotypes with mildly-to-moderately increased plasma cholesterol A double-blind , placebo-controlled , cross-over study was carried out in 25 healthy , nonobese middle-aged men to test the effect of guar gum on glucose and lipid metabolism , blood pressure , and fibrinolysis . Ten grams guar or placebo granulate was given three times a day for 6 wk with a 2-wk run-in before and a wash-out period after . Decreases in fasting blood glucose ( P < 0.001 ) , cholesterol ( P < 0.001 ) , triglycerides ( P < 0.05 ) , plasminogen activator inhibitor-1 activity ( P < 0.01 ) , systolic blood pressure ( P < 0.01 ) , and diastolic blood pressure ( P < 0.001 ) were seen during guar treatment when compared with placebo . Insulin sensitivity , measured with the euglycemic-clamp technique , increased ( P < 0.01 ) , adipose tissue-glucose uptake measured in vitro increased ( P < 0.001 ) , and 24-h urinary excretion of sodium and potassium increased ( P < 0.001 ) during guar treatment . Fasting plasma insulin , renin , aldosterone , and fibrinogen concentrations as well as skeletal-muscle electrolytes , urinary catecholamines , and body weight remained unaltered . These findings support a role for guar in the treatment of the metabolic syndrome in which insulin resistance seems to play a pivotal role A weight-reducing potential has been ascribed to high dietary fibre intake . To investigate the practical reliability of this hypothesis , fifty-three moderately overweight females ( BMI > 27.5 kg/m2 ) on reduced energy intake ( 1200 kcal/day ) were treated for 24 weeks with a fibre supplement on a r and omly , double-blind , placebo-controlled basis . The fibre was administered as an initial dose of 6 g and a maintenance dose of 4 g. Body weight and blood pressure were recorded weekly during the first 3 months and thereafter every second week . Blood sample s were drawn at start and at end of the study . Initial body weights were 75.6 + /- 1.6 kg in the fibre group versus 75.5 + /- 1.6 kg in the placebo group . After treatment , mean weight loss in the fibre group was 8.0 kg versus 5.8 kg in the placebo group ( p < 0.05 ) . Systolic and diastolic blood pressures were significantly reduced in both groups without differences between the groups . Serum concentrations of cholesterol , triglycerides and uric acid were significantly reduced in the group with reduced energy intake , whereas no additional effect was observed when fibre was supplemented . Serum concentrations of potassium and sodium did not change significantly . The results suggest that a dietary fibre supplement in combination with a hypocaloric diet is of value as an adjunct in the management of overweight |
13,637 | 28,586,127 | Cervical cerclage reduces the risk of preterm birth in women at high-risk of preterm birth and probably reduces risk of perinatal deaths . | BACKGROUND Cervical cerclage is a well-known surgical procedure carried out during pregnancy .
It involves positioning of a suture ( stitch ) around the neck of the womb ( cervix ) , aim ing to give mechanical support to the cervix and thereby reduce risk of preterm birth .
The effectiveness and safety of this procedure remains controversial .
This is an up date of a review last published in 2012 .
OBJECTIVES To assess whether the use of cervical stitch in singleton pregnancy at high risk of pregnancy loss based on woman 's history and /or ultrasound finding of ' short cervix ' and /or physical exam improves subsequent obstetric care and fetal outcome . | OBJECTIVE The objective of the study was to assess cerclage to prevent recurrent preterm birth in women with short cervix . STUDY DESIGN Women with prior spontaneous preterm birth less than 34 weeks were screened for short cervix and r and omly assigned to cerclage if cervical length was less than 25 mm . RESULTS Of 1014 women screened , 302 were r and omized ; 42 % of women not assigned and 32 % of those assigned to cerclage delivered less than 35 weeks ( P = .09 ) . In planned analyses , birth less than 24 weeks ( P = .03 ) and perinatal mortality ( P = .046 ) were less frequent in the cerclage group . There was a significant interaction between cervical length and cerclage . Birth less than 35 weeks ( P = .006 ) was reduced in the less than 15 mm stratum with a null effect in the 15 - 24 mm stratum . CONCLUSION In women with a prior spontaneous preterm birth less than 34 weeks and cervical length less than 25 mm , cerclage reduced previable birth and perinatal mortality but did not prevent birth less than 35 weeks , unless cervical length was less than 15 mm OBJECTIVE The aim of this study was to compare perinatal outcomes of patients with second-trimester ultrasonographic evidence of preterm dilatation of the internal os treated with cerclage versus those of patients not treated with cerclage . STUDY DESIGN From May 1998 through June 1999 patients with ultrasonographic evidence of preterm dilatation of the internal os between 16 and 24 weeks ' gestation were r and omly assigned to receive a McDonald cerclage or no cerclage . Before r and om assignment all patients underwent amniocentesis and urogenital cultures and then received 48 hours of therapy with indomethacin and antibiotics . After treatment each patient was followed up as an outpatient with bed rest and weekly ultrasonographic evaluation . RESULTS Of the 61 patients 31 were r and omly assigned to cerclage and 30 were r and omly assigned to no cerclage . There were no differences between groups with respect to maternal demographic characteristics , risk factors for preterm birth , cervical measurements , rescue procedures , readmission , chorioamnionitis , and abruptio placentae . The mean gestational age at delivery ( 33.5 + /- 6.3 weeks ) and the perinatal death rate ( 12 . 9 % ) in the cerclage group were similar to the mean gestational age at delivery ( 34.7 + /- 4.7 weeks ; P = .4 ) and the perinatal death rate ( 10.0 % ; P = .9 ) in the no-cerclage group . CONCLUSION Treatment with McDonald cerclage of preterm dilatation of the cervix detected ultrasonographically during the second trimester did not improve perinatal outcomes Objective : To assess whether type of suture material affects cerclage efficacy for preterm birth ( PTB ) prevention . Methods : Secondary analysis of a multicenter trial of ultrasound-indicated cerclage for short cervical length ( CL ) , in which women with prior spontaneous PTB at 16–33 6/7 weeks , a singleton gestation and CL < 25 mm between 16–22 6/7 weeks , were r and omized to McDonald cerclage or no cerclage . Outcomes of women who underwent cerclage were analyzed by type of suture material , comparing polyester braided thread ( Mersilene ™ or Ethibond ™ ) to Mersilene tape ™ . Primary outcome was PTB < 35 weeks . Results : 138 women underwent McDonald cerclage : 84 ( 61 % ) received polyester braided thread and 46 ( 33 % ) Mersilene tape ™ . Eight ( 6 % ) received monofilament suture and were excluded from analysis . Rates of PTB < 35 weeks were similar , 35 % for polyester braided thread vs 24 % for Mersilene tape ™ ( p = .24 ) . Birth gestational age was also similar among the 2 groups ( p = .18 ) . Conclusion : Type of suture material may not affect ultrasound-indicated cerclage efficacy in high-risk women with short CL , but further study is needed . Polyester braided thread ( Mersilene ™ or Ethibond ™ ) and polyester braided Mersilene tape ™ seem to have similar efficacy OBJECTIVE To compare the effects of therapeutic cerclage and bed rest vs. just bed rest on cervical length and to relate these effects to the risk of preterm delivery . DESIGN Cervical length was measured in patients at high risk of cervical incompetence . When a cervical length < 25 mm was measured before 27 weeks ' gestation , r and omization for therapeutic cerclage and bed rest vs. just bed rest was performed . After r and omization , cervical length was measured weekly . For statistical analysis , t-test and Fisher 's exact tests were used and P < 0.05 was considered statistically significant . RESULTS Nineteen women were r and omly allocated to receive a therapeutic cerclage and bed rest and 16 were allocated to receive bed rest only . Mean cervical lengths and mean gestational ages before r and omization were comparable between both groups , overall 19.8 mm and 20.7 weeks . Cervical length was measured again at a mean gestation of 22.1 weeks . Mean cervical length ( 31 mm ) was significantly ( P < 0.0001 ) longer after cerclage than after bed rest only ( 19 mm ) . A cervical length > or = 25 mm was measured in 22 of the 35 included women , 16 in the cerclage group and six in the bed-rest group ( P = 0.006 ) . Of these 22 women , only one delivered before 34 weeks ' gestation , which was significantly less frequent than six out of 13 women with a cervical length < 25 mm ( P = 0.006 ) . CONCLUSIONS Therapeutic cerclage with bed rest increases cervical length more often than bed rest alone . A postintervention cervical length > or = 25 mm reduces the risk of preterm delivery in women at high risk of cervical incompetence and a preintervention cervical length < 25 mm OBJECTIVE The study was undertaken to measure cerclage location within the cervix and to determine whether placement closer to the internal os is related to perinatal outcome . STUDY DESIGN We analyzed data collected during a r and omized trial of cervical cerclage versus no cerclage that was conducted at Lehigh Valley Hospital between May 1998 and June 2001 in women with ultrasound findings of short cervix less than 25 mm or funneling between 16 and 24 weeks ' gestation . Women who were r and omly assigned to the cerclage arm had cervical measurements performed before cerclage , including dilation of the internal os , depth of membrane prolapse into the endocervical canal , cervical length below any funnel ( distal length ) , and total cervical length ( including any funnel ) . Measurements obtained after cerclage placement included the distance from external os to cerclage ( A ) , and a repeat of the same four measurements . The distance from the external os to the cerclage ( A ) was divided by the total cervical length ( B ) and a cerclage to cervical length ratio ( A/B ) was calculated . The relationship between these measurements and gestational age at birth was assessed by linear regression analysis . RESULTS Of 150 patients enrolled , 74 received a McDonald cerclage suture . Mean distal cervical length was 1.9+/-0.9 cm before and 2.9+/-1.0 cm after cerclage ( P=.001 ) . The mean distance between the cerclage and external os ( A ) was 1.8+/-0.6 cm ; the total cervical length after cerclage ( B ) was 3.6+/-0.9 cm . The mean cerclage to cervical length ratio ( A/B ) was 0.5+/-0.1 . Linear regression analysis did not demonstrate a correlation between either the cerclage to external os measurement ( A ) or the cervical length ratio ( A/B ) and gestational age at birth ( R(2)=0.0006 and 0.008 , P=.8 and .6 , respectively ) . CONCLUSION The length of the cervix below the level of cerclage is not related to duration of pregnancy in women treated with cerclage because of ultrasound evidence of cervical effacement Internal os cerclage for cervical incompetence was performed in 90 patients who had previous McDonald procedure failure ( 70 patients ) or had unfavorable cervical anatomy ( short or lacerated cervix ) for primary McDonald type cerclage ( 20 patients ) . Two different techniques were used : the Shirodkar operation ( n = 44 ) with Mersilene b and , and a simpler new technique ( n = 46 ) . The new technique is characterized by anterior colpotomy for exposure of the internal os , and a 0.6 mm nylon suture encircling the cervix to be tied high in the posterior fornix . The pregnancy outcome for both groups was similar . Late abortions of 8.7 and 11 % and premature deliveries of 13 and 18 % occurred in the new technique and the Shirodkar groups , respectively . The removal of the suture was generally difficult in the Shirodkar group and in eight patients analgesia and sedation were required . In the new technique group , the removal was easier and in only one patient was sedation required ( p less than 0.0001 ) . Severe vaginal discharge was found in 52 % of the Shirodkar patients and none in the other group . Apparently the monofilament nylon suture prevented this side effect . It seems that the new technique is simpler to perform , involves fewer side effects , the removal of the suture is easier , and it is as effective as the Shirodkar procedure OBJECTIVE To determine the effectiveness of cerclage pessary in the prevention of preterm birth in asymptomatic Chinese women with a short cervix at 20 to 24 weeks . METHODS Low-risk women carrying singleton pregnancies were screened with transvaginal ultrasound , and those with a cervical length < 25 mm at 20 to 24 weeks were recruited into a r and omized controlled trial , comparing the prophylactic use of cerclage pessary with expectant management . The analysis was by intent-to-treat . The primary outcome measure was preterm delivery before 34 weeks . RESULTS Among 4438 screened women , 203 women ( 4.6 % ) met the inclusion criteria and 108 ( 58 % ) consented for the study . A total of 53 and 55 women were allocated to pessary and control groups , respectively . There was no difference in background demographics , including the mean cervical length ( 19.6 mm versus 20.5 mm ) and the mean gestational age at r and omization ( both 21.9 weeks ) . Delivery before 34 weeks occurred in 9.4 % and 5.5 % ( p = 0.46 ) in the pessary and the control groups , respectively . No differences in major side effects were noted between the groups . CONCLUSION In our population , < 5 % had a cervical length of less than 25 mm at 20 to 24 weeks ' gestation . The prophylactic use of cerclage pessary did not reduce the rate of preterm delivery before 34 weeks AIM To compare the effectiveness of the double cervical cerclage method versus the single method in women with recurrent second-trimester delivery . METHOD In this r and omized clinical trial , we included 33 singleton pregnancies suffering from recurrent second-trimester pregnancy loss ( ≥2 consecutive fetal loss during second-trimester or with a history of unsuccessful procedures utilizing the McDonald method ) , due to cervical incompetence . Patients were r and omly assigned to undergo either the classic McDonald method ( n = 14 ) or the double cerclage method ( n = 19 ) . The successful pregnancy rate and gestational age at delivery was also compared between the two groups . RESULTS The two study groups were comparable regarding their baseline characteristics . The successful pregnancy rate did not differ significantly between those who underwent the double cerclage method or the classic McDonald cerclage method ( 100 % vs 85.7 % ; P = 0.172 ) . In the same way , the preterm delivery rate ( < 34 weeks of gestation ) was comparable between the two study groups ( 10.5 % vs 35.7 % ; P = 0.106 ) . Those undergoing the double cerclage method had longer gestational duration ( 37.2 ± 2.6 vs 34.3 ± 3.8 weeks ; P = 0.016 ) . CONCLUSION The double cervical cerclage method seems to provide better cervical support , as compared with the classic McDonald cerclage method , in those suffering from recurrent pregnancy loss , due to cervical incompetence The pregnant women at higher risk of preterm labor , referred to the perinatal clinic of Kosar University Hospital in Urmia district of Iran , were enrolled into a parallel r and omized clinical trial . In the investigational arm of the clinical trial , a double cervical cerclage procedure was performed addition to McDonald cerclage . In the control group however , only McDonald cerclage was performed . Extreme preterm labor ( GA < 33 weeks ) was the primary endpoint of this clinical trial . Age , gestational age at cerclage time , and gravidity were not found to be statistically different between the groups . Means of gestational age were 37.4 and 36.2 weeks , respectively , for the investigational and control groups . The gestational age was 1.2 weeks longer for double cerclage group but the difference was not found to be statistically significant . Preterm birth before 33 weeks of gestation was not experienced by any of the patients who received double cerclage , but five women in control group developed such an extreme preterm labor ( P < 0.05 ) . The absolute risk reduction in using double cerclage over traditional method was 18 percent ( 95 % confidence interval , 4%–32 % ) . Double cerclage appeared to have higher efficacy than traditional cerclage in preventing preterm labor <33 weeks of gestation BACKGROUND Previous r and omized trials have shown that progesterone administration in women who previously delivered prematurely reduces the risk of recurrent premature delivery . Asymptomatic women found at midgestation to have a short cervix are at greatly increased risk for spontaneous early preterm delivery , and it is unknown whether progesterone reduces this risk in such women . METHODS Cervical length was measured by transvaginal ultrasonography at a median of 22 weeks of gestation ( range , 20 to 25 ) in 24,620 pregnant women seen for routine prenatal care . Cervical length was 15 mm or less in 413 of the women ( 1.7 % ) , and 250 ( 60.5 % ) of these 413 women were r and omly assigned to receive vaginal progesterone ( 200 mg each night ) or placebo from 24 to 34 weeks of gestation . The primary outcome was spontaneous delivery before 34 weeks . RESULTS Spontaneous delivery before 34 weeks of gestation was less frequent in the progesterone group than in the placebo group ( 19.2 % vs. 34.4 % ; relative risk , 0.56 ; 95 % confidence interval [ CI ] , 0.36 to 0.86 ) . Progesterone was associated with a nonsignificant reduction in neonatal morbidity ( 8.1 % vs. 13.8 % ; relative risk , 0.59 ; 95 % CI , 0.26 to 1.25 ; P=0.17 ) . There were no serious adverse events associated with the use of progesterone . CONCLUSIONS In women with a short cervix , treatment with progesterone reduces the rate of spontaneous early preterm delivery . ( Clinical Trials.gov number , NCT00422526 [ Clinical Trials.gov ] . ) Background Cervical incompetence is one of the causes of preterm birth and mid-trimester pregnancy loss . Cervical cerclage is a surgical procedure to treat cervical incompetence . Cervical cerclage reduces the incidence of preterm birth in women at risk of recurrent preterm birth , without a statistically significant reduction in perinatal mortality or neonatal morbidity . Multifilament/braided sutures such as Mersilene tape have been traditionally used for cervical cerclage . Braided sutures , particularly mesh-like non-absorbable sutures , have been associated with an increased risk of infection and , hence , some obstetricians prefer to use monofilament/non-braided sutures . However , these cl aims are not substantiated by any scientific or clinical evidence .We propose a pilot/feasibility study which will provide the necessary information for planning a definitive trial investigating the clinical effectiveness of monofilament non-braided suture material s in reducing pregnancy loss rate following cervical cerclage compared to the traditional multifilament braided sutures . Methods / Design Women eligible for elective or ultrasound-indicated cerclage at 12 to 21 + 6 weeks of gestation will be r and omised to having the procedure using either a monofilament non-braided suture ( Ethilon ) or a Multifilament braided suture ( Mersilene tape ) inserted using a McDonald technique . Consent for participation in the Cerclage outcome by the type of suture ( COTS ) study will be obtained from each eligible participant . Clinical trials registration COTS is registered with the International St and ard Research for Clinical Trials ( IS RCT N17866773 ) . Registered on 27 March 2013 Background Clinical ly , once a woman has been identified as being at risk of spontaneous preterm birth ( sPTB ) due to a short cervical length , a decision regarding prophylactic treatment must be made . Three interventions have the potential to improve outcomes : cervical cerclage ( stitch ) , vaginal progesterone and cervical pessary . Each has been shown to have similar benefit in reduction of sPTB , but there have been no r and omised control trials ( RCTs ) to compare them . Methods This open label multi-centre UK RCT trial , will evaluate whether the three interventions are equally efficacious to prevent premature birth in women who develop a short cervix ( < 25 mm on transvaginal ultrasound ) . Participants will be asymptomatic and between 14 + 0 and 23 + 6 weeks ’ gestation in singleton pregnancies . Eligible women will be r and omised to cervical cerclage , Arabin pessary or vaginal progesterone ( 200 mg once daily ) ( n = 170 women per group).The obstetric endpoints are premature birth rate < 37 weeks ’ of gestation ( primary ) , 34 weeks and 30 weeks ( secondary outcomes ) and short-term neonatal outcomes ( a composite of death and major morbidity ) . It will also explore whether intervention success can be predicted by pre-intervention biomarker status . Discussion Preterm birth is the leading cause of perinatal morbidity and mortality and a short cervix is a useful way of identifying those most at risk . However , best management of these women has presented a clinical conundrum for decades . Given the promise offered by cerclage , Arabin pessary and vaginal progesterone for prevention of preterm birth in individual trials , direct comparison of these prophylactic interventions is now essential to establish whether one treatment is superior . If , as we hypothesise , the three interventions are equally efficacious , this study will empower women to make a choice of treatments based on personal preference and quality of life issues also explored by the study .Our exploratory analysis into whether the response to intervention is related to the pre-intervention biomarker status further our underst and ing of the pathophysiology of spontaneous preterm birth and help focus future research questions .Trial registration EudraCT Number : 2015 - 000456 - 15 . Registered 11th March Objective To determine the relationship between high vaginal pro-inflammatory cytokines and cervical shortening in women at high risk of spontaneous preterm labor and to assess the influence of cervical cerclage and vaginal progesterone on this relationship . Methods This prospect i ve longitudinal observational study assessed 112 women with at least one previous preterm delivery between 16 and 34 weeks ’ gestation . Transvaginal cervical length was measured and cervico-vaginal fluid sample d every two weeks until 28 weeks . If the cervix shortened ( < 25 mm ) before 24 weeks ’ gestation , women ( cases ) were r and omly assigned to cerclage or progesterone and sample d weekly . Cytokine concentrations were measured in a subset of cervico-vaginal fluid sample s ( n = 477 from 78 women ) by 11-plex fluid-phase immunoassay . Results All 11 inflammatory cytokines investigated were detected in cervico-vaginal fluid from women at high risk of preterm birth , irrespective of later cervical shortening . At less than 24 weeks ’ gestation and prior to intervention , women destined to develop a short cervix ( n = 36 ) exhibited higher cervico-vaginal concentrations than controls ( n = 42 ) of granulocyte-macrophage colony-stimulating factor [ ( GM-CSF ) 16.2 fold increase , confidence interval ( CI ) 1.8–147 ; p = 0.01 ] and monocyte chemotactic protein-1 [ ( MCP-1 ) 4.8 , CI 1.0–23.0 ; p = 0.05 ] . Other cytokines were similar between cases and controls . Progesterone treatment did not suppress cytokine concentrations . Interleukin (IL)-6 , IL-8 , granulocyte colony-stimulating factor ( G-CSF ) , interferon (IFN)-γ and tumour necrosis factor (TNF)-α concentrations were higher following r and omization to cerclage versus progesterone ( p<0.05 ) . Cerclage , but not progesterone treatment , was followed by a significant increase in cervical length [ mean 11.4 mm , CI 5.0–17.7 ; p<0.001 ] . Conclusions Although GM-CSF and MCP-1 cervico-vaginal fluid concentrations were raised , the majority of cervico-vaginal cytokines did not increase in association with cervical shortening . Progesterone treatment showed no significant anti-inflammation action on cytokine concentrations . Cerclage insertion was associated with an increase in the majority of inflammatory markers and cervical length BACKGROUND Women who have had a spontaneous preterm delivery are at greatly increased risk for preterm delivery in subsequent pregnancies . The results of several small trials have suggested that 17 alpha-hydroxyprogesterone caproate ( 17P ) may reduce the risk of preterm delivery . METHODS We conducted a double-blind , placebo-controlled trial involving pregnant women with a documented history of spontaneous preterm delivery . Women were enrolled at 19 clinical centers at 16 to 20 weeks of gestation and r and omly assigned by a central data center , in a 2:1 ratio , to receive either weekly injections of 250 mg of 17P or weekly injections of an inert oil placebo ; injections were continued until delivery or to 36 weeks of gestation . The primary outcome was preterm delivery before 37 weeks of gestation . Analysis was performed according to the intention-to-treat principle . RESULTS Base-line characteristics of the 310 women in the progesterone group and the 153 women in the placebo group were similar . Treatment with 17P significantly reduced the risk of delivery at less than 37 weeks of gestation ( incidence , 36.3 percent in the progesterone group vs. 54.9 percent in the placebo group ; relative risk , 0.66 [ 95 percent confidence interval , 0.54 to 0.81 ] ) , delivery at less than 35 weeks of gestation ( incidence , 20.6 percent vs. 30.7 percent ; relative risk , 0.67 [ 95 percent confidence interval , 0.48 to 0.93 ] ) , and delivery at less than 32 weeks of gestation ( 11.4 percent vs. 19.6 percent ; relative risk , 0.58 [ 95 percent confidence interval , 0.37 to 0.91 ] ) . Infants of women treated with 17P had significantly lower rates of necrotizing enterocolitis , intraventricular hemorrhage , and need for supplemental oxygen . CONCLUSIONS Weekly injections of 17P result ed in a substantial reduction in the rate of recurrent preterm delivery among women who were at particularly high risk for preterm delivery and reduced the likelihood of several complications in their infants OBJECTIVE To compare preterm delivery rates ( before 34 weeks of gestation ) and neonatal morbidity and mortality in patients with risk factors or symptoms of cervical incompetence managed with therapeutic McDonald cerclage and bed rest versus bed rest alone . STUDY DESIGN Cervical length was measured in patients with risk factors or symptoms of cervical incompetence . Risk factors for cervical incompetence included previous preterm delivery before 34 weeks of gestation that met clinical criteria for the diagnosis of cervical incompetence , previous preterm premature rupture of membranes before 32 weeks of gestation , history of cold knife conization , diethylstilbestrol exposure , and uterine anomaly . When a cervical length of < 25 mm was measured before a gestational age of 27 weeks , a r and omization for therapeutic cerclage and bed rest ( cerclage group ) or bed rest alone ( bed rest group ) was performed . The analysis is based on intention to treat . RESULTS Of the 35 women who met the inclusion criteria , 19 were allocated r and omly to the cerclage group and 16 to the bed rest group . Both groups were comparable for mean cervical length and mean gestational age at time of r and omization , mean overall 20 mm and 21 weeks . Preterm delivery before 34 weeks was significantly more frequent in the bed rest group than in the cerclage group ( 7 of 16 vs none , respectively ; P = .002 ) . There was no statistically significant difference in neonatal survival between the groups ( 13 neonates survived in the bed rest group vs all in the cerclage group ) . The compound neonatal morbidity , defined as admission to the neonatal intensive care unit or neonatal death , was significantly higher in the bed rest group than in the cerclage group ( 8 of 16 vs 1 of 19 , respectively ; P = .005 ; RR = 9.5 , 95 % CI , 1.3 - 68.1 ) . CONCLUSIONS Therapeutic cerclage with bed rest reduces preterm delivery before 34 weeks of gestation and compound neonatal morbidity in women with risk factors and /or symptoms of cervical incompetence and a cervical length of < 25 mm before 27 weeks of gestation OBJECTIVE The purpose of this study was to determine the efficacy of cerclage and bed rest versus bed rest-only for the prevention of preterm birth in women with a short cervix found on transvaginal ultrasound examination . STUDY DESIGN Women with > or = 1 of high-risk factors for preterm birth ( > or = 1 preterm birth at < 35 weeks of gestation , > or = 2 curettages , diethylstilbestrol exposure , cone biopsy , Mullerian anomaly , or twin gestation ) were screened with transvaginal ultrasonography of the cervix every 2 weeks from 14 weeks of gestation to 23 weeks 6 days of gestation . Enrollment was offered to both asymptomatic women who were at high risk and who were identified to have short cervix ( < 25 mm ) or significant funneling ( > 25 % ) and nonscreened women who were at low risk and who were identified incidentally . The women who gave written consent were assigned r and omly to receive either McDonald cerclage or bed rest-only . Both groups received similar counseling and treatment . Primary outcome was preterm birth at < 35 weeks of gestation . RESULTS Sixty-one women were assigned r and omly . Forty-seven pregnancies ( 77 % ) were high-risk singleton gestations . Thirty-one women ( 51 % ) were allocated to cerclage , and 30 women ( 49 % ) were allocated to bed rest . There were no differences between the groups in demographic characteristics , risk factors , and cervical variables . Preterm birth at < 35 weeks of gestation occurred in 14 women ( 45 % ) in the cerclage group and in 14 women ( 47 % ) in the bed rest group ( relative risk , 0.94 ; 95 % CI , 0.34 - 2.58 ) . There was no difference in any obstetric or neonatal outcomes . A sub analysis of singleton pregnancies with previous preterm birth at < 35 weeks of gestation and a short cervix of < 25 mm ( n = 31 women ) also revealed no significant difference in recurrent preterm birth at < 35 weeks of gestation ( 40 % vs 56 % ; relative risk , 0.52 ; 95 % CI , 0.12 - 2.17 ) . CONCLUSION Cerclage did not prevent preterm birth in women with a short cervix . These results should be confirmed by larger trials OBJECTIVE The purpose of this study was to assess funnel type and pregnancy duration in women with previous spontaneous preterm birth and cervical length < 25 mm . STUDY DESIGN We performed a secondary analysis of a multicenter r and omized trial of cerclage . At the r and omization scan that documented short cervix , the presence and type of funnel ( U or V ) were recorded . RESULTS One hundred forty-seven of 301 women ( 49 % ) had funneling : V-shaped funnel , 99 women ; U-shaped funnel , 48 women . U-shaped funnel was associated significantly with preterm birth at < 24 , < 28 , < 35 , and < 37 weeks of gestation . In multivariable models that controlled for r and omization cervical length and cerclage , women with U-shaped funnel delivered earlier than women with either V-shaped funnel or no funnel . Interaction between cerclage and U-shaped funnel was observed , and analyses that were stratified by cerclage showed that women with a U-shaped funnel and cerclage delivered at a mean of 33.8 + /- 6.6 weeks of gestation , compared with women who did not receive cerclage ( 28.9 + /- 6.9 weeks of gestation ) . CONCLUSION U-shaped funnels in high-risk women with a short cervix are associated with earlier birth To determine the value of transvaginal sonography in women with a previous history of second trimester miscarriage due to cervical incompetence , 55 patients were subjected to either elective cervical cerclage or follow-up ( every second patient ) with weekly evaluations of the cervix by transvaginal ultrasonography . Emergency cerclage was applied when significant cervical changes were noted . All patients were evaluated with cervical cultures and ultrasound . Women with infection , fibroids , uterine malformations and multiple pregnancies were excluded from the study . The study population was divided in two groups . In group I ( n=27 ) elective cerclage was applied during the 14th week . Women in group II ( n=28 ) were subjected to serial weekly evaluations of the cervix by transvaginal ultrasonograms . In 18 cases emergency cerclage was applied due to significant cervical changes . In group I , labor started before the 33rd week in two cases ( 7.4 % ) , between 33 and 37 weeks in nine ( 33.3 % ) and after the 37th week in 16 cases ( 59.2 % ) . Out of the 18 patients in group II who had cervical cerclage after ultrasonographic evaluation , four ( 22.2 % ) delivered before the 33rd week , three ( 16.6 % ) between 33 and 37 weeks and 11 ( 61.1 % ) after the 37th week . No statistical difference was noted between the two groups referring to pregnancy outcome ( p<0.1 ) . We concluded that ultrasound-guided management despite cervical shortening , does not result in unfavorable pregnancy outcome . A significant number of patients can avoid the operation Purpose To measure the outcome of emergency cervical cerclage ( ECC ) combined with progesterone vs. progesterone alone in pregnancy prolongation for preterm labor at 24–28 weeks . Methods One hundred patients in early labor were allocated r and omly into two equal groups . Group A were treated by ECC and progesterone , and group B were on the same progesterone dose only treatment . Results No significant differences were observed in both groups as regard demographic data , fetal gestational age or cervical state on admission . However , a significant pregnancy prolongation was observed in group A ( 28.44 ± 12.73 days vs. 9.96 ± 3.27 in group B , p < 0.001 ) with subsequent increase in fetal gestational age ( 32.04 ± 3.2 vs. 27.86 ± 3.213 , p < 0.001 ) , heavier weight , higher Apgar score at 1 and 5 min , and lower rate of cesarean delivery ( 1033.1 ± 170.83 vs. 715.1 ± 138.73 , p < 0.001 ) ( 2.68 ± 1.132 vs. 2.14 ± 0.93 , p < 0.001 ) , ( 5.48 ± 2.6 vs. 2.38 ± 1.59 , p = 0.01 ) and ( 16 vs. 62 % , p = 0.01 ) , respectively . Also neonatal outcomes in terms of early neonatal deaths were lower in this group ( 18 vs. 46 % , p = 0.049 ) . Conclusions ECC is effective in pregnancy prolongation when judiciously used in combination with progesterone compared to progesterone alone BACKGROUND Cervical cerclage has been widely used in the past 50 years to prevent early preterm birth and its associated neonatal mortality and morbidity . Results of r and omised trials have not generally lent support to this practice , but this absence of benefit may be due to suboptimum patient selection , which was essentially based on obstetric history . A more effective way of identifying the high-risk group for early preterm delivery might be by transvaginal sonographic measurement of cervical length . We undertook a multicentre r and omised controlled trial to investigate whether , in women with a short cervix identified by routine transvaginal scanning at 22 - 24 weeks ' gestation , the insertion of a Shirodkar suture reduces early preterm delivery . METHODS Cervical length was measured in 47?123 women . The cervix was 15 mm or less in 470 , and 253 ( 54 % ) of these women participated in the study and were r and omised to cervical cerclage ( 127 ) or to expectant management ( 126 ) . Primary outcome was the frequency of delivery before 33 completed weeks ( 231 days ) of pregnancy . FINDINGS The proportion of preterm delivery before 33 weeks was similar in both groups , 22 % ( 28 of 127 ) in the cerclage group versus 26 % ( 33 of 126 ) in the control group ( relative risk=0.84 , 95 % CI 0.54 - 1.31 , p=0.44 ) , with no significant differences in perinatal or maternal morbidity or mortality . INTERPRETATION The insertion of a Shirodkar suture in women with a short cervix does not substantially reduce the risk of early preterm delivery . Routine sonographic measurement of cervical length at 22 - 24 weeks identifies a group at high risk of early preterm birth Abstract Objective : The purpose was to determine the effect of vaginal pessaries in patients at risk for spontaneous preterm birth ( SPB ) . Study Design : Transvaginal sonography ( TVS ) was longitudinally performed to measure cervical length ( CL ) in 258 singleton at risk for SPB and 282 twin pregnancies . Pairs with or without treatment were matched for gestational age and the CL at examination . Results : In 4 singleton and 7 twin pregnancies the CL was < 15 mm before 24 weeks , the mean interval between pessary insertion and delivery was 13 + 2 and 12 + 5 weeks respectively . For the matched control analysis , 12 pairs with singleton and 23 pairs with twin pregnancies were compared . For singleton pregnancies , the mean interval between TVS and delivery was 99 ( 70–134 ) days in the treatment and 67 ( 2–130 ) days in the control group ( p = 0.0184 ) , the mean gestational age at delivery was 38 ( 36 + 6–41 ) and 33 + 4 ( 26–38 ) weeks respectively ( p = 0.02 ) . For twin pregnancies , the interval was 85 ( 43–129 ) days in the treatment and 67 ( 21–100 ) days in the control group ( p = 0.001 ) , gestational age at delivery was 35 + 6 ( 33–37 + 4 ) and 33 + 2 ( 24 + 4–37 + 2 ) respectively ( p = 0.02 ) . Within singleton pregnancies with pessary , there was no SPB < 36 weeks compared to 6/12 cases in the control group ( p < 0.001 ) . Within twin pregnancies , the rates were 8/23 cases with SPB < 36 weeks but none < 32 weeks , compared to 12/23 cases with SPB < 36 weeks and 7/23 cases < 32 weeks in the control group ( p < 0.001 ) . Conclusions : Insertion of a vaginal pessary may be a cost-effective preventive treatment in patients at risk for SPB . Prospect i ve controlled trials are needed History-indicated cervical cerclage is offered to patients who are at risk of spontaneous preterm birth ( SPTB ) , though the indications are controversial . A common practice of offering cerclage after three prior SPTBs or midtrimester losses ( MTLs ) is based on findings of the subgroup analysis of the 1993 Royal College of Obstetricians and Gynaecologists ( RCOG ) r and omized trial of cervical cerclage . The subgroup analysis was performed by repeating the primary analysis within individual subgroups , which can lead to erroneous conclusions . We repeated the subgroup analysis by evaluating the interaction between the characteristic of interest and treatment allocation in a regression model . The interaction between cerclage and any prior PTB as a binary variable was non-significant . Among subjects delivering at < 37 weeks , there was a significant interaction between cerclage and prior PTBs as a continuous variable or ≥ 3 ( p-values 0.04 and 0.03 , respectively ) . There were no significant interactions between cerclage and the aforementioned outcomes among women who delivered at <33 weeks , though this may have been secondary to a smaller number of SPTB in this range . Our findings lend credence to the current recommendations regarding the use of history-indicated cerclage , though they remain subject to the inherent limitations of subgroup analyses OBJECTIVES Women with a sonographic short cervix in the mid-trimester are at increased risk for preterm delivery . This study was undertaken to determine the efficacy and safety of using micronized vaginal progesterone gel to reduce the risk of preterm birth and associated neonatal complications in women with a sonographic short cervix . METHODS This was a multicenter , r and omized , double-blind , placebo-controlled trial that enrolled asymptomatic women with a singleton pregnancy and a sonographic short cervix ( 10 - 20 mm ) at 19 + 0 to 23 + 6 weeks of gestation . Women were allocated r and omly to receive vaginal progesterone gel or placebo daily starting from 20 to 23 + 6 weeks until 36 + 6 weeks , rupture of membranes or delivery , whichever occurred first . R and omization sequence was stratified by center and history of a previous preterm birth . The primary endpoint was preterm birth before 33 weeks of gestation . Analysis was by intention to treat . RESULTS Of 465 women r and omized , seven were lost to follow-up and 458 ( vaginal progesterone gel , n=235 ; placebo , n=223 ) were included in the analysis . Women allocated to receive vaginal progesterone had a lower rate of preterm birth before 33 weeks than did those allocated to placebo ( 8.9 % ( n=21 ) vs 16.1 % ( n=36 ) ; relative risk ( RR ) , 0.55 ; 95 % CI , 0.33 - 0.92 ; P=0.02 ) . The effect remained significant after adjustment for covariables ( adjusted RR , 0.52 ; 95 % CI , 0.31 - 0.91 ; P=0.02 ) . Vaginal progesterone was also associated with a significant reduction in the rate of preterm birth before 28 weeks ( 5.1 % vs 10.3 % ; RR , 0.50 ; 95 % CI , 0.25 - 0.97 ; P=0.04 ) and 35 weeks ( 14.5 % vs 23.3 % ; RR , 0.62 ; 95 % CI , 0.42 - 0.92 ; P=0.02 ) , respiratory distress syndrome ( 3.0 % vs 7.6 % ; RR , 0.39 ; 95 % CI , 0.17 - 0.92 ; P=0.03 ) , any neonatal morbidity or mortality event ( 7.7 % vs 13.5 % ; RR , 0.57 ; 95 % CI , 0.33 - 0.99 ; P=0.04 ) and birth weight < 1500 g ( 6.4 % ( 15/234 ) vs 13.6 % ( 30/220 ) ; RR , 0.47 ; 95 % CI , 0.26 - 0.85 ; P=0.01 ) . There were no differences in the incidence of treatment-related adverse events between the groups . CONCLUSIONS The administration of vaginal progesterone gel to women with a sonographic short cervix in the mid-trimester is associated with a 45 % reduction in the rate of preterm birth before 33 weeks of gestation and with improved neonatal outcome OBJECTIVES We sought to determine the predictive accuracy for preterm delivery of transvaginal ultrasonography of the cervix between 14 and 24 weeks ' gestation in high-risk patients and to determine whether cerclage prevents preterm delivery in patients with ultrasonographic cervical changes . STUDY DESIGN Patients with asymptomatic singleton pregnancies at high risk for preterm delivery were followed prospect ively from 14 weeks ' to 23 weeks 6 days ' gestation with transvaginal ultrasonography of the cervix . The subgroup of patients with either a cervical length of < 25 mm or funneling of > 25 % or both was offered McDonald salvage cerclage , which was performed at the discretion of the patient and the obstetrician . The 2 groups ( with and without cerclage ) were compared for the primary outcome of preterm delivery at < 35 weeks ' gestation . RESULTS One hundred sixty-eight women were followed , including 97 ( 58 % ) with > /=1 prior 14- to 34-week preterm deliveries . Of 63 ( 37 . 5 % ) patients identified as having cervical changes , 23 ( 37 % ) had preterm delivery ; of 105 patients with no cervical changes , 8 ( 8 % ) had preterm delivery ( relative risk , 4.8 ; 95 % confidence interval , 2 . 3 - 10.1 ) . The sensitivity , specificity , and positive and negative predictive values of either a short cervix of < 25 mm or funneling of > 25 % or both were 74 % , 70 % , 37 % , and 92 % , respectively . Of 63 pregnancies in which there were cervical changes , 39 underwent cerclage and 24 did not . These 2 groups were similar for demographic characteristics , risk factors , and transvaginal ultrasonographic cervical length and funneling but dissimilar for gestational age at identification of cervical changes ( 18.3 vs 21.2 weeks ' gestation in the groups with and without cerclage , respectively ; P < .001 ) . Multivariate logistic regression analysis after adjustment for gestational age at cervical changes showed no difference in the rate of preterm delivery between the groups with and without cerclage ( odds ratio , 1.1 ; 95 % confidence interval , 0.3 - 4.6 ) . Stratified analysis of patients identified between 18 and 24 weeks revealed 22 pregnancies with cerclage and 22 pregnancies without cerclage , which was similar for all characteristics studied . The incidence of preterm delivery remained similar ( 27 % vs 23 % , respectively ; P = .7 ) , as did days from cervical changes to delivery ( 111 vs 96 , respectively ; P = .2 ) . CONCLUSIONS Transvaginal ultrasonography of the cervix between 14 and 24 weeks ' gestation is a good predictor of preterm delivery in high-risk pregnancies . Cerclage may not prevent preterm delivery in patients identified to be at high risk for this outcome by transvaginal ultrasonography OBJECTIVE The purpose of this study was to identify the risk factors that are associated with increased neonatal morbidity in patients who were treated for sonographic evidence of internal os dilation and distal cervical shortening during the second trimester . STUDY DESIGN From May 1998 to June 2000 patients between 16 and 24 weeks of gestation with the following sonographic criteria were r and omly assigned to McDonald cerclage or no cerclage : internal os dilation and either membrane prolapse into the endocervical canal at least 25 % of the total cervical length but not beyond the external os or a shortened distal cervix < 2.5 cm . Before r and omization , all patients were treated identically with an amniocentesis , multiple urogenital cultures , and therapy with indomethacin and clindamycin for 48 to 72 hours . Except for the cerclage , all patients were treated identically after r and omization . Multiple variables of perinatal outcome were analyzed . A regression model with gestational age at delivery as the dependent variable was constructed and repeated with neonatal morbidity as the dependent variable . This model was applied to 3 population s : the cerclage group , the no cerclage group , and both groups combined . RESULTS Of the 135 patients , 20 patients declined r and omization , and 2 patients were diagnosed with acute chorioamnionitis . Of the 113 patients remaining , 55 patients were r and omly assigned to the cerclage group , and 58 patients were r and omly assigned to the no cerclage group . There were 8 rescue cerclage procedures ( 4 in each group ) . Regression analysis showed that readmission for preterm labor , chorioamnionitis , and abruption were consistently associated with early gestational age at delivery and increased morbidity . Cerclage did not affect perinatal outcome . CONCLUSION The sonographic findings of second trimester internal os dilation , membrane prolapse , and distal cervical shortening likely represent a common pathway of several pathophysiologic processes . Use of cerclage does not alter any perinatal outcome variables . Increased neonatal morbidity in these patients appears to be associated with sub clinical infection , preterm labor , and abruption OBJECTIVE The objective of this study was to compare different management strategies for women at risk for cervical incompetence . STUDY DESIGN In an ongoing r and omized trial patients with a previous preterm delivery at < 34 weeks ' gestation who met clinical criteria for the diagnosis of cervical incompetence are allocated to receive a prophylactic cerclage ( prophylactic cerclage group ) or not ( observational group ) in a proportion of 1:2 . Transvaginal ultrasonographic follow-up examination of the cervix is performed in both groups . When a patient of the latter group has a cervical length < 25 mm at < 27 weeks ' gestation , a further r and om assignment of therapeutic cerclage or no cerclage is performed . The analysis is by intent to treat . RESULTS Primary r and om assignment allocated 23 women to the prophylactic cerclage group and 44 to the observational group . Both groups were comparable with respect to obstetric history . No significant difference was found between the prophylactic cerclage group and the observational group in preterm delivery at < 34 weeks ' gestation ( 3/23 vs 6/44 , respectively ) and neonatal survival ( 21/23 vs 41/44 , respectively ) . A cervical length < 25 mm was found in 18 patients ( 41 % ) in the observational group at a mean gestational age of 19.1 + /- 2.9 weeks ' gestation . Incidence of preterm delivery at < 34 weeks ' gestation was significantly higher in the group with short cervical length ( 6/18 vs 0/26 ; P = .003 ) . Secondary r and om assignment of the 18 patients with short cervical length allocated 10 to undergo therapeutic cerclage . Preterm delivery at < 34 weeks ' gestation was significantly less frequent in the therapeutic cerclage group ( 1/10 vs 5/8 ) . CONCLUSION Transvaginal ultrasonographic serial follow-up examinations of the cervix in women at risk for cervical incompetence , with secondary intervention as indicated , appears to be a safe alternative to the traditional prophylactic cerclage . Transvaginal ultrasonographic follow-up examination of the cervix can save the majority of women from unnecessary intervention . Placement of a therapeutic cerclage may reduce the incidence of preterm delivery at < 34 weeks ' gestation among high-risk patients BACKGROUND The role of the cervix in the pathogenesis of premature delivery is controversial . In a prospect i ve , multicenter study of pregnant women , we used vaginal ultrasonography to measure the length of the cervix ; we also documented the incidence of spontaneous delivery before 35 weeks ' gestation . METHODS At 10 university-affiliated prenatal clinics , we performed vaginal ultrasonography at approximately 24 and 28 weeks of gestation in women with singleton pregnancies . We then assessed the relation between the length of the cervix and the risk of spontaneous preterm delivery . RESULTS We examined 2915 women at approximately 24 weeks of gestation and 2531 of these women again at approximately 28 weeks . Spontaneous preterm delivery ( at less than 35 weeks ) occurred in 126 of the women ( 4.3 percent ) examined at 24 weeks . The length of the cervix was normally distributed at 24 and 28 weeks ( mean [ + /- SD ] , 35.2 + /- 8.3 mm and 33.7 + /- 8.5 mm , respectively ) . The relative risk of preterm delivery increased as the length of the cervix decreased . When women with shorter cervixes at 24 weeks were compared with women with values above the 75th percentile , the relative risks of preterm delivery among the women with shorter cervixes were as follows : 1.98 for cervical lengths at or below the 75th percentile ( 40 mm ) , 2.35 for lengths at or below the 50th percentile ( 35 mm ) , 3.79 for lengths at or below the 25th percentile ( 30 mm ) , 6.19 for lengths at or below the 10th percentile ( 26 mm ) , 9.49 for lengths at or below the 5th percentile ( 22 mm ) , and 13.99 for lengths at or below the 1st percentile ( 13 mm ) ( P < 0.001 for values at or below the 50th percentile ; P = 0.008 for values at or below the 75th percentile ) . For the lengths measured at 28 weeks , the corresponding relative risks were 2.80 , 3.52 , 5.39 , 9.57 , 13.88 , and 24.94 ( P < 0.001 for values at or below the 50th percentile ; P = 0.003 for values at the 75th percentile ) . CONCLUSIONS The risk of spontaneous preterm delivery is increased in women who are found to have a short cervix by vaginal ultrasonography during pregnancy BACKGROUND Comparing the relative effectiveness of interventions on specific outcomes across trials can be problematic due to differences in the choice and definitions of outcome measures used by research ers . We sought to identify a minimum set of outcome measures for evaluating models of maternity care from the perspective of key stakeholders . METHODS A 3-round , electronic Delphi survey design was used . Setting was multinational , comprising a range of key stakeholders . Participants consisted of a single heterogeneous panel of maternity service users , midwives , obstetricians , pediatricians/neonatologists , family physicians/general practitioners , policy-makers , service practitioners , and research ers of maternity care . Members of the panel self-assessed their expertise in evaluating models of maternity care . RESULTS A total of 320 people from 28 countries expressed willingness to take part in this survey . Round 1 was completed by 218 ( 68.1 % ) participants , of whom 173 ( 79.4 % ) completed round 2 and 152 ( 87.9 % ) of these completed round 3 . Fifty outcomes were identified , with both a mean value greater than the overall group mean for all outcomes combined ( x=4.18 ) and rated 4 or more on a 5-point Likert-type scale for importance of inclusion in a minimum data set of outcome measures by at least 70 percent of respondents . Three outcomes were collapsed into a single outcome so that the final minimum set includes 48 outcomes . CONCLUSIONS Given the inconsistencies in the choice of outcome measures routinely collected and reported in r and omized evaluations of maternity care , it is hoped that use of the data set will increase the potential for national and international comparisons of models for maternity care . Although not intended to be prescriptive or to inhibit the collection of other outcomes , we hope that the core set will make it easier to assess the care of women and their babies during pregnancy and childbirth Objective : To assess cerclage benefit in women with short cervix also receiving 17-α-hydroxyprogesterone caproate ( 17P ) to prevent recurrent preterm birth ( PTB ) . Methods : Secondary analysis of a multicenter trial of ultrasound-indicated cerclage for shortened cervical length ( CL ) . Women with prior spontaneous PTB at 16–33 6/7 weeks , singleton gestation and CL < 25 mm between 16 and 22 6/7 weeks were counseled on use of 17P and r and omized to cerclage or no cerclage . Outcomes of women who received 17P were analyzed by r and omization group . Primary outcome was PTB < 35 weeks . Results : 99 women received 17P : 47 cerclage ; 52 no cerclage . Rates of PTB < 35 weeks were similar , 30 % for cerclage and 38 % for no cerclage ( aOR 0.64 ( 0.27–1.52 ) ) . In women with CL < 15 mm , PTB < 35 weeks was reduced for the cerclage group ( 17 % vs. 75 % , p = 0.02 ) . However , this difference was nullified after controlling for total progesterone doses received ( p = 0.40 ) . Conclusions : Cerclage was shown not to offer additional benefit for the prevention of recurrent PTB in women with short CL < 25 mm receiving 17P , but the sample size is insufficient for a definite conclusion given the 36 % nonsignificant decrease in the odds of PTB < 35 weeks . Cerclage may further offer substantial benefit to women with very short CL < 15 mm and further study is needed OBJECTIVE The purpose of this study was to compare preterm delivery rates and neonatal morbidity/mortality rates for women with cervical incompetence with membranes at or beyond a dilated external cervical os that was treated with emergency cerclage , bed rest plus indomethacin , versus just bed rest . STUDY DESIGN Women with cervical incompetence with membranes at or beyond a dilated external cervical os , before 27 weeks of gestation , were treated with antibiotics and bed rest and r and omly assigned for emergency cerclage and indomethacin or bed rest only . RESULTS Twenty-three women were included ; 13 women were allocated r and omly to the emergency cerclage and indomethacin group , and 10 women were allocated r and omly to the bed rest-only group . Gestational age at time of r and omization was 22.2 weeks in the emergency cerclage and indomethacin group and 23.0 weeks in the bed rest-only group . Mean interval from r and omization until delivery was 54 days in the emergency cerclage and indomethacin group and 20 days in the bed rest-only group ( P=.046 ) . Mean gestational age at delivery was 29.9 weeks in the emergency cerclage and indomethacin group and 25.9 weeks in the bed rest-only group . Preterm delivery before 34 weeks of gestation was significantly lower in the emergency cerclage and indomethacin group , with 7 of 13 deliveries versus all 10 deliveries in the bed rest-only group ( P=.02 ) . CONCLUSIONS Emergency cerclage , indomethacin , antibiotics , and bed rest reduce preterm delivery before 34 weeks compared with bed rest and antibiotics alone To evaluate the efficiency of cerclage or pessary a prospect i ve r and om study has been done from 1982 to 1983 . Pelvic score of Bishop and tocolysis index of Baumgarten were used to define the situation at the beginning . Success has been estimated with help of neonatal parameters ( birth weight , Apgar score and RDS-morbidity ) and final gestational week . Both methods are equal in their effects OBJECTIVE The purpose of this study was to estimate the effect of bacterial vaginosis on midtrimester cervical length in women at increased risk for recurrent spontaneous preterm birth . STUDY DESIGN We conducted a secondary analysis of prer and omization data from a multicenter trial of ultrasound-indicated cerclage . Women with previous spontaneous preterm birth at < 34 weeks ' gestation underwent initial cervical length assessment and vaginal fluid collection at 16 - 21 weeks 6 days gestation . Gram stains were scored with Nugent criteria . With serial scans , the shortest cervical length was observed . RESULTS Records for 949 women had complete data . In unadjusted regression models , Nugent score ( P = .003 ) and vaginal fluid pH ( P = .008 ) were related inversely to cervical length . Women with bacterial vaginosis based on Nugent score ≥7 ( P = .04 ) or pH ≥5 ( P = .016 ) had significantly lower cervical length than unaffected women ; however , all of these effects were null after covariate adjustment . CONCLUSION Nugent score , pH level , and bacterial vaginosis are associated inversely with cervical length ; however , these relationships become null after adjustment for relevant covariates Abstract Objective : To determine pregnancy outcome in patients with short cervix on transvaginal ultrasound between 16 and 24 weeks ' gestation treated with McDonald cerclage compared to weekly intramuscular injections of 17 α-hydroxyprogesterone caproate ( 17OHP-C ) . Methods : From November 2003 through December 2006 , asymptomatic , singleton pregnancies were screened with transvaginal ultrasound between 16–24 weeks ' gestation . Patients with a cervical length ( CL ) ≤25 mm were offered enrollment . Patients were r and omly assigned to treatment with McDonald cerclage or weekly intramuscular injections of 17OHP-C. The primary outcome was spontaneous preterm birth ( PTB ) prior to 35 weeks ' gestation . Results : Seventy-nine patients met inclusion criteria ; 42 were r and omly assigned to the cerclage and 37 to 17OHP-C. Spontaneous PTB prior to 35 weeks ' gestation occurred in 16/42 ( 38.1 % ) of the cerclage group and in 16/37 ( 43.2 % ) of the 17OHP-C group ( relative risk , 1.14 95 % CI , 0.67 , 1.93 ) . A post hoc analysis of patients with a prior PTB showed no difference in spontaneous PTB < 35 weeks between groups . A similar analysis of patients with a CL≤15 mm showed a reduction in spontaneous PTB < 35 weeks in the cerclage group ( relative risk 0.48 , 0.24–0.97 ) . Conclusion : Women with CL ≤25 mm in the second-trimester appear to have similar risks of delivering prior to 35 weeks ' gestation when treated with 17OHP-C or McDonald cerclage . However , cerclage may be more effective in preventing spontaneous PTB in women with CL≤15 mm OBJECTIVE We sought to compare history-indicated placement of cervical cerclage based on history- vs ultrasound-indicated placement in women at risk of preterm birth . STUDY DESIGN We conducted a r and omized controlled trial of history-indicated cervical cerclage suture based on history ( clinician preference ) vs ultrasound ( < 20 mm cervical length ) indicated in women at increased risk . RESULTS The incidence of the primary outcome , preterm delivery between 24(+0 ) and 33(+6 ) weeks , was similar : 19/125 ( 15 % ) in the history-indicated group vs 18/122 ( 15 % ) in the ultrasound-indicated group ( relative risk [ RR ] , 0.97 ; 95 % confidence interval [ CI ] , 0.54 - 1.76 ) . Those women r and omized to the ultrasound-indicated arm were significantly more likely to receive a cerclage ( 32 % vs 19 % ; RR , 1.66 ; 95 % CI , 1.07 - 2.47 ) and progesterone ( 39 % vs 25 % ; RR , 1.55 ; 95 % CI , 1.06 - 2.25 ) . CONCLUSION Screening women at high risk with cervical ultrasound to determine cerclage placement results in more intervention but similar outcome compared with history-indicated placement Summary . A total of 506 women at moderate risk of preterm delivery were r and omly allocated to either cervical cerclage or a control group . Significantly more women in the group allocated to cerclage were admitted to hospital for reasons other than the operation and more received oral toco‐lytic drugs . There were also more caesarean sections and more preterm deliveries in the women allocated to cerclage although the differences between the two groups were small and not statistically significant OBJECTIVE To evaluate whether increasing body mass index ( BMI ) alters the efficacy of ultrasound-directed cerclage in women with a history of preterm birth . METHODS This was a planned secondary analysis of a multicenter trial in which women with a singleton gestation and prior spontaneous preterm birth ( 17 to 33 + 6 weeks ' gestation ) were screened for a short cervix by serial transvaginal ultrasound evaluations between 16 and 22 + 6 weeks . Women with a short cervix ( cervical length < 25 mm ) were r and omly assigned to cerclage or not . Linear and logistic regression were used to assess the relationship between BMI and continuous and categorical variables , respectively . RESULTS Overall , in the screened women ( n = 986 ) , BMI was not associated with cervical length ( P = 0.68 ) , gestational age at delivery ( P = 0.12 ) or birth at < 35 weeks ( P = 0.68 ) . For the cerclage group ( n = 148 ) , BMI had no significant effect . For the no-cerclage group ( n = 153 ) , BMI was associated with a decrease in gestational age at delivery , with an estimated slope of - 0.14 weeks per kg/m(2 ) ( P = 0.03 ; including adjustment for cervical length ) . This result was driven primarily by several women with BMI > 47 kg/m(2 ) . CONCLUSION In women at high risk for recurrent preterm birth , BMI was not associated with cervical length or gestational age at birth . BMI did not appear to adversely affect ultrasound-indicated cerclage OBJECTIVE The objective of the study was to compare pregnancy outcomes in selected women with a dilated cervix who underwent expectant management or physical examination-indicated cerclage . STUDY DESIGN This was a historical cohort study conducted by the Global Network for Perinatal and Reproductive Health . Women between 14(0/7 ) and 25(6/7 ) weeks ' gestation with a dilated cervix were identified at 10 centers by ultrasound or digital examination . Primary outcome was time from presentation until delivery ( weeks ) . Secondary outcomes were neonatal survival , birthweight greater than 1500 g and preterm birth less than 28 weeks . Multivariate regression was used to assess the likelihood of neonatal outcomes and control for confounders . RESULTS Of 225 women , 152 received a physical examination-indicated cerclage , and 73 were managed expectantly without cerclage . Cervical dilation , gestational age at presentation , and antenatal steroid use differed between groups . In the adjusted analyses , cerclage was associated with longer interval from presentation until delivery , improved neonatal survival , birthweight greater than 1500 g and preterm birth less than 28 weeks , compared with expectant management . Similar results were obtained in the analyses limited to women dilated between 2 and 4 cm ( n = 122 ) . CONCLUSION In this study , the largest cohort reported to date , physical examination-indicated cerclage appears to prolong gestation and improve neonatal survival , compared with expectant management in selected women with cervical dilation between 14(0/7 ) and 25(6/7 ) weeks . A r and omized , controlled trial should be conducted to determine whether these potential benefits outweigh the risks of cerclage placement in this population Fifty patients with cervical incompetence were r and omised to have cervical cerclage either as in patients , spending 3 days in hospital post-procedure on supervised bed rest or as out patients spending the time at home on bed rest . Both groups had a clinical diagnosis of cervical incompetence and both had either McDonald or Shirodkar cerclage with mersilene tape . Both groups were given salbutamol tablets for tocolysis , postoperatively . There were no significant difference in the demographic variables between the groups such as previous cerclage , gestational age at insertion , parity and gestational age at delivery . There were also no significant differences in early complications such as bleeding . Most late complications were also not different , including the spontaneous abortion rate , premature rupture of membranes , cervical dystocia and preterm delivery . However , more patients in the outpatient group had premature contractions ( 26·1 % vs. 4·3 % P = 0·0479 ) . More patients in the inpatient group had a delivery of a live neonate , 86·9 % vs. 78·3 % , but the difference was not statistically significant . In conclusion , out patient cerclage appears to be a valid option , the higher rate of premature contraction in this group is not a cause for concern in view of the similar mean gestational age at delivery OBJECTIVE We sought to assess pregnancy outcome along a continuum of cervical lengths ( CLs ) ≥25 mm . STUDY DESIGN We conducted planned secondary analysis of a r and omized cerclage trial of women with prior spontaneous preterm birth 17(0)-34(6/7 ) weeks . Outcomes of women who maintained CLs ≥25 mm were analyzed . Women with CLs < 25 mm r and omized to no cerclage comprised an internal comparison group . RESULTS Of 1014 screened , 153 had CL < 25 mm , and 672 had CL ≥25 mm . Birth < 35 weeks occurred in 16 % of the ≥25 mm cohort . The relationship between CLs ≥25 mm and birth gestational age was null ( P = .15 ) . In the < 25 mm group , progressively shorter CLs predicted birth < 35 weeks ( P < .001 ) ; this relationship was null in the ≥25 mm group ( P = .17 ) . CONCLUSION The continuum of CLs ≥25 mm measured between 16(0/7)-22(6/7 ) weeks does not predict gestational length in women with prior spontaneous preterm birth AIM To evaluate the effect of double cervical cerclage on the prevention of preterm delivery , and perinatal and maternal outcomes in women with previous fetal loss in the second trimester . METHODS Between January 2001 and December 2006 we conducted a prospect i ve study in which patients with a previous preterm delivery at the second trimester who met clinical criteria for the diagnosis of cervical incompetence were r and omly allocated to receive double cervical cerclage or traditional single cervical cerclage at a ratio of 1:2 . RESULTS The perinatal and maternal outcomes of the two groups were compared . A total of 17 women were allocated to the double cervical cerclage group , and 34 to the traditional single cervical cerclage group . The single cervical cerclage group had a higher incidence of preterm delivery at < 28 weeks than the double cerclage group ( 29.4 vs 5.9 % , respectively , P = 0.0528 ) . The mean gestational age and birth weight in the double cervical cerclage group were significantly higher than in the traditional single cervical cerclage group ( 35.9 + /- 5.4 vs 32.9 + /- 7.5 weeks , respectively for gestational age , P = 0.045 ; 2696 + /- 911 vs 2242 + /- 1119 g , respectively for birth weight , P = 0.048 ) . No significant differences in rates of neonatal survival ( P = 0.241 ) and neonatal admission to the intensive care unit were found between the two groups . CONCLUSION Our results demonstrated that double cervical cerclage may significantly improve perinatal outcome in women with at least one previous pregnancy loss in the second trimester OBJECTIVE To examine the natural history of cervical length shortening in women who had experienced at least one prior spontaneous preterm birth at between 17 + 0 and 33 + 6 weeks ' gestation . METHODS This was an analysis of prer and omization data from the multicenter Vaginal Ultrasound Cerclage Trial . Serial cervical length was measured by transvaginal sonography in 1014 high-risk women at 16 + 0 to 22 + 6 weeks . We performed survival analyses in which the outcome was cervical length shortening<25 mm and data were censored if this did not occur before 22 + 6 weeks ' gestation . The incidence of cervical length shortening and the time to shortening were compared for women whose earliest prior preterm birth was in the mid-trimester , defined as < 24 weeks , vs. those at weeks 24 - 33 . Similar comparisons were performed based on each patient 's most recent birth history . RESULTS Time to cervical length shortening by survival analysis was significantly shorter ( hazard ratio (HR)=2.2 , P<0.0001 ) and the relative risk ( RR ) of shortening significantly higher ( RR=1.8 , P<0.0001 ) for women whose earliest prior spontaneous preterm birth was at < 24 weeks . A larger effect was observed for women whose most recent birth was at < 24 weeks ( HR=2.8 , P<0.0001 ; RR=2.1 , P<0.0001 ) . The observed hazard ratios remained significant after adjusting for confounders in a multivariable Cox proportional hazards model . CONCLUSION Women with a prior spontaneous preterm birth at < 24 weeks are at a higher risk of cervical shortening , and do so at a higher rate and at an earlier gestational age , than do women with a later preterm birth history |
13,638 | 31,368,738 | This effect was moderated by which mindfulness question naire was used , by the type of active control condition , and by whether the MBI and control were matched for amount of session time .
When mindfulness facet scores were analyzed separately , MBIs showed significantly greater pre – post increases than active controls in observing , nonjudging , and nonreactivity but not in describing or acting with awareness .
Although findings provide partial support for the differential sensitivity of mindfulness question naires to change with treatment , the nonsignificant difference in pre – post change when the MBI and control were matched for session time highlights the need to clarify how mindfulness skills are acquired in MBIs and in other interventions and whether revisions to mindfulness question naires would increase their specificity to changes in mindfulness skills | In support of the construct validity of mindfulness question naires , meta-analytic review s have reported that scores increase in mindfulness-based interventions ( MBIs ) .
However , several studies have also found increased mindfulness scores in interventions with no explicit mindfulness training , raising a question about differential sensitivity to change with treatment .
The central question was whether increases in mindfulness scores would be greater in the MBI than in the comparison group . | OBJECTIVE To compare the efficacy of Mindfulness-Based Addiction Treatment ( MBAT ) to a Cognitive Behavioral Treatment ( CBT ) that matched MBAT on treatment contact time , and a Usual Care ( UC ) condition that comprised brief individual counseling . METHOD Participants ( N = 412 ) were 48.2 % African American , 41.5 % non-Latino White , 5.4 % Latino , and 4.9 % other , and 57.6 % reported a total annual household income < $ 30,000 . The majority of participants were female ( 54.9 % ) . Mean cigarettes per day was 19.9 ( SD = 10.1 ) . Following the baseline visit , participants were r and omized to UC ( n = 103 ) , CBT ( n = 155 ) , or MBAT ( n = 154 ) . All participants were given self-help material s and nicotine patch therapy . CBT and MBAT groups received 8 2-hr in-person group counseling sessions . UC participants received 4 brief individual counseling sessions . Biochemically verified smoking abstinence was assessed 4 and 26 weeks after the quit date . RESULTS Logistic r and om effects model analyses over time indicated no overall significant treatment effects ( completers only : F(2 , 236 ) = 0.29 , p = .749 ; intent-to-treat : F(2 , 401 ) = 0.9 , p = .407 ) . Among participants classified as smoking at the last treatment session , analyses examining the recovery of abstinence revealed a significant overall treatment effect , F(2 , 103 ) = 4.41 , p = .015 ( MBAT vs. CBT : OR = 4.94 , 95 % CI : 1.47 to 16.59 , p = .010 , Effect Size = .88 ; MBAT vs. UC : OR = 4.18 , 95 % CI : 1.04 to 16.75 , p = .043 , Effect Size = .79 ) . CONCLUSION Although there were no overall significant effects of treatment on abstinence , MBAT may be more effective than CBT or UC in promoting recovery from lapses . ( PsycINFO Data base BACKGROUND Research suggests that an 8-week mindfulness-based cognitive therapy ( MBCT ) course may be effective for generalised anxiety disorder ( GAD ) . AIMS To compare changes in anxiety levels among participants with GAD r and omly assigned to MBCT , cognitive-behavioural therapy-based psychoeducation and usual care . METHOD In total , 182 participants with GAD were recruited ( trial registration number : CUHK_CCT00267 ) and assigned to the three groups and followed for 5 months after baseline assessment with the two intervention groups followed for an additional 6 months . Primary outcomes were anxiety and worry levels . RESULTS Linear mixed models demonstrated significant group × time interaction ( F(4,148 ) = 5.10 , P = 0.001 ) effects for decreased anxiety for both the intervention groups relative to usual care . Significant group × time interaction effects were observed for worry and depressive symptoms and mental health-related quality of life for the psychoeducation group only . CONCLUSIONS These results suggest that both of the interventions appear to be superior to usual care for the reduction of anxiety symptoms Objective : We compared mindfulness-based cognitive therapy ( MBCT ) with both cognitive psychological education ( CPE ) and treatment as usual ( TAU ) in preventing relapse to major depressive disorder ( MDD ) in people currently in remission following at least 3 previous episodes . Method : A r and omized controlled trial in which 274 participants were allocated in the ratio 2:2:1 to MBCT plus TAU , CPE plus TAU , and TAU alone , and data were analyzed for the 255 ( 93 % ; MBCT = 99 , CPE = 103 , TAU = 53 ) retained to follow-up . MBCT was delivered in accordance with its published manual , modified to address suicidal cognitions ; CPE was modeled on MBCT , but without training in meditation . Both treatments were delivered through 8 weekly classes . Results : Allocated treatment had no significant effect on risk of relapse to MDD over 12 months follow-up , hazard ratio for MBCT vs. CPE = 0.88 , 95 % CI [ 0.58 , 1.35 ] ; for MBCT vs. TAU = 0.69 , 95 % CI [ 0.42 , 1.12 ] . However , severity of childhood trauma affected relapse , hazard ratio for increase of 1 st and ard deviation = 1.26 ( 95 % CI [ 1.05 , 1.50 ] ) , and significantly interacted with allocated treatment . Among participants above median severity , the hazard ratio was 0.61 , 95 % CI [ 0.34 , 1.09 ] , for MBCT vs. CPE , and 0.43 , 95 % CI [ 0.22 , 0.87 ] , for MBCT vs. TAU . For those below median severity , there were no such differences between treatment groups . Conclusion : MBCT provided significant protection against relapse for participants with increased vulnerability due to history of childhood trauma , but showed no significant advantage in comparison to an active control treatment and usual care over the whole group of patients with recurrent depression Background : Social anxiety disorder ( SAD ) is characterized by distorted self-views . The goal of this study was to examine whether mindfulness-based stress reduction ( MBSR ) alters behavioral and brain measures of negative and positive self-views . Methods : Fifty-six adult patients with generalized SAD were r and omly assigned to MBSR or a comparison aerobic exercise ( AE ) program . A self-referential encoding task was administered at baseline and post-intervention to examine changes in behavioral and neural responses in the self-referential brain network during functional magnetic resonance imaging . Patients were cued to decide whether positive and negative social trait adjectives were self-descriptive or in upper case font . Results : Behaviorally , compared to AE , MBSR produced greater decreases in negative self-views , and equivalent increases in positive self-views . Neurally , during negative self versus case , compared to AE , MBSR led to increased brain responses in the posterior cingulate cortex ( PCC ) . There were no differential changes for positive self versus case . Secondary analyses showed that changes in endorsement of negative and positive self-views were associated with decreased social anxiety symptom severity for MBSR , but not AE . Additionally , MBSR-related increases in dorsomedial prefrontal cortex ( DMPFC ) activity during negative self-view versus case were associated with decreased social anxiety related disability and increased mindfulness . Analysis of neural temporal dynamics revealed MBSR-related changes in the timing of neural responses in the DMPFC and PCC for negative self-view versus case . Conclusion : These findings suggest that MBSR attenuates maladaptive habitual self-views by facilitating automatic ( i.e. , uninstructed ) recruitment of cognitive and attention regulation neural networks . This highlights potentially important links between self-referential and cognitive-attention regulation systems and suggests that MBSR may enhance more adaptive social self-referential processes in patients with SAD Background : Tinnitus is experienced by up to 15 % of the population and can lead to significant disability and distress . There is rarely a medical or surgical target and psychological therapies are recommended . We investigated whether mindfulness-based cognitive therapy ( MBCT ) could offer an effective new therapy for tinnitus . Methods : This single-site r and omized controlled trial compared MBCT to intensive relaxation training ( RT ) for chronic , distressing tinnitus in adults . Both treatments involved 8 weekly , 120-min sessions focused on either relaxation ( RT ) or mindfulness meditation ( MBCT ) . Assessment s were completed at baseline and at treatment commencement 8 weeks later . The primary outcomes were tinnitus severity ( Tinnitus Question naire ) and psychological distress ( Clinical Outcomes in Routine Evaluation - Non-Risk , CORE-NR ) , 16 weeks after baseline . The analysis utilized a modified intention-to-treat approach . Results : A total of 75 patients were r and omly allocated to MBCT ( n = 39 ) or RT ( n = 36 ) . Both groups showed significant reductions in tinnitus severity and loudness , psychological distress , anxiety , depression , and disability . MBCT led to a significantly greater reduction in tinnitus severity than RT , with a mean difference of 6.3 ( 95 % CI 1.3 - 11.4 , p = 0.016 ) . Effects persisted 6 months later , with a mean difference of 7.2 ( 95 % CI 2.1 - 2.3 , p = 0.006 ) and a st and ardized effect size of 0.56 ( 95 % CI 0.16 - 0.96 ) . Treatment was effective regardless of initial tinnitus severity , duration , or hearing loss . Conclusions : MBCT is effective in reducing tinnitus severity in chronic tinnitus patients compared to intensive RT . It also reduces psychological distress and disability . Future studies should explore the generalizability of this approach and how outcome relates to different aspects of the intervention BACKGROUND Individuals with a history of recurrent depression have a high risk of repeated depressive relapse or recurrence . Maintenance antidepressants for at least 2 years is the current recommended treatment , but many individuals are interested in alternatives to medication . Mindfulness-based cognitive therapy ( MBCT ) has been shown to reduce risk of relapse or recurrence compared with usual care , but has not yet been compared with maintenance antidepressant treatment in a definitive trial . We aim ed to see whether MBCT with support to taper or discontinue antidepressant treatment ( MBCT-TS ) was superior to maintenance antidepressants for prevention of depressive relapse or recurrence over 24 months . METHODS In this single-blind , parallel , group r and omised controlled trial ( PREVENT ) , we recruited adult patients with three or more previous major depressive episodes and on a therapeutic dose of maintenance antidepressants , from primary care general practice s in urban and rural setting s in the UK . Participants were r and omly assigned to either MBCT-TS or maintenance antidepressants ( in a 1:1 ratio ) with a computer-generated r and om number sequence with stratification by centre and symptomatic status . Participants were aware of treatment allocation and research assessors were masked to treatment allocation . The primary outcome was time to relapse or recurrence of depression , with patients followed up at five separate intervals during the 24-month study period . The primary analysis was based on the principle of intention to treat . The trial is registered with Current Controlled Trials , IS RCT N26666654 . FINDINGS Between March 23 , 2010 , and Oct 21 , 2011 , we assessed 2188 participants for eligibility and recruited 424 patients from 95 general practice s. 212 patients were r and omly assigned to MBCT-TS and 212 to maintenance antidepressants . The time to relapse or recurrence of depression did not differ between MBCT-TS and maintenance antidepressants over 24 months ( hazard ratio 0·89 , 95 % CI 0·67 - 1·18 ; p=0·43 ) , nor did the number of serious adverse events . Five adverse events were reported , including two deaths , in each of the MBCT-TS and maintenance antidepressants groups . No adverse events were attributable to the interventions or the trial . INTERPRETATION We found no evidence that MBCT-TS is superior to maintenance antidepressant treatment for the prevention of depressive relapse in individuals at risk for depressive relapse or recurrence . Both treatments were associated with enduring positive outcomes in terms of relapse or recurrence , residual depressive symptoms , and quality of life . FUNDING National Institute for Health Research ( NIHR ) Health Technology Assessment ( HTA ) programme , and NIHR Collaboration for Leadership in Applied Health Research and Care South West Peninsula Background : Caregivers of people with chronic conditions are more likely than non-caregivers to have depression and emotional problems . Few studies have examined the effectiveness of mindfulness-based stress reduction ( MBSR ) in improving their mental well-being . Methods : Caregivers of persons with chronic conditions who scored 7 or above in the Caregiver Strain Index were r and omly assigned to the 8-week MBSR group ( n = 70 ) or the self-help control group ( n = 71 ) . Vali date d instruments were used to assess the changes in depressive and anxiety symptoms , quality of life , self-efficacy , self-compassion and mindfulness . Assessment s were conducted at baseline , post-intervention and at the 3-month follow-up . Results : Compared to the participants in the control group , participants in the MBSR group had a significantly greater decrease in depressive symptoms at post-intervention and at 3 months post-intervention ( p < 0.01 ) . The improvement in state anxiety symptoms was significantly greater among participants in the MBSR group than those of the control group at post-intervention ( p = 0.007 ) , although this difference was not statistically significant at 3 months post-intervention ( p = 0.084 ) . There was also a statistically significant larger increase in self-efficacy ( controlling negative thoughts ; p = 0.041 ) and mindfulness ( p = 0.001 ) among participants in the MBSR group at the 3-month follow-up compared to the participants in the control group . No statistically significant group effects ( MBSR vs. control ) were found in perceived stress , quality of life or self-compassion . Conclusions : MBSR appears to be a feasible and acceptable intervention to improve mental health among family caregivers with significant care burden , although further studies that include an active control group are needed to make the findings more conclusive OBJECTIVE To determine whether neurocognitive performance and clinical outcomes can be enhanced by a mindfulness intervention in older adults with stress disorders and cognitive complaints . To explore decreased hypothalamic-pituitary-adrenal ( HPA ) axis activity as a possible mechanism . METHODS 103 adults aged 65 years or older with an anxiety or depressive disorder ( diagnosed according to DSM-IV criteria ) and subjective neurocognitive difficulties were recruited in St. Louis , Missouri , or San Diego , California , from September 2012 through August 2013 and r and omly assigned in groups of 5 - 8 to mindfulness-based stress reduction ( MBSR ) or a health education control condition matched for time , attention , and credibility . The primary outcomes were memory ( assessed by immediate and delayed paragraph and list recall ) and cognitive control ( Delis-Kaplan Executive Function System Verbal Fluency Test and Color Word Interference Test ) . Other outcomes included clinical symptoms ( worry , depression , anxiety , and global improvement ) . HPA axis activity was assessed using peak salivary cortisol . Outcomes were measured immediately post-intervention and ( for clinical outcomes only ) at 3- and 6-month follow up . RESULTS On the basis of intent-to-treat principles using data from all 103 participants , the mindfulness group experienced greater improvement on a memory composite score ( P = .046 ) . Groups did not differ on change in cognitive control . Participants receiving MBSR also improved more on measures of worry ( P = .042 ) and depression ( P = .049 ) at posttreatment and on worry ( P = .02 ) , depression ( P = .002 ) , and anxiety ( P = .002 ) at follow-up and were more likely to be rated as much or very much improved as rated by the Clinical Global Impressions-Improvement scale ( 47 % vs 27 % , χ² = 4.5 , P = .03 ) . Cortisol level decreased to a greater extent in the mindfulness group , but only among those participants with high baseline cortisol . CONCLUSIONS In this population of older adults with stress disorders and neurocognitive difficulties , a mindfulness intervention improves clinical outcomes such as excessive worry and depression and may include some forms of immediate memory performance . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01693874 Objective : Both Mindfulness Based Cognitive Therapy ( MBCT ) and Cognitive Therapy ( CT ) enhance self-management of prodromal symptoms associated with depressive relapse , albeit through divergent therapeutic procedures . We evaluated rates of relapse in remitted depressed patients receiving MBCT and CT . Decentering and dysfunctional attitudes were assessed as treatment-specific process markers . Method : Participants in remission from Major Depressive Disorder ( MDD ; N = 166 ) were r and omized to 8 weeks of either MBCT ( N = 82 ) or CT ( N = 84 ) and were followed for 24 months , with process markers measured every 3 months . Attendance in both treatments was high ( 6.3/8 session ) and treatment fidelity and competence were evaluated . Relapse was defined as a return of symptoms meeting the criteria for major depression on Module A of the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders ( SCID ) . Results : Intention-to-treat analyses indicated no differences between MBCT and CT in either rates of relapse to MDD or time to relapse across 24 months of follow up . Both groups experienced significant increases in decentering and participants in CT reported greater reductions in dysfunctional attitudes . Within both treatments , participants who relapsed evidence d lower decentering scores than those who stayed well over the follow up . Conclusions : This is the first study to directly compare relapse prophylaxis following MBCT and CT directly . The lack of group differences in time to relapse supports the view that both interventions are equally effective and that increases in decentering achieved via either treatment are associated with greater protection . These findings lend credence to Teasdale et al. ’s ( 2002 ) contention that , even though they may be taught through dissimilar methods , CT and MBCT help participants develop similar metacognitive skills for the regulation of distressing thoughts and emotions OBJECTIVE The aim of this study was to investigate the potential of mindfulness-based stress reduction ( MBSR ) as a treatment for chronic primary insomnia . DESIGN A r and omized controlled trial was conducted . SETTING The study was conducted at a university health center . PATIENTS Thirty adults with primary chronic insomnia based on criteria of the Diagnostic and Statistical Manual of Mental Disorders , Text Revision , 4th Edition were r and omized 2:1 to MBSR or pharmacotherapy ( PCT ) . INTERVENTIONS Mindfulness-based stress reduction , a program of mindfulness meditation training consisting of eight weekly 2.5 hour classes and a daylong retreat , was provided , with ongoing home meditation practice expectations during three-month follow-up ; PCT , consisting of three milligrams of eszopiclone ( LUNESTA ) nightly for eight weeks , followed by three months of use as needed . A 10-minute sleep hygiene presentation was included in both interventions . MAIN OUTCOMES The Insomnia Severity Index ( ISI ) , Pittsburgh Sleep Quality Index ( PSQI ) , sleep diaries , and wrist actigraphy were collected pretreatment , posttreatment ( eight weeks ) , and at five months ( self-reports only ) . RESULTS Between baseline and eight weeks , sleep onset latency ( SOL ) measured by actigraphy decreased 8.9 minutes in the MBSR arm ( P < .05 ) . Large , significant improvements were found on the ISI , PSQI , and diary-measured total sleep time , SOL , and sleep efficiency ( P < .01 , all ) from baseline to five-month follow-up in the MBSR arm . Changes of comparable magnitude were found in the PCT arm . Twenty-seven of 30 patients completed their assigned treatment . This study provides initial evidence for the efficacy of MBSR as a viable treatment for chronic insomnia as measured by sleep diary , actigraphy , well-vali date d sleep scales , and measures of remission and clinical recovery PURPOSE This study was design ed to evaluate potential preventive effects of meditation or exercise on incidence , duration , and severity of acute respiratory infection ( ARI ) illness . METHODS Community-recruited adults aged 50 years and older were r and omized to 1 of 3 study groups : 8-week training in mindfulness meditation , matched 8-week training in moderate-intensity sustained exercise , or observational control . The primary outcome was area-under-the-curve global illness severity during a single cold and influenza season , using the Wisconsin Upper Respiratory Symptom Survey ( WURSS-24 ) to assess severity . Health care visits and days of missed work were counted . Nasal wash collected during ARI illness was assayed for neutrophils , interleukin-8 , and viral nucleic acid . RESULTS Of 154 adults r and omized into the study , 149 completed the trial ( 82 % female , 94 % white , mean age 59.3 ± 6.6 years ) . There were 27 ARI episodes and 257 days of ARI illness in the meditation group ( n = 51 ) , 26 episodes and 241 illness days in the exercise group ( n = 47 ) , and 40 episodes and 453 days in the control group ( n = 51 ) . Mean global severity was 144 for meditation , 248 for exercise , and 358 for control . Compared with control , global severity was significantly lower for meditation ( P = .004 ) . Both global severity and total days of illness ( duration ) trended toward being lower for the exercise group ( P=.16 and P=.032 , respectively ) , as did illness duration for the meditation group ( P=.034 ) . Adjusting for covariates using zero-inflated multivariate regression models gave similar results . There were 67 ARI-related days of-work missed in the control group , 32 in the exercise group ( P = .041 ) , and 16 in the meditation group ( P < .001 ) . Health care visits did not differ significantly . Viruses were identified in 54 % of sample s from meditation , 42 % from exercise , and 54 % from control groups . Neutrophil count and interleukin-8 levels were similar among intervention groups . CONCLUSIONS Training in meditation or exercise may be effective in reducing ARI illness burden For people at risk of depressive relapse , mindfulness-based cognitive therapy ( MBCT ) has an additive benefit to usual care ( H. F. Coelho , P. H. Canter , & E. Ernst , 2007 ) . This study asked if , among patients with recurrent depression who are treated with antidepressant medication ( ADM ) , MBCT is comparable to treatment with maintenance ADM ( m-ADM ) in ( a ) depressive relapse prevention , ( b ) key secondary outcomes , and ( c ) cost effectiveness . The study design was a parallel 2-group r and omized controlled trial comparing those on m-ADM ( N = 62 ) with those receiving MBCT plus support to taper/discontinue antidepressants ( N = 61 ) . Relapse/recurrence rates over 15-month follow-ups in MBCT were 47 % , compared with 60 % in the m-ADM group ( hazard ratio = 0.63 ; 95 % confidence interval : 0.39 to 1.04 ) . MBCT was more effective than m-ADM in reducing residual depressive symptoms and psychiatric comorbidity and in improving quality of life in the physical and psychological domains . There was no difference in average annual cost between the 2 groups . Rates of ADM usage in the MBCT group was significantly reduced , and 46 patients ( 75 % ) completely discontinued their ADM . For patients treated with ADM , MBCT may provide an alternative approach for relapse prevention Purpose Cancer-related cognitive impairment ( CRCI ) is a common , fatigue-related symptom that disrupts cancer survivors ’ quality of life . Few interventions for CRCI exist . As part of a r and omized pilot study targeting cancer-related fatigue , the effects of mindfulness-based stress reduction ( MBSR ) on survivors ’ cognitive outcomes were investigated . Methods Breast and colorectal cancer survivors ( n = 71 ) with moderate-to-severe fatigue were r and omized to MBSR ( n = 35 ) or a fatigue education and support ( ES ; n = 36 ) condition . The Attentional Function Index ( AFI ) and the Stroop test were used to assess survivors ’ cognitive function at baseline ( T1 ) , after the 8-week intervention period ( T2 ) , and 6 months later ( T3 ) using intent-to-treat analysis . Mediation analyses were performed to explore mechanisms of intervention effects on cognitive functioning . Results MBSR participants reported significantly greater improvement on the AFI total score compared to ES participants at T2 ( d = 0.83 , p = 0.001 ) and T3 ( d = 0.55 , p = 0.021 ) . MBSR also significantly outperformed ES on most AFI subscales , although both groups improved over time . MBSR produced greater Stroop accuracy rates relative to ES at T2 ( r = 0.340 , p = 0.005 ) and T3 ( r = 0.280 , p = 0.030 ) , with improved accuracy over time only for the MBSR group . There were no significant differences in Stroop reaction time between groups . Improvements in mindfulness mediated the effect of group ( e.g. , MBSR vs. ES ) on AFI total score at T2 and T3 . Conclusions Additional r and omized trials with more comprehensive cognitive measures are warranted to definitively assess the efficacy of MBSR for CRCI . Implication s for Cancer SurvivorsThis pilot study has important implication s for all cancer survivors as it is the first published trial to show that MBSR offers robust and durable improvements in CRCI & NA ; Mindfulness‐based stress reduction ( MBSR ) is a structured 8‐week group program teaching mindfulness meditation and mindful yoga exercises . MBSR aims to help participants develop nonjudgmental awareness of moment‐to‐moment experience . Fibromyalgia is a clinical syndrome with chronic pain , fatigue , and insomnia as major symptoms . Efficacy of MBSR for enhanced well‐being of fibromyalgia patients was investigated in a 3‐armed trial , which was a follow‐up to an earlier quasi‐r and omized investigation . A total of 177 female patients were r and omized to one of the following : ( 1 ) MBSR , ( 2 ) an active control procedure controlling for nonspecific effects of MBSR , or ( 3 ) a wait list . The major outcome was health‐related quality of life ( HRQoL ) 2 months post‐treatment . Secondary outcomes were disorder‐specific quality of life , depression , pain , anxiety , somatic complaints , and a proposed index of mindfulness . Of the patients , 82 % completed the study . There were no significant differences between groups on primary outcome , but patients overall improved in HRQoL at short‐term follow‐up ( P = 0.004 ) . Post hoc analyses showed that only MBSR manifested a significant pre‐to‐post‐intervention improvement in HRQoL ( P = 0.02 ) . Furthermore , multivariate analysis of secondary measures indicated modest benefits for MBSR patients . MBSR yielded significant pre‐to‐post‐intervention improvements in 6 of 8 secondary outcome variables , the active control in 3 , and the wait list in 2 . In conclusion , primary outcome analyses did not support the efficacy of MBSR in fibromyalgia , although patients in the MBSR arm appeared to benefit most . Effect sizes were small compared to the earlier , quasi‐r and omized investigation . Several method ological aspects are discussed , e.g. , patient burden , treatment preference and motivation , that may provide explanations for differences . In a 3‐armed r and omized controlled trial in female patients suffering from fibromyalgia , patients benefited modestly from a mindfulness‐based stress reduction intervention Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Most of the extant literature investigating the health effects of mindfulness interventions relies on wait-list control comparisons . The current article specifies and vali date s an active control condition , the Health Enhancement Program ( HEP ) , thus providing the foundation necessary for rigorous investigations of the relative efficacy of Mindfulness Based Stress Reduction ( MBSR ) and for testing mindfulness as an active ingredient . 63 participants were r and omized to either MBSR ( n = 31 ) or HEP ( n = 32 ) . Compared to HEP , MBSR led to reductions in thermal pain ratings in the mindfulness- but not the HEP-related instruction condition ( η(2 ) = .18 ) . There were significant improvements over time for general distress ( η(2 ) = .09 ) , anxiety ( η(2 ) = .08 ) , hostility ( η(2 ) = .07 ) , and medical symptoms ( η(2 ) = .14 ) , but no effects of intervention . Practice was not related to change . HEP is an active control condition for MBSR while remaining inert to mindfulness . These cl aims are supported by results from a pain task . Participant-reported outcomes ( PROs ) replicate previous improvements to well-being in MBSR , but indicate that MBSR is no more effective than a rigorous active control in improving these indices . These results emphasize the importance of using an active control condition like HEP in studies evaluating the effectiveness of MBSR Improvements in attentional performance are at the core of proposed mechanisms for stress reduction in mindfulness meditation practice s. However , this cl aim can be question ed because no previous studies have actively manipulated test effort in control groups and controlled for effects of stress reduction per se . In a blinded design , 48 young , healthy meditation novices were r and omly assigned to a mindfulness-based stress reduction ( MBSR ) , nonmindfulness stress reduction ( NMSR ) , or inactive control group . At posttest , inactive controls were r and omly split into nonincentive and incentive controls , the latter receiving a financial reward to improve attentional performance . Pre- and postintervention , 5 vali date d attention paradigms were employed along with self-report scales on mindfulness and perceived stress and saliva cortisol sample s to measure physiological stress . Attentional effects of MBSR , NMSR , and the financial incentive were comparable or significantly larger in the incentive group on all reaction-time-based measures . However , selective attention in the MBSR group improved significantly more than in any other group . Similarly , only the MBSR intervention improved the threshold for conscious perception and visual working memory capacity . Furthermore , stress-reducing effects of MBSR were supported because those in the MBSR group showed significantly less perceived and physiological stress while increasing their mindfulness levels significantly . We argue that MBSR may contribute uniquely to attentional improvements but that further research focusing on non-reaction-time-based measures and outcomes less confounded by test effort is needed . Critically , our data demonstrate that previously observed improvements of attention after MBSR may be seriously confounded by test effort and nonmindfulness stress reduction OBJECTIVE We evaluated the comparative effectiveness of mindfulness-based cognitive therapy ( MBCT ) versus an active control condition ( ACC ) for depression relapse prevention , depressive symptom reduction , and improvement in life satisfaction . METHOD Ninety-two participants in remission from major depressive disorder with residual depressive symptoms were r and omized to either an 8-week MBCT or a vali date d ACC that is structurally equivalent to MBCT and controls for nonspecific effects ( e.g. , interaction with a facilitator , perceived social support , treatment outcome expectations ) . Both interventions were delivered according to their published manuals . RESULTS Intention-to-treat analyses indicated no differences between MBCT and ACC in depression relapse rates or time to relapse over a 60-week follow-up . Both groups experienced significant and equal reductions in depressive symptoms and improvements in life satisfaction . A significant quadratic interaction ( Group × Time ) indicated that the pattern of depressive symptom reduction differed between groups . The ACC experienced immediate symptom reduction postintervention and then a gradual increase over the 60-week follow-up . The MBCT group experienced a gradual linear symptom reduction . The pattern for life satisfaction was identical but only marginally significant . CONCLUSIONS MBCT did not differ from an ACC on rates of depression relapse , symptom reduction , or life satisfaction , suggesting that MBCT is no more effective for preventing depression relapse and reducing depressive symptoms than the active components of the ACC . Differences in trajectory of depressive symptom improvement suggest that the intervention-specific skills acquired may be associated with differential rates of therapeutic benefit . This study demonstrates the importance of comparing psychotherapeutic interventions to active control conditions Background : Due to the clinical challenges of treatment-resistant depression ( TRD ) , we evaluated the efficacy of mindfulness-based cognitive therapy ( MBCT ) relative to a structurally equivalent active comparison condition as adjuncts to treatment-as-usual ( TAU ) pharmacotherapy in TRD . Methods : This single-site , r and omized controlled trial compared 8-week courses of MBCT and the Health Enhancement Program ( HEP ) , comprising physical fitness , music therapy and nutritional education , as adjuncts to TAU pharmacotherapy for outpatient adults with TRD . The primary outcome was change in depression severity , measured by percent reduction in the total score on the 17-item Hamilton Depression Rating Scale ( HAM-D17 ) , with secondary depression indicators of treatment response and remission . Results : We enrolled 173 adults ; mean length of a current depressive episode was 6.8 years ( SD = 8.9 ) . At the end of 8 weeks of treatment , a multivariate analysis showed that relative to the HEP condition , the MBCT condition was associated with a significantly greater mean percent reduction in the HAM-D17 ( 36.6 vs. 25.3 % ; p = 0.01 ) and a significantly higher rate of treatment responders ( 30.3 vs. 15.3 % ; p = 0.03 ) . Although numerically superior for MBCT than for HEP , the rates of remission did not significantly differ between treatments ( 22.4 vs. 13.9 % ; p = 0.15 ) . In these models , state anxiety , perceived stress and the presence of personality disorder had adverse effects on outcomes . Conclusions : MBCT significantly decreased depression severity and improved treatment response rates at 8 weeks but not remission rates . MBCT appears to be a viable adjunct in the management of TRD Mindfulness-based cognitive therapy ( MBCT ) showed efficacy for currently depressed patients . However , most of the available studies suffer from important method ological shortcomings , including the lack of adequate control groups . The present study aims to compare MBCT with a psycho-educational control group design ed to be structurally equivalent to the MBCT program but excluding the main putative " active ingredient " of MBCT ( i.e. , mindfulness meditation practice ) for the treatment of patients with major depression ( MD ) who did not achieve remission following at least 8 weeks of antidepressant treatment . Out of 106 screened subjects , 43 were r and omized to receive MBCT or psycho-education and were prospect ively followed for 26 weeks . MD severity was assessed with the Hamilton Rating Scale for Depression ( HAM-D ) and the Beck Depression Inventory-II ( BDI-II ) . Measures of anxiety , mindfulness , and quality of life were also included . All assessment s were performed at baseline , 4 , 8 , 17 and 26-weeks . Both HAM-D and BDI scores , as well as quality of life and mindfulness scores , showed higher improvements , which were particularly evident over the long-term period , in the MBCT group than in the psycho-education group . Although limited by a small sample size , the results of this study suggest the superiority of MBCT over psycho-education for non-remitted MD subjects Background This study evaluated the efficacy of a mindfulness training programme ( mindfulness-based stress reduction ( MBSR ) ) in improving asthma-related quality of life and lung function in patients with asthma . Methods A r and omised controlled trial compared an 8-week MBSR group-based programme ( n=42 ) with an educational control programme ( n=41 ) in adults with mild , moderate or severe persistent asthma recruited at a university hospital outpatient primary care and pulmonary care clinic . Primary outcomes were quality of life ( Asthma Quality of Life Question naire ) and lung function ( change from baseline in 2-week average morning peak expiratory flow ( PEF ) ) . Secondary outcomes were asthma control assessed by 2007 National Institutes of Health/National Heart Lung and Blood Institute guidelines , and stress ( Perceived Stress Scale ( PSS ) ) . Follow-up assessment s were conducted at 10 weeks , 6 and 12 months . Results At 12 months MBSR result ed in clinical ly significant improvements from baseline in quality of life ( differential change in Asthma Quality of Life Question naire score for MBSR vs control : 0.66 ( 95 % CI 0.30 to 1.03 ; p<0.001 ) ) but not in lung function ( morning PEF , PEF variability and forced expiratory volume in 1 s ) . MBSR also result ed in clinical ly significant improvements in perceived stress ( differential change in PSS score for MBSR vs control : −4.5 ( 95 % CI −7.1 to −1.9 ; p=0.001 ) ) . There was no significant difference ( p=0.301 ) in percentage of patients in MBSR with well controlled asthma ( 7.3 % at baseline to 19.4 % ) compared with the control condition ( 7.5 % at baseline to 7.9 % ) . Conclusions MBSR produced lasting and clinical ly significant improvements in asthma-related quality of life and stress in patients with persistent asthma , without improvements in lung function . Clinical Trial Registration Number Asthma and Mindfulness-Based Reduction ( MBSR ) Identifier : NCT00682669 . clinical trials.gov CONTEXT Mindfulness-based cognitive therapy ( MBCT ) is a group-based psychosocial intervention design ed to enhance self-management of prodromal symptoms associated with depressive relapse . OBJECTIVE To compare rates of relapse in depressed patients in remission receiving MBCT against maintenance antidepressant pharmacotherapy , the current st and ard of care . DESIGN Patients who met remission criteria after 8 months of algorithm-informed antidepressant treatment were r and omized to receive maintenance antidepressant medication , MBCT , or placebo and were followed up for 18 months . SETTING Outpatient clinics at the Centre for Addiction and Mental Health , Toronto , Ontario , Canada , and St Joseph 's Healthcare , Hamilton , Ontario . PARTICIPANTS One hundred sixty patients aged 18 to 65 years meeting DSM-IV criteria for major depressive disorder with a minimum of 2 past episodes . Of these , 84 achieved remission ( 52.5 % ) and were assigned to 1 of the 3 study conditions . INTERVENTIONS Patients in remission discontinued their antidepressants and attended 8 weekly group sessions of MBCT , continued taking their therapeutic dose of antidepressant medication , or discontinued active medication and were switched to placebo . MAIN OUTCOME MEASURE Relapse was defined as a return , for at least 2 weeks , of symptoms sufficient to meet the criteria for major depression on module A of the Structured Clinical Interview for DSM-IV . RESULTS Intention-to-treat analyses showed a significant interaction between the quality of acute-phase remission and subsequent prevention of relapse in r and omized patients ( P = .03 ) . Among unstable remitters ( 1 or more Hamilton Rating Scale for Depression score > 7 during remission ) , patients in both MBCT and maintenance treatment showed a 73 % decrease in hazard compared with placebo ( P = .03 ) , whereas for stable remitters ( all Hamilton Rating Scale for Depression scores ≤7 during remission ) there were no group differences in survival . CONCLUSIONS For depressed patients achieving stable or unstable clinical remission , MBCT offers protection against relapse/recurrence on a par with that of maintenance antidepressant pharmacotherapy . Our data also highlight the importance of maintaining at least 1 long-term active treatment in unstable remitters BACKGROUND An appreciation of cognitive predictors of change in treatment outcome may help to better underst and differential treatment outcomes . The aim of this study was to examine how rumination and mindfulness impact on treatment outcome in two group-based interventions for non-melancholic depression : Cognitive Behaviour Therapy ( CBT ) and Mindfulness-Based Cognitive Therapy ( MBCT ) . METHOD Sixty-nine participants were r and omly allocated to either 8-weekly sessions of group CBT or MBCT . Complete data were obtained from 45 participants ( CBT = 26 , MBCT = 19 ) . Outcome was assessed at completion of group treatments . RESULTS Depression scores improved for participants in both group interventions , with no significant differences between the two treatment conditions . There were no significant differences between the interventions at post-treatment on mindfulness or rumination scores . Rumination scores significantly decreased from pre- to post-treatment for both conditions . In the MBCT condition , post-treatment rumination scores were significantly associated with post-treatment mindfulness scores . CONCLUSIONS Results suggest that decreases in rumination scores may be a common feature following both CBT and MBCT interventions . However , post-treatment rumination scores were associated with post-treatment mindfulness in the MBCT condition , suggesting a unique role for mindfulness in underst and ing treatment outcome for MBCT OBJECTIVE The goal of this study was to investigate treatment outcome and mediators of cognitive-behavioral group therapy ( CBGT ) versus mindfulness-based stress reduction ( MBSR ) versus waitlist ( WL ) in patients with generalized social anxiety disorder ( SAD ) . METHOD One hundred eight unmedicated patients ( 55.6 % female ; mean age = 32.7 years , SD = 8.0 ; 43.5 % Caucasian , 39 % Asian , 9.3 % Hispanic , 8.3 % other ) were r and omized to CBGT versus MBSR versus WL and completed assessment s at baseline , posttreatment/WL , and at 1-year follow-up , including the Liebowitz Social Anxiety Scale-Self-Report ( primary outcome ; Liebowitz , 1987 ) as well as measures of treatment-related processes . RESULTS Linear mixed model analysis showed that CBGT and MBSR both produced greater improvements on most measures compared with WL . Both treatments yielded similar improvements in social anxiety symptoms , cognitive re appraisal frequency and self-efficacy , cognitive distortions , mindfulness skills , attention focusing , and rumination . There were greater decreases in subtle avoidance behaviors following CBGT than MBSR . Mediation analyses revealed that increases in re appraisal frequency , mindfulness skills , attention focusing , and attention shifting , and decreases in subtle avoidance behaviors and cognitive distortions , mediated the impact of both CBGT and MBSR on social anxiety symptoms . However , increases in re appraisal self-efficacy and decreases in avoidance behaviors mediated the impact of CBGT ( vs. MBSR ) on social anxiety symptoms . CONCLUSIONS CBGT and MBSR both appear to be efficacious for SAD . However , their effects may be a result of both shared and unique changes in underlying psychological processes The Mindful Attention Awareness Scale ( MAAS ) measures perceived degree of inattentiveness in different context s and is often used as a reversed indicator of mindfulness . MAAS is hypothesized to reflect a psychological trait or disposition when used outside attentional training context s , but the long-term test-retest reliability of MAAS scores is virtually untested . It is unknown whether MAAS predicts psychological health after controlling for st and ardized socioeconomic status classifications . First , MAAS translated to Danish was vali date d psychometrically within a r and omly invited healthy adult community sample ( N = 490 ) . Factor analysis confirmed that MAAS scores quantified a unifactorial construct of excellent composite reliability and consistent convergent validity . Structural equation modeling revealed that MAAS scores contributed independently to predicting psychological distress and mental health , after controlling for age , gender , income , socioeconomic occupational class , stressful life events , and social desirability ( β = 0.32-.42 , ps < .001 ) . Second , MAAS scores showed satisfactory short-term test-retest reliability in 100 retested healthy university students . Finally , MAAS sample mean scores as well as individuals ' scores demonstrated satisfactory test-retest reliability across a 6 months interval in the adult community ( retested N = 407 ) , intraclass correlations ≥ .74 . MAAS scores displayed significantly stronger long-term test-retest reliability than scores measuring psychological distress ( z = 2.78 , p = .005 ) . Test-retest reliability estimates did not differ within demographic and socioeconomic strata . Scores on the Danish MAAS were psychometrically vali date d in healthy adults . MAAS 's inattentiveness scores reflected a unidimensional construct , long-term reliable disposition , and a factor of independent significance for predicting psychological health . ( PsycINFO Data base OBJECTIVE Neuroticism , a characteristic associated with increased stress vulnerability and the tendency to experience distress , is strongly linked to risk of different forms of psychopathology . However , there are few evidence -based interventions to target neuroticism . This pilot study investigated the efficacy and acceptability of mindfulness-based cognitive therapy ( MBCT ) compared with an online self-help intervention for individuals with high levels of neuroticism . The MBCT was modified to address psychological processes that are characteristic of neuroticism . METHOD Participants with high levels of neuroticism were r and omized to MBCT ( n=17 ) or an online self-help intervention ( n=17 ) . Self-report question naires were administered preintervention and again at 4weeks postintervention . RESULTS Intention-to-treat analyses found that MBCT participants had significantly lower levels of neuroticism postintervention than the control group . Compared with the control group , the MBCT group also experienced significant reductions in rumination and increases in self-compassion and decentering , of which the latter two were correlated with reductions in neuroticism within the MBCT group . Low drop-out rates , high levels of adherence to home practice , and positive feedback from MBCT participants provide indications that this intervention may be an acceptable form of treatment for individuals who are vulnerable to becoming easily stressed . CONCLUSIONS MBCT specifically modified to target neuroticism-related processes is a promising intervention for reducing neuroticism . Results support evidence suggesting neuroticism is malleable and amenable to psychological intervention . MBCT for neuroticism warrants further investigation in a larger study IMPORTANCE Treatment of chronic low back pain ( LBP ) in older adults is limited by the adverse effects of analgesics . Effective nonpharmacologic treatment options are needed . OBJECTIVE To determine the effectiveness of a mind-body program at increasing function and reducing pain in older adults with chronic LBP . DESIGN , SETTING , AND PARTICIPANTS This single-blind , r and omized clinical trial compared a mind-body program ( n = 140 ) with a health education program ( n = 142 ) . Community-dwelling older adults residing within the Pittsburgh metropolitan area were recruited from February 14 , 2011 , to June 30 , 2014 , with 6-month follow-up completed by April 9 , 2015 . Eligible participants were 65 years or older with functional limitations owing to their chronic LBP ( ≥11 points on the Rol and and Morris Disability Question naire ) and chronic pain ( duration ≥3 months ) of moderate intensity . Data were analyzed from March 1 to July 1 , 2015 . INTERVENTIONS The intervention and control groups received an 8-week group program followed by 6 monthly sessions . The intervention was modeled on the Mindfulness-Based Stress Reduction program ; the control program , on the " 10 Keys " to Healthy Aging . MAIN OUTCOMES AND MEASURES Follow-up occurred at program completion and 6 months later . The score on the Rol and and Morris Disability Question naire was the primary outcome and measured functional limitations owing to LBP . Pain ( current , mean , and most severe in the past week ) was measured with the Numeric Pain Rating Scale . Secondary outcomes included quality of life , pain self-efficacy , and mindfulness . Intent-to-treat analyses were conducted . RESULTS Of 1160 persons who underwent screening , 282 participants enrolled in the trial ( 95 men [ 33.7 % ] and 187 women [ 66.3 % ] ; mean [ SD ] age,74.5 [ 6.6 ] years ) . The baseline mean ( SD ) Rol and and Morris Disability Question naire scores for the intervention and control groups were 15.6 ( 3.0 ) and 15.4 ( 3.0 ) , respectively . Compared with the control group , intervention participants improved an additional -1.1 ( mean , 12.1 vs 13.1 ) points at 8 weeks and -0.04 ( mean , 12.2 vs 12.6 ) points at 6 months ( effect sizes , -0.23 and -0.08 , respectively ) on the Rol and and Morris Disability Question naire . By 6 months , the intervention participants improved on the Numeric Pain Rating Scale current and most severe pain measures an additional -1.8 points ( 95 % CI , -3.1 to -0.05 points ; effect size , -0.33 ) and -1.0 points ( 95 % CI , -2.1 to 0.2 points ; effect size , -0.19 ) , respectively . The changes in Numeric Pain Rating Scale mean pain measure after the intervention were not significant ( -0.1 [ 95 % CI , -1.1 to 1.0 ] at 8 weeks and -1.1 [ 95 % CI , -2.2 to -0.01 ] at 6 months ; effect size , -0.01 and -0.22 , respectively ) . CONCLUSIONS AND RELEVANCE A mind-body program for chronic LBP improved short-term function and long-term current and most severe pain . The functional improvement was not sustained , suggesting that future development of the intervention could focus on durability . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01405716 We sought to examine psychological mechanisms of treatment outcomes of a mindfulness meditation intervention for generalized anxiety disorder ( GAD ) . We examined mindfulness and decentering as two potential therapeutic mechanisms of action of GAD symptom reduction in patients r and omized to receive either mindfulness-based stress reduction ( MBSR ) or an attention control class ( N = 38 ) . Multiple mediation analyses were conducted using a non-parametric cross product of the coefficients approach that employs bootstrapping . Analyses revealed that change in decentering and change in mindfulness significantly mediated the effect of MBSR on anxiety . When both mediators were included in the model , the multiple mediation analysis revealed a significant indirect effect through increases in decentering , but not mindfulness . Furthermore , the direct effect of MBSR on decrease in anxiety was not significant , suggesting that decentering fully mediated the relationship . Results also suggested that MBSR reduces worry through an increase in mindfulness , specifically by increases in awareness and nonreactivity . Improvements in GAD symptoms result ing from MBSR are in part explained by increased levels of decentering CONTEXT Patients who have received solid organ transplants continue to experience a myriad of complex symptoms related to their underlying disease and to chronic immunosuppression that reduce the quality of life . Beneficial nonpharmacologic therapies to address these symptoms have not been established in the transplant population . OBJECTIVE Assess the efficacy of mindfulness-based stress reduction ( MBSR ) in reducing symptoms of anxiety , depression , and poor sleep in transplant patients . DESIGN , SETTING , AND PATIENTS Controlled trial with a two-staged r and omization . Recipients of kidney , kidney/pancreas , liver , heart , or lung transplants were r and omized to MBSR ( n=72 ) or health education ( n=66 ) initially or after serving in a waitlist . Mean age was 54 years ( range 21 - 75 ) ; 55 % were men , and 91 % were white . INTERVENTIONS MBSR , a mindfulness meditation training program consisting of eight weekly 2.5-hour classes ; health education , a peer-led active control . PRIMARY OUTCOME MEASURES Anxiety ( State-Trait Anxiety Inventory ) , depression ( Center for Epidemiologic Studies Depression Scale ) , and sleep quality ( Pittsburgh Sleep Quality Index ) scales assessed by self-report at baseline , 8 weeks , 6 months , and 1 year . RESULTS Benefits of MBSR were above and beyond those afforded by the active control . MBSR reduced anxiety and sleep symptoms ( P < .02 ) , with medium treatment effects ( .51 and .56 ) at 1 year compared to health education in intention-to-treat analyses . Within the MBSR group , anxiety , depression , and sleep symptoms decreased and quality -of-life measures improved by 8 weeks ( P < .01 , all ) , and benefits were retained at 1 year ( P < .05 , all ) . Initial symptom reductions in the health education group were smaller and not sustained . Comparisons to the waitlist confirmed the impact of MBSR on both symptoms and quality of life , whereas health education improvements were limited to quality -of-life ratings . CONCLUSIONS MBSR reduced distressing symptoms of anxiety , depression , and poor sleep and improved quality of life . Benefits were sustained over 1 year . A health education program provided fewer benefits , and effects were not as durable . MBSR is a relatively inexpensive , safe , and effective community-based intervention A considerable proportion of patients with chronic obstructive pulmonary disease ( COPD ) entering pulmonary rehabilitation ( PR ) report psychological distress , which is often accompanied by poor physical health status . Mindfulness-based cognitive therapy ( MBCT ) has been shown to improve psychological and physical outcomes in other chronic diseases . We therefore evaluated the efficacy of MBCT as an add-on to a st and ard PR programme in COPD . COPD patients eligible for PR were cluster r and omised to receive either an 8-week , group-based MBCT programme as an add-on to an 8-week PR programme ( n=39 ) , or PR alone ( n=45 ) . The primary outcomes of psychological distress and physical health status impairment were measured with the Hospital Anxiety and Depression Scale ( HADS ) and the COPD Assessment Test ( CAT ) before r and omisation ( T1 ) , mid- ( T2 ) and post-intervention ( T3 ) , and at 3 ( T4 ) and 6 ( T5 ) months ’ follow-up . A statistically significant time × arm effect was found for the HADS ( Cohen 's d=0.62 , 95 % CIs (d)=0.18–1.06 , p=0.010 ) . The treatment effect on the CAT failed to reach statistical significance ( d=0.42 , 95 % CIs (d)=−0.06–0.90 , p=0.061 ) . MBCT showed a statistically significant and durable effect on psychological distress , indicating that MBCT may be an efficacious add-on to st and ard PR programmes in COPD . Mindfulness-based cognitive therapy : an efficacious add-on to PR programmes to reduce psychological distress in COPD BACKGROUND Mindfulness-based cognitive therapy ( MBCT ) and maintenance antidepressant medication ( mADM ) both reduce the risk of relapse in recurrent depression , but their combination has not been studied . Our aim was to investigate whether the addition of MBCT to mADM is a more effective prevention strategy than mADM alone . METHODS This study is one of two multicenter r and omised trials comparing the combination of MBCT and mADM to either intervention on its own . In the current trial , recurrently depressed patients in remission who had been using mADM for 6 months or longer ( n=68 ) , were r and omly allocated to either MBCT+mADM ( n=33 ) or mADM alone ( n=35 ) . Primary outcome was depressive relapse/recurrence within 15 months . Key secondary outcomes were time to relapse/recurrence and depression severity . Analyses were based on intention-to-treat . RESULTS There were no significant differences between the groups on any of the outcome measures . LIMITATIONS The current study included patients who had recovered from depression with mADM and who preferred the certainty of continuing medication to the possibility of participating in MBCT . Lower expectations of mindfulness in the current trial , compared with the parallel trial , may have caused selection bias . In addition , recruitment was hampered by the increasing availability of MBCT in the Netherl and s , and even about a quarter of participants included in the trial who were allocated to the control group chose to get MBCT elsewhere . CONCLUSIONS For this selection of recurrently depressed patients in remission and using mADM for 6 months or longer , MBCT did not further reduce their risk for relapse/recurrence or their ( residual ) depressive symptoms Reincarceration rates are high among substance-involved criminal offenders . This study ( conducted during 2010–2011 in an urban area and funded by a Washington State University-Vancouver mini-grant ) used a r and omized design to examine the effectiveness of mindfulness-based relapse prevention ( MBRP ) as compared to relapse prevention ( RP ) , as part of a residential addictions treatment program for women referred by the criminal-justice system ( N = 105 ) . At 15-week follow up , regression analyses found women in MBRP , compared to RP , reported significantly fewer drug use days and fewer legal and medical problems . Study limitations and future research directions for study ing the efficacy of MBRP are discussed Objective To evaluate the feasibility and cardiometabolic effects of mindfulness‐based stress reduction ( MBSR ) in women with overweight or obesity . Methods Eighty‐six women with BMI ≥ 25 kg/m2 were r and omized to 8 weeks of MBSR or health education and followed for 16 weeks . The primary outcome was the Toronto Mindfulness Scale . Secondary outcomes included the Perceived Stress Scale‐10 , fasting glucose , and blood pressure . Results Compared to health education , the MBSR group demonstrated significantly improved mindfulness at 8 weeks ( mean change from baseline , 4.5 vs. −1.0 ; P = 0.03 ) and significantly decreased perceived stress at 16 weeks ( −3.6 vs. −1.3 , P = 0.01 ) . In the MBSR group , there were significant reductions in fasting glucose at 8 weeks ( −8.9 mg/dL , P = 0.02 ) and at 16 weeks ( −9.3 mg/dL , P = 0.02 ) compared to baseline . Fasting glucose did not significantly improve in the health education group . There were no significant changes in blood pressure , weight , or insulin resistance in the MBSR group . Conclusions In women with overweight or obesity , MBSR significantly reduces stress and may have beneficial effects on glucose . Future studies demonstrating long‐term cardiometabolic benefits of MBSR will be key for establishing MBSR as an effective tool in the management of obesity BACKGROUND Insomnia is an important but often overlooked side effect of cancer . Dysfunctional sleep beliefs have been identified as an important perpetuating factor for insomnia . Mindfulness practice has been demonstrated to improve sleep quality but it is unknown whether these effects relate to changes in dysfunctional sleep beliefs . PURPOSE This study is a secondary analysis of a r and omized controlled trial comparing mindfulness-based cancer recovery ( MBCR ) to cognitive behavior therapy for insomnia ( CBT-I ) in cancer patients with insomnia . This present analysis compares program impact on mindfulness , dysfunctional sleep beliefs , and insomnia severity clinical cutoffs . METHODS Patients ( MBCR , n = 32 ; CBT-I , n = 40 ) were assessed at baseline , post-program , and 3-month follow-up . RESULTS Across both groups , patients showed improvements over time in acting with awareness ( P = .021 ) and not judging experiences ( P = .023 ) . Changes in dysfunctional sleep beliefs produced by the CBT-I group exceeded those produced by MBCR at post-program and follow-up ( P < .001 ) . Acting with awareness , non-judging , and non-reacting were the facets of mindfulness associated with an overall reduction in dysfunctional sleep beliefs . There were no significant differences between the MBCR and CBT-I groups in the percentage of patients exceeding insomnia severity clinical cutoffs at post-program or follow-up . CONCLUSIONS This study supports the use of both CBT-I and MBCR to reduce insomnia severity and suggests the development of mindfulness facets as a method of reducing dysfunctional sleep beliefs This pilot study compared mindfulness-based cognitive therapy ( MBCT ) with a self-help guide based on cognitive behaviour therapy ( CBT ) for university students experiencing difficulties due to perfectionism . Participants were r and omised to an MBCT intervention specifically tailored for perfectionism or pure CBT self-help . Question naires were completed at baseline , 8 weeks later ( corresponding to the end of MBCT ) and at 10-week follow-up . Post-intervention intention-to-treat ( ITT ) analyses identified that MBCT participants ( n = 28 ) had significantly lower levels of perfectionism and stress than self-help participants ( n = 32 ) . There was significant MBCT superiority for changes in unhelpful beliefs about emotions , rumination , mindfulness , self-compassion and decentering . At 10-week follow-up , effects were maintained in the MBCT group , and analyses showed superior MBCT outcomes for perfectionism and daily impairment caused by perfectionism . Pre-post changes in self-compassion significantly mediated the group differences in pre-post changes in clinical perfectionism . Greater frequency of mindfulness practice was associated with larger improvements in self-compassion . MBCT is a promising intervention for perfectionist students , which may result in larger improvements than pure CBT self-help . The findings require replication with a larger sample The Five Factor Mindfulness Question naire ( FFMQ ) measures 5 factor-analytically derived mindfulness aspects ( Observe , Describe , Non-Judgment , Non-Reactivity , and Acting with Awareness ) and is commonly used as an indicator of mindfulness in population surveys and studies of mindfulness-based interventions ( MBI ) . Outside MBI , FFMQ scores are hypothesized to reflect relatively stable human dispositions of importance to psychological health . However , the long-term test – retest reliability of FFMQ scores is virtually untested and it remains unknown whether FFMQ scores predict psychological health after controlling for st and ardized socioeconomic status classifications . First , we focused on psychometric validation of the FFMQ translated to Danish in a r and omly invited healthy and nonmeditating adult community sample ( N = 490 ) . Confirmatory factor analyses primarily supported a four-factor construct excluding the Observe facet . The four-factor model showed adequate composite reliability , convergent validity and satisfactory-excellent internal consistency , Cronbach & agr;s = .72–.91 . Structural equation modeling revealed that FFMQ Total scores were positively related to income and socioeconomic status but independently predicted psychological distress and mental health scores , respectively , after controlling for age , gender , body mass index , socioeconomic job classification , stressful life events , and social desirability , & bgr ; = −.24–.29 , ps < .001 . Second , FFMQ scores showed adequate short-term ( two weeks ) test – retest reliability among 99 healthy university students , Spearman ’s & rgr;s ≥ .82 . Finally , all FFMQ mean scores showed satisfactory test – retest reliability across a long-term ( six months ) interval ( N = 407 ) , intraclass correlation coefficients ≥.74 . We recommend the Danish FFMQ for further use . The Observe facet should be interpreted with caution . Remaining FFMQ facet scores comprise an internally consistent four-dimensional construct reflecting long-term-reliable human dispositions of independent significance for predicting mental health The current study attempted a rigorous test of the construct validity of a widely used self-report measure of dispositional mindfulness , the Five Facet Mindfulness Question naire ( FFMQ ) , within the context of an active controlled r and omized trial ( n = 130 ) . The trial included three arms : mindfulness-based stress reduction ( MBSR ) , an active control condition that did not include instruction in mindfulness meditation ( Health Enhancement Program [ HEP ] ) , and a waitlist control condition . Partial evidence for the convergent validity of the FFMQ was shown in correlations at baseline between FFMQ facets and measures of psychological symptoms and psychological well-being . In addition , facets of the FFMQ were shown to increase over the course of an MBSR intervention relative to a waitlist control condition . However , the FFMQ failed to show discriminant validity . Specifically , facets of the FFMQ were shown to increase over the course of the HEP intervention relative to the waitlist control condition . MBSR and HEP , in contrast , did not differ in changes in FFMQ score over time . Implication s of these findings for the measurement and theory of mindfulness and MBSR are discussed . ( PsycINFO Data base IMPORTANCE Mindfulness-based interventions may be acceptable to veterans who have poor adherence to existing evidence -based treatments for posttraumatic stress disorder ( PTSD ) . OBJECTIVE To compare mindfulness-based stress reduction with present-centered group therapy for treatment of PTSD . DESIGN , SETTING , AND PARTICIPANTS R and omized clinical trial of 116 veterans with PTSD recruited at the Minneapolis Veterans Affairs Medical Center from March 2012 to December 2013 . Outcomes were assessed before , during , and after treatment and at 2-month follow-up . Data collection was completed on April 22 , 2014 . INTERVENTIONS Participants were r and omly assigned to receive mindfulness-based stress reduction therapy ( n = 58 ) , consisting of 9 sessions ( 8 weekly 2.5-hour group sessions and a daylong retreat ) focused on teaching patients to attend to the present moment in a nonjudgmental , accepting manner ; or present-centered group therapy ( n = 58 ) , an active-control condition consisting of 9 weekly 1.5-hour group sessions focused on current life problems . MAIN OUTCOMES AND MEASURES The primary outcome , change in PTSD symptom severity over time , was assessed using the PTSD Checklist ( range , 17 - 85 ; higher scores indicate greater severity ; reduction of 10 or more considered a minimal clinical ly important difference ) at baseline and weeks 3 , 6 , 9 , and 17 . Secondary outcomes included PTSD diagnosis and symptom severity assessed by independent evaluators using the Clinician-Administered PTSD Scale along with improvements in depressive symptoms , quality of life , and mindfulness . RESULTS Participants in the mindfulness-based stress reduction group demonstrated greater improvement in self-reported PTSD symptom severity during treatment ( change in mean PTSD Checklist scores from 63.6 to 55.7 vs 58.8 to 55.8 with present-centered group therapy ; between-group difference , 4.95 ; 95 % CI , 1.92 - 7.99 ; P=.002 ) and at 2-month follow-up ( change in mean scores from 63.6 to 54.4 vs 58.8 to 56.0 , respectively ; difference , 6.44 ; 95 % CI , 3.34 - 9.53 , P < .001 ) . Although participants in the mindfulness-based stress reduction group were more likely to show clinical ly significant improvement in self-reported PTSD symptom severity ( 48.9 % vs 28.1 % with present-centered group therapy ; difference , 20.9 % ; 95 % CI , 2.2%-39.5 % ; P = .03 ) at 2-month follow-up , they were no more likely to have loss of PTSD diagnosis ( 53.3 % vs 47.3 % , respectively ; difference , 6.0 % ; 95 % CI , -14.1 % to 26.2 % ; P = .55 ) . CONCLUSIONS AND RELEVANCE Among veterans with PTSD , mindfulness-based stress reduction therapy , compared with present-centered group therapy , result ed in a greater decrease in PTSD symptom severity . However , the magnitude of the average improvement suggests a modest effect . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01548742 IMPORTANCE Mindfulness-based stress reduction ( MBSR ) has not been rigorously evaluated for young and middle-aged adults with chronic low back pain . OBJECTIVE To evaluate the effectiveness for chronic low back pain of MBSR vs cognitive behavioral therapy ( CBT ) or usual care . DESIGN , SETTING , AND PARTICIPANTS R and omized , interviewer-blind , clinical trial in an integrated health care system in Washington State of 342 adults aged 20 to 70 years with chronic low back pain enrolled between September 2012 and April 2014 and r and omly assigned to receive MBSR ( n = 116 ) , CBT ( n = 113 ) , or usual care ( n = 113 ) . INTERVENTIONS CBT ( training to change pain-related thoughts and behaviors ) and MBSR ( training in mindfulness meditation and yoga ) were delivered in 8 weekly 2-hour groups . Usual care included whatever care participants received . MAIN OUTCOMES AND MEASURES Co primary outcomes were the percentages of participants with clinical ly meaningful ( ≥30 % ) improvement from baseline in functional limitations ( modified Rol and Disability Question naire [ RDQ ] ; range , 0 - 23 ) and in self-reported back pain bothersomeness ( scale , 0 - 10 ) at 26 weeks . Outcomes were also assessed at 4 , 8 , and 52 weeks . RESULTS There were 342 r and omized participants , the mean ( SD ) [ range ] age was 49.3 ( 12.3 ) [ 20 - 70 ] years , 224 ( 65.7 % ) were women , mean duration of back pain was 7.3 years ( range , 3 months-50 years ) , 123 ( 53.7 % ) attended 6 or more of the 8 sessions , 294 ( 86.0 % ) completed the study at 26 weeks , and 290 ( 84.8 % ) completed the study at 52 weeks . In intent-to-treat analyses at 26 weeks , the percentage of participants with clinical ly meaningful improvement on the RDQ was higher for those who received MBSR ( 60.5 % ) and CBT ( 57.7 % ) than for usual care ( 44.1 % ) ( overall P = .04 ; relative risk [ RR ] for MBSR vs usual care , 1.37 [ 95 % CI , 1.06 - 1.77 ] ; RR for MBSR vs CBT , 0.95 [ 95 % CI , 0.77 - 1.18 ] ; and RR for CBT vs usual care , 1.31 [ 95 % CI , 1.01 - 1.69 ] ) . The percentage of participants with clinical ly meaningful improvement in pain bothersomeness at 26 weeks was 43.6 % in the MBSR group and 44.9 % in the CBT group , vs 26.6 % in the usual care group ( overall P = .01 ; RR for MBSR vs usual care , 1.64 [ 95 % CI , 1.15 - 2.34 ] ; RR for MBSR vs CBT , 1.03 [ 95 % CI , 0.78 - 1.36 ] ; and RR for CBT vs usual care , 1.69 [ 95 % CI , 1.18 - 2.41 ] ) . Findings for MBSR persisted with little change at 52 weeks for both primary outcomes . CONCLUSIONS AND RELEVANCE Among adults with chronic low back pain , treatment with MBSR or CBT , compared with usual care , result ed in greater improvement in back pain and functional limitations at 26 weeks , with no significant differences in outcomes between MBSR and CBT . These findings suggest that MBSR may be an effective treatment option for patients with chronic low back pain . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01467843 |
13,639 | 26,331,893 | Furthermore , the risk of infections with aflibercept was substantially higher than bevacizumab .
CONCLUSIONS Aflibercept is associated with a significant increased risk of developing severe infections in patients with solid tumours . | AIMS Aflibercept is an engineered humanized vascular endothelial growth factor (VEGF)-targeted agent .
Severe infections are serious adverse event associated with aflibercept .
However , the contribution of aflibercept to infection is still unknown .
We thus conducted this meta- analysis to investigate the overall incidence and risk of developing severe infections in cancer patients treated with aflibercept . | Introduction : Aflibercept ( vascular endothelial growth factor [ VEGF ] trap ) , a recombinant fusion protein , blocks the activity of VEGF-A and placental growth factor and has demonstrated activity in pretreated patients with lung cancer in a phase I trial . This study evaluated the efficacy and safety of intravenous aflibercept in patients with platinum- and erlotinib-resistant lung adenocarcinoma . Methods : An open-label , single arm , multicenter trial was conducted , with the primary end point of response rate ( modified RECIST ) . Additional endpoints included safety , duration of response , progression-free survival , and overall survival . Patients with platinum- and erlotinib-resistant lung adenocarcinoma were eligible . Aflibercept 4.0 mg/kg intravenous every 2 weeks was administered until progression of disease or intolerable toxicity . Results : Ninety-eight patients were enrolled ; 89 were evaluable for response . Median age was 60 years , 41 % were men with Eastern Cooperative Oncology Group performance status 0/1/2 in 35/55/9 % of patients . The overall response rate was 2.0 % , ( 95 % confidence interval , 0.2 - 7.2 % ) . Median progression-free survival was 2.7 months , and overall was survival 6.2 months . Six- and 12-month survival rates were 54 and 29 % , respectively . A median of four cycles was administered ( range 1 - 22 ) . Common grade 3/4 toxicities included dyspnea ( 21 % ) , hypertension ( 23 % ) , and proteinuria ( 10 % ) . Two cases of grade 5 hemoptysis were reported , and one case each of tracheoesophageal fistula , decreased cardiac ejection fraction , cerebral ischemia , and reversible posterior leukoencephalopathy . Conclusions : Aflibercept has minor single agent activity in heavily pretreated lung adenocarcinoma , and is well tolerated , with no unexpected toxicities . Further studies evaluating aflibercept in lung cancer , in combination with chemotherapy and other targeted therapies , are ongoing PURPOSE Development of new therapies for previously treated small-cell lung cancer ( SCLC ) is a major unmet need . Here , we describe a r and omized , phase II trial of weekly topotecan with or without ziv-aflibercept ( VEGF-trap ) in this clinical setting . PATIENTS AND METHODS Patients with previously treated SCLC ( one line of platinum-based chemotherapy ) , performance status of 0 to 1 , adequate organ function , treated brain metastases , and no recent vascular events or bleeding diatheses were eligible . Eligible patients were stratified as platinum-sensitive or platinum-refractory and r and omly assigned to receive weekly topotecan 4 mg/m(2 ) intravenously ( IV ) with or without ziv-aflibercept 6 mg/kg IV every 21 days . Progression-free survival ( PFS ) at 3 months was the primary end point . RESULTS In 189 r and omly assigned patients , treatment arms were well balanced with regard to clinical characteristics . The 3-month PFS was significantly improved with the addition of ziv-aflibercept in patients who had platinum-refractory disease ( 27 % v 10 % ; P = .02 ) but not in patients with platinum-sensitive disease ( 24 % v 15 % ; P = .22 ) . Although response rate was low , disease control rate was higher with combination therapy than with topotecan alone in patients who had platinum-sensitive disease ( 37 % v 18 % ; P = .05 ) and in those who had platinum-refractory disease ( 25 % v 15 % ; P = .14 ) . Overall survival ( OS ) was not significantly improved in either strata . Grade s 3 to 5 toxicities were more common with the addition of ziv-aflibercept . CONCLUSION Ziv-aflibercept improved the 3-month PFS in patients who had platinum-refractory SCLC , but its addition increased toxicity . OS was similar with combined ziv-aflibercept and topotecan compared with topotecan in both strata |
13,640 | 24,371,842 | All drug classes demonstrated increases in 6MWD when compared with placebo , and combination therapy showed improved 6MWD compared with monotherapy .
Although no studies were powered to detect a mortality reduction , monotherapy was associated with improved 6MWD and reduced hospitalization rates .
Our findings also suggest an improvement in 6MWD when a second drug is added to monotherapy | BACKGROUND Current treatments for pulmonary arterial hypertension ( PAH ) have been shown to improve dyspnea , 6-min walk distance ( 6MWD ) , and pulmonary hemodynamics , but few studies were design ed to compare treatment regimens or assess the impact of treatment on mortality .
METHODS We conducted a systematic review to evaluate the comparative effectiveness and safety of monotherapy or combination therapy for PAH using endothelin receptor antagonists , phosphodiesterase inhibitors , or prostanoids . | BACKGROUND Primary pulmonary hypertension is a progressive disease for which no treatment has been shown in a prospect i ve , r and omized trial to improve survival . METHODS We conducted a 12-week prospect i ve , r and omized , multicenter open trial comparing the effects of the continuous intravenous infusion of epoprostenol ( formerly called prostacyclin ) plus conventional therapy with those of conventional therapy alone in 81 patients with severe primary pulmonary hypertension ( New York Heart Association functional class III or IV ) . RESULTS Exercise capacity was improved in the 41 patients treated with epoprostenol ( median distance walked in six minutes , 362 m at 12 weeks vs. 315 m at base line ) , but it decreased in the 40 patients treated with conventional therapy alone ( 204 m at 12 weeks vs. 270 m at base line ; P < 0.002 for the comparison of the treatment groups ) . Indexes of the quality of life were improved only in the epoprostenol group ( P < 0.01 ) . Hemodynamics improved at 12 weeks in the epoprostenol-treated patients . The changes in mean pulmonary-artery pressure for the epoprostenol and control groups were -8 percent and + 3 percent , respectively ( difference in mean change , -6.7 mm Hg ; 95 percent confidence interval , -10.7 to -2.6 mm Hg ; P < 0.002 ) , and the mean changes in pulmonary vascular resistance for the epoprostenol and control groups were -21 percent and + 9 percent , respectively ( difference in mean change , -4.9 mm Hg/liter/min ; 95 percent confidence interval , -7.6 to -2.3 mm Hg/liter/min ; P < 0.001 ) . Eight patients died during the study , all of whom had been r and omly assigned to conventional therapy ( P = 0.003 ) . Serious complications included four episodes of catheter-related sepsis and one thrombotic event . CONCLUSIONS As compared with conventional therapy , the continuous intravenous infusion of epoprostenol produced symptomatic and hemodynamic improvement , as well as improved survival in patients with severe primary pulmonary hypertension Background — Eisenmenger syndrome is characterized by the development of pulmonary arterial hypertension with consequent intracardiac right-to-left shunt and hypoxemia in patients with preexisting congenital heart disease . Because Eisenmenger syndrome is associated with increased endothelin expression , patients may benefit from endothelin receptor antagonism . Theoretically , interventions that have some effect on the systemic vascular bed could worsen the shunt and increase hypoxemia . Methods and Results — The Bosentan R and omized Trial of Endothelin Antagonist Therapy-5 ( BREATHE-5 ) was a 16-week , multicenter , r and omized , double-blind , placebo-controlled study evaluating the effect of bosentan , a dual endothelin receptor antagonist , on systemic pulse oximetry ( primary safety end point ) and pulmonary vascular resistance ( primary efficacy end point ) in patients with World Health Organization functional class III Eisenmenger syndrome . Hemodynamics were assessed by right- and left-heart catheterization . Secondary end points included exercise capacity assessed by 6-minute walk distance , additional hemodynamic parameters , functional capacity , and safety . Fifty-four patients were r and omized 2:1 to bosentan ( n=37 ) or placebo ( n=17 ) for 16 weeks . The placebo-corrected effect on systemic pulse oximetry was 1.0 % ( 95 % confidence interval , −0.7 to 2.8 ) , demonstrating that bosentan did not worsen oxygen saturation . Compared with placebo , bosentan reduced pulmonary vascular resistance index ( −472.0 dyne · s · cm−5 ; P=0.0383 ) . The mean pulmonary arterial pressure decreased ( −5.5 mm Hg ; P=0.0363 ) , and the exercise capacity increased ( 53.1 m ; P=0.0079 ) . Four patients discontinued as a result of adverse events , 2 ( 5 % ) in the bosentan group and 2 ( 12 % ) in the placebo group . Conclusions — In this first placebo-controlled trial in patients with Eisenmenger syndrome , bosentan was well tolerated and improved exercise capacity and hemodynamics without compromising peripheral oxygen saturation Background — Safe , effective therapy is needed for pediatric pulmonary arterial hypertension . Methods and Results — Children ( n=235 ; weight ≥8 kg ) were r and omized to low- , medium- , or high-dose sildenafil or placebo orally 3 times daily for 16 weeks in the Sildenafil in Treatment-Naive Children , Aged 1–17 Years , With Pulmonary Arterial Hypertension ( STARTS-1 ) study . The primary comparison was percent change from baseline in peak oxygen consumption ( PV[Combining Dot Above]O2 ) for the 3 sildenafil doses combined versus placebo . Exercise testing was performed in 115 children able to exercise reliably ; the study was powered for this population . Secondary end points ( assessed in all patients ) included hemodynamics and functional class . The estimated mean±SE percent change in PV[Combining Dot Above]O2 for the 3 doses combined versus placebo was 7.7±4.0 % ( 95 % confidence interval , −0.2 % to 15.6 % ; P=0.056 ) . PV[Combining Dot Above]O2 , functional class , and hemodynamics improved with medium and high doses versus placebo ; low-dose sildenafil was ineffective . Most adverse events were mild to moderate in severity . STARTS-1 completers could enter the STARTS-2 extension study ; patients who received sildenafil in STARTS-1 continued the same dose , whereas placebo-treated patients were r and omized to low- , medium- , or high-dose sildenafil . In STARTS-2 ( ongoing ) , increased mortality was observed with higher doses . Conclusions — Sixteen-week sildenafil monotherapy is well tolerated in pediatric pulmonary arterial hypertension . Percent change in PV[Combining Dot Above]O2 for the 3 sildenafil doses combined was only marginally significant ; however , PV[Combining Dot Above]O2 , functional class , and hemodynamic improvements with medium and high doses suggest efficacy with these doses . Combined with STARTS-2 data , the overall profile favors the medium dose . Further investigation is warranted to determine optimal dosing based on age and weight . Clinical Trial Registration — http://www . clinical trials.gov . Unique identifier : NCT00159913 BACKGROUND Sildenafil inhibits phosphodiesterase type 5 , an enzyme that metabolizes cyclic guanosine monophosphate , thereby enhancing the cyclic guanosine monophosphate-mediated relaxation and growth inhibition of vascular smooth-muscle cells , including those in the lung . METHODS In this double-blind , placebo-controlled study , we r and omly assigned 278 patients with symptomatic pulmonary arterial hypertension ( either idiopathic or associated with connective-tissue disease or with repaired congenital systemic-to-pulmonary shunts ) to placebo or sildenafil ( 20 , 40 , or 80 mg ) orally three times daily for 12 weeks . The primary end point was the change from baseline to week 12 in the distance walked in six minutes . The change in mean pulmonary-artery pressure and World Health Organization ( WHO ) functional class and the incidence of clinical worsening were also assessed , but the study was not powered to assess mortality . Patients completing the 12-week r and omized study could enter a long-term extension study . RESULTS The distance walked in six minutes increased from baseline in all sildenafil groups ; the mean placebo-corrected treatment effects were 45 m ( + 13.0 percent ) , 46 m ( + 13.3 percent ) , and 50 m ( + 14.7 percent ) for 20 , 40 , and 80 mg of sildenafil , respectively ( P<0.001 for all comparisons ) . All sildenafil doses reduced the mean pulmonary-artery pressure ( P=0.04 , P=0.01 , and P<0.001 , respectively ) , improved the WHO functional class ( P=0.003 , P<0.001 , and P<0.001 , respectively ) , and were associated with side effects such as flushing , dyspepsia , and diarrhea . The incidence of clinical worsening did not differ significantly between the patients treated with sildenafil and those treated with placebo . Among the 222 patients completing one year of treatment with sildenafil monotherapy , the improvement from baseline at one year in the distance walked in six minutes was 51 m. CONCLUSIONS Sildenafil improves exercise capacity , WHO functional class , and hemodynamics in patients with symptomatic pulmonary arterial hypertension Background — Treatment options for pulmonary arterial hypertension target the prostacyclin , endothelin , or nitric oxide pathways . Tadalafil , a phosphodiesterase type-5 inhibitor , increases cGMP , the final mediator in the nitric oxide pathway . Methods and Results — In this 16-week , double-blind , placebo-controlled study , 405 patients with pulmonary arterial hypertension ( idiopathic or associated ) , either treatment-naive or on background therapy with the endothelin receptor antagonist bosentan , were r and omized to placebo or tadalafil 2.5 , 10 , 20 , or 40 mg orally once daily . The primary end point was the change from baseline to week 16 in the distance walked in 6 minutes . Changes in World Health Organization functional class , clinical worsening , and health-related quality of life were also assessed . Patients completing the 16-week study could enter a long-term extension study . Tadalafil increased the distance walked in 6 minutes in a dose-dependent manner ; only the 40-mg dose met the prespecified level of statistical significance ( P<0.01 ) . Overall , the mean placebo-corrected treatment effect was 33 m ( 95 % confidence interval , 15 to 50 m ) . In the bosentan-naive group , the treatment effect was 44 m ( 95 % confidence interval , 20 to 69 m ) compared with 23 m ( 95 % confidence interval , −2 to 48 m ) in patients on background bosentan therapy . Tadalafil 40 mg improved the time to clinical worsening ( P=0.041 ) , incidence of clinical worsening ( 68 % relative risk reduction ; P=0.038 ) , and health-related quality of life . The changes in World Health Organization functional class were not statistically significant . The most common treatment-related adverse events reported with tadalafil were headache , myalgia , and flushing . Conclusions — In patients with pulmonary arterial hypertension , tadalafil 40 mg was well tolerated and improved exercise capacity and quality of life measures and reduced clinical worsening STUDY OBJECTIVE To determine the efficacy of continuous intravenous infusion of prostacyclin ( epoprostenol ) in primary pulmonary hypertension . DESIGN R and omized trial with 8-week treatment periods and nonr and omized treatment for up to 18 months . SETTING Four referral centers . PATIENTS Sequential sample of 24 patients with primary pulmonary hypertension . Nineteen patients completed the study . Four patients died and one left the study because of adverse effects ( pulmonary edema ) . INTERVENTIONS Continuous intravenous prostacyclin administered by portable infusion pump at doses determined by acute responses during baseline catheterization in ten patients . Nine patients were treated with anticoagulants , oral vasodilators , and diuretics . MEASUREMENTS AND MAIN RESULTS Starting with a baseline value for total pulmonary resistance of 21.6 units , there was a decrease of 7.9 units ( 95 % CI , -13.1 to -2.2 ; P = 0.022 ) in the prostacyclin-treated group after 8 weeks ; there was virtually no change in the conventional therapy group ( from 20.6 to 20.4 units , not significant ) . Six of ten prostacyclin-treated patients who completed the 8-week study period had reductions in mean pulmonary artery pressure of greater than 10 mm Hg , whereas only one of nine in the conventional treatment group had a similar response ( P = 0.057 ) . Nine patients receiving prostacyclin for up to 18 months have persistent hemodynamic effects , although dose requirements have increased with time . Complications have been attributable to the drug delivery system . CONCLUSIONS Prostacyclin produces substantial and sustained hemodynamic and symptomatic responses in severe primary pulmonary hypertension and may be useful in the management of some patients with this disease The efficacy and safety of combining bosentan , an orally active dual endothelin receptor antagonist and epoprostenol , a continuously infused prostagl and in , in the treatment of pulmonary arterial hypertension ( PAH ) was investigated . In this double-blind , placebo-controlled prospect i ve study , 33 patients with PAH started epoprostenol treatment ( 2 ng·kg−1min−1 starting dose , up to 14±2 ng·kg−1min−1 at week 16 ) and were r and omised for 16 weeks in a 2:1 ratio to bosentan ( 62.5 mg b.i.d for 4 weeks then 125 mg b.i.d ) or placebo . Haemodynamics , exercise capacity and functional class improved in both groups at week 16 . In the combination treatment group , there was a trend for a greater ( although nonsignificant ) improvement in all measured haemodynamic parameters . There were four withdrawals in the bosentan/epoprostenol group ( two deaths due to cardiopulmonary failure , one clinical worsening , and one adverse event ) and one withdrawal in the placebo/epoprostenol group ( adverse event ) . This study showed a trend but no statistical significance towards haemodynamics or clinical improvement due to the combination of bosentan and epoprostenol therapy in patients with pulmonary arterial hypertension . Several cases of early and late major complications were reported . Additional information is needed to evaluate the risk/benefit ratio of combined bosentan-epoprostenol therapy in pulmonary arterial hypertension Addition of inhaled iloprost to bosentan may have beneficial effects in patients with idiopathic pulmonary arterial hypertension ( IPAH ) . A multicentre , open , r and omised , controlled trial was performed to assess the safety and efficacy of inhaled iloprost in patients with IPAH who had already been treated with bosentan . The trial was terminated early after a futility analysis predicted failure with respect to the predetermined sample size . At that time , 40 patients were r and omised to receive either bosentan alone ( control group ) or bosentan plus inhaled iloprost ( combination group ) for a 12-week period . The primary end-point , change in 6-min walking distance , was not met ( mean changes + 1 m and -9 m in the control and combination group , respectively ) . These results may have been skewed by three outliers in the iloprost group who presented with severe clinical worsening . None of the secondary end-points including functional class , peak oxygen uptake , and time to clinical worsening differed significantly between groups . The current study failed to show a positive effect of adding inhaled iloprost to bosentan in idiopathic pulmonary arterial hypertension patients . Further studies involving larger sample sizes and long-term follow-up are needed to determine the efficacy of adding inhaled iloprost to bosentan in patients with idiopathic pulmonary arterial hypertension AIMS To investigate the long-term safety of inhaled iloprost in patients with pulmonary hypertension ( pH ) , including idiopathic PAH ( IPAH group ) and other forms of pulmonary hypertension ( PHother ) . METHODS AND RESULTS Sixty-three patients ( IPAH group , n=40 , PHother n=23 ) were enrolled to receive inhaled iloprost either from baseline or after 3 months in a prospect i ve , open-label 2-year study . Iloprost was inhaled 6 - 9 times daily with a night pause employing a jet nebulizer delivering an inhaled single dose of 4microg at the mouthpiece . In the case of side effects the single dose was reduced to 2microg . Sixty patients received at least 1 dose of inhaled iloprost . Thirty-six patients completed at least 630 days of therapy ( 25 IPAH , 11 PHother ) , 19 patients dropped out prematurely and 8 patients died ( 3 IPAH , 5 PHother ) . There were no drug-induced toxicities and only mild to moderate side effects . The most common side effects were coughing and flushing . Two-year survival was estimated at 85 % ( IPAH group 91 % , PHother 78 % ) . A modified analysis was performed to correct for differential drop-out . It included follow-up data from the premature discontinuations and revealed a 2-year survival of 87 % [ 95 % CI , 76%-98 % ] in the IPAH group while the predicted survival was 63 % . The iloprost dose increased by 16 % over 2 years . CONCLUSION Inhaled iloprost is well tolerated as long-term therapy and no substantial dose increase is required . Although uncontrolled , the data suggest a long-term clinical benefit from continued therapy with inhaled iloprost RATIONALE Although the phosphodiesterase type 5 inhibitors sildenafil and tadalafil have demonstrated efficacy in patients with pulmonary arterial hypertension ( PAH ) , monotherapy with these agents has not been conclusively shown to reduce clinical worsening events . OBJECTIVES To evaluate the safety and efficacy of the phosphodiesterase type 5 inhibitor vardenafil in Chinese patients with PAH . METHODS In a r and omized , double-blind , placebo-controlled study , 66 patients with PAH were r and omized 2:1 to vardenafil ( 5 mg once daily for 4 wk then 5 mg twice daily ; n = 44 ) or placebo ( n = 22 ) for 12 weeks . Patients completing this phase were then treated with open-label vardenafil ( 5 mg twice daily ) for a further 12 weeks . MEASUREMENTS AND MAIN RESULTS At Week 12 , the mean placebo-corrected 6-minute walking distance was increased with vardenafil ( 69 m ; P < 0.001 ) , and this improvement was maintained for at least 24 weeks . Vardenafil also increased the mean placebo-corrected cardiac index ( 0.39 L·min(-1)·m(-2 ) ; P = 0.005 ) and decreased mean pulmonary arterial pressure and pulmonary vascular resistance ( -5.3 mm Hg , P = 0.047 ; -4.7 Wood U , P = 0.003 ; respectively ) at Week 12 . Four patients in the placebo group ( 20 % ) and one in the vardenafil group ( 2.3 % ) had clinical worsening events ( hazard ratio 0.105 ; 95 % confidence interval , 0.012 - 0.938 ; P = 0.044 ) . Vardenafil was associated with only mild and transient adverse events . CONCLUSIONS Vardenafil is effective and well tolerated in patients with PAH at a dose of 5 mg twice daily BACKGROUND Pulmonary arterial hypertension ( PAH ) is a life threatening disease for which phosphodiesterase-5 inhibitor sildenafil is recently approved . We aim ed to evaluate the efficacy and safety of tadalafil , a long acting congener of sildenafil , in treatment of PAH related to previous left to right shunt lesions . METHODS In this blinded , cross over study , 11 patients with severe PAH related to congenital left to right shunt lesions ( Eisenmenger syndrome ) were r and omly assigned to tadalafil ( 20 mg daily ) or placebo for 4 weeks period , separated by a wash out period of at least 2 weeks . They were symptomatic with a six minute walk distance (6MWD)>or=50 m. The change in 6MWD , echo-Doppler determined pulmonary artery systolic pressure ( PASP ) , WHO Class and modified Borg Dyspnea Index ( BDI ) were assessed after each therapy . RESULTS Eight patients who completed the study protocol were analyzed . Tadalafil was associated with a significant increase in 6MWD ( mean 409.25 SD 40.25 m vs 319.37 SD 42.39 m , p<0.0001 ) , reduction in PASP ( 88.75 SD 23.26 mmHg vs 109.5 SD 23.78 mmHg , p<0.0001 ) , improvement in BDI ( 4.62 SD 2.56 vs 6.37 SD 2.61 , p=0.021 ) and WHO Class ( 6 patients vs 2 patients ) , compared to placebo . Tadalafil was well tolerated with no significant untoward effects . CONCLUSIONS Tadalafil , in patients with PAH related to previous congenital left to right shunt lesions , lead to a significant improvement in exercise capacity ( 6MWD ) , PASP and WHO Class with reduced perceived exertion and was well tolerated Doppler‐defined pulmonary hypertension ( PH ) in sickle cell disease ( SCD ) is associated with 40 % mortality at 40 months . To assess the effect of bosentan in SCD‐PH , two r and omized , double‐blind , placebo‐controlled , 16‐week studies were initiated . Safety concerns are particularly relevant in SCD due to comorbid conditions . ASSET‐1 and ‐2 enrolled patients with pulmonary arterial hypertension ( PAH ) and pulmonary venous hypertension ( PH ) , respectively . Haemodynamics and 6‐min walk distance ( 6MWD ) were obtained at baseline and week 16 . The studies were terminated due to slow site initiation and patient enrolment ( n = 26 ) . Bosentan appeared to be well tolerated . Although sample sizes were limited , in ASSET‐1 at baseline , 6MWD correlated with cardiac output ( CO ; P = 0·006 ) with non‐significant inverse correlations between 6MWD and pulmonary vascular resistance ( PVR ; P = 0·07 ) and between 6MWD and right atrial pressure ( P = 0·08 ) . In ASSET‐2 at baseline , there was a non‐significant correlation between 6MWD and CO ( P = 0·06 ) . Due to limited sample sizes , efficacy endpoints were not analysed . However , in both studies , non‐significant increases in CO were observed with bosentan compared to placebo . Similarly , non‐significant decreases in PVR were observed with bosentan . Limited data in SCD‐PH suggest that a low 6MWD predicts a low CO . St and ard‐dose bosentan appears to be well tolerated . Further investigation is warranted . Clinical trials.gov registration numbers NCT00310830 , NCT00313196 , NCT00360087 RATIONALE Phosphodiesterase type 5 ( PDE5 ) inhibition has been proposed for the treatment for pulmonary arterial hypertension ( PAH ) . OBJECTIVE This study compared adding sildenafil , a PDE5 inhibitor , to conventional treatment with the current practice of adding bosentan , an endothelin receptor antagonist . METHODS Twenty-six patients with PAH , idiopathic or associated with connective tissue disease , World Health Organization ( WHO ) functional class III , were r and omized in a double-blind fashion to receive sildenafil ( 50 mg twice daily for 4 weeks , then 50 mg three times daily ) or bosentan ( 62.5 mg twice daily for 4 weeks , then 125 mg twice daily ) over 16 weeks . MEASUREMENTS Changes in right ventricular ( RV ) mass ( using cardiovascular magnetic resonance ) , 6-minute walk distance , cardiac function , brain natriuretic peptide , and Borg dyspnea index . MAIN RESULTS When analyzed by intention to treat , there were no significant differences between the two treatment groups . One patient on sildenafil died suddenly . Patients on sildenafil who completed the protocol showed significant changes from baseline , namely , reductions in RV mass ( -8.8 g ; 95 % confidence interval [ CI ] , -2 , -16 ; n = 13 , p = 0.015 ) and plasma brain natriuretic peptide levels ( -19.4 fmol x ml(-1 ) ; 95 % CI , -5 , -34 ; p = 0.014 ) and improvements in 6-minute walk distance ( 114 m ; 95 % CI , 67 , 160 ; p = 0.0002 ) , cardiac index ( 0.3 L x min(-1 ) x m(-2 ) ; 95 % CI , 0.1 , 0.4 ; p = 0.008 ) , and systolic left ventricular eccentricity index ( -0.2 ; 95 % CI , -0.02 , -0.37 ; p = 0.031 ) . Bosentan improved 6-minute walk distance ( 59 m ; 95 % CI , 29 , 89 ; n = 12 , p = 0.001 ) and cardiac index ( 0.3 ; 95 % CI , 0.1 , 0.4 ; p = 0.008 ) . CONCLUSIONS Sildenafil added to conventional treatment reduces RV mass and improves cardiac function and exercise capacity in patients with PAH , WHO functional class III . Safety monitoring is important until more experience is obtained Pulmonary hypertension is characterized by progressive elevation of pulmonary artery pressure and vascular resistance , often leading to right ventricular failure and death ( 1 - 3 ) . Continuous intravenous infusion of epoprostenol improves prognosis and symptoms in patients with primary ( idiopathic ) pulmonary hypertension ( 4 - 8 ) . R and omized , controlled clinical trials of epoprostenol for secondary pulmonary hypertension have not been conducted . Pulmonary hypertension frequently complicates the scleroderma spectrum of disease , which includes diffuse scleroderma , limited scleroderma ( the CREST syndrome [ calcinosis cutis , the Raynaud phenomenon , esophageal dysfunction , sclerodactyly , and telangectasia ] ) , and the overlap syndrome . These multisystem diseases are characterized by connective tissue and vascular abnormalities ; vascular lesions are prominent in all affected tissues ( 9 ) . Pulmonary hypertension occurs in up to 33 % of patients with diffuse scleroderma and 10 % to 50 % of those with the CREST syndrome ( 10 , 11 ) , in which it is one of the leading causes of death ( 12 , 13 ) . Pulmonary hypertension in the scleroderma spectrum of disease may be associated with interstitial pulmonary fibrosis or may consist of a direct involvement of small and medium-sized pulmonary arteries and arterioles with smooth-muscle hyperplasia , medial hypertrophy , and intimal proliferation ( 10 , 13 , 14 ) . Principal involvement of the pulmonary vasculature is more common in the CREST syndrome , whereas patients with pulmonary hypertension and diffuse scleroderma more often have interstitial lung disease ( 13 ) . No therapies have been proven effective for pulmonary hypertension secondary to the scleroderma spectrum of disease . Small numbers of patients have responded to captopril ( 15 ) , nifedipine ( 16 - 20 ) , and prazosin . In a short-term study of intravenous epoprostenol in seven patients with scleroderma ( two with diffuse scleroderma and five with limited scleroderma ) , six had a decrease in mean pulmonary artery pressure and pulmonary vascular resistance ( 21 ) . In a small study of pulmonary hypertension secondary to connective tissue disease , long-term infusion therapy with a prostacyclin analogue , iloprost , result ed in improvement in New York Heart Association ( NYHA ) functional class and quality of life but a variable hemodynamic response ( 22 ) . Results from a single-center , uncontrolled study suggest that long-term , continuously infused epoprostenol therapy can produce hemodynamic and symptomatic responses in patients with connective tissue disease who have severe pulmonary hypertension that is refractory to conventional medical therapy ( 23 ) . The rationale for using continuous epoprostenol infusion to treat pulmonary hypertension secondary to the scleroderma spectrum of disease was based on the efficacy of this therapy for primary pulmonary hypertension ( 4 - 8 ) and recognition that scleroderma is a disease characterized by vasospasm and structural changes in the walls of blood vessels . Prostacyclin is a naturally occurring substance produced by vascular endothelium that has vasodilating , antiplatelet aggregation , and cytoprotective effects ( 24 - 33 ) . Endogenous production of prostacyclin is decreased in an animal model of neonatal pulmonary hypertension ( 34 ) and in adult humans with pulmonary hypertension ( 35 ) . Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in patients with primary pulmonary hypertension ( 36 ) . Endothelial dysfunction also plays an important role in the vascular manifestations of the scleroderma spectrum of disease ( 37 , 38 ) , including the Raynaud phenomenon and digital ischemia , which cause considerable morbidity . Calcium-channel blockers ( 39 - 45 ) , enalapril ( 46 ) , and intermittent intravenous infusions of prostacyclin ( 47 - 49 ) and iloprost ( 50 - 54 ) improve the Raynaud phenomenon in some patients . Mixed results have been obtained with oral prostacyclin analogues ( 55 , 56 ) , and a recent multicenter trial of oral iloprost showed no benefit ( 57 ) . The effect of long-term , continuously infused epoprostenol on the severity of the Raynaud phenomenon and on digital ulcer counts has not been previously evaluated . Our 12-week multicenter , open-label , r and omized study was design ed to determine whether the beneficial effect of epoprostenol seen in patients with primary pulmonary hypertension could be extended to patients with pulmonary hypertension secondary to the scleroderma spectrum of disease . Our objective was to evaluate the effects of continuous infusion of epoprostenol on exercise capacity in patients with pulmonary hypertension secondary to the scleroderma spectrum of disease . A secondary objective was assessment of the effects of long-term continuous epoprostenol infusion on cardiopulmonary hemodynamics , Borg Dyspnea Score , Dyspnea-Fatigue Rating , NYHA functional class , survival , and safety . Vasospastic manifestations , such as the Raynaud phenomenon and digital ulcerations , were also followed . Methods Patient Selection Eligible patients had pulmonary hypertension secondary to the scleroderma spectrum of disease in accordance with the inclusion and exclusion criteria summarized in Table 1 . For the purpose s of this study , the scleroderma spectrum of disease was defined as systemic sclerosis with diffuse or limited scleroderma ( 58 ) ; systemic sclerosis that overlapped with another connective tissue disease ; or the presence of definite features of systemic sclerosis , including the Raynaud phenomenon and positive test result for antinuclear antibody , plus positive test results for anticentromere antibody , anti-Scl 70 antibody , or nailfold capillary abnormalities . Systemic sclerosis with limited cutaneous involvement ( the CREST syndrome ) was defined as the presence of any three of the following conditions : subcutaneous calcinosis , the Raynaud phenomenon , esophageal dysfunction ( defined clinical ly ) , sclerodactyly , or telangectasia . Patients with interstitial lung disease of a more than mild degree were not included in the study because such patients were thought to be less likely to show benefit . Table 1 . Key Inclusion and Exclusion Criteria On the basis of a previous 12-week study of the effects of epoprostenol infusion in patients with severe primary pulmonary hypertension ( 6 ) and using the 6-minute walk test as the primary outcome measure , we calculated that 50 patients per treatment group would provide 80 % power to detect a difference of 50 meters in the average change from baseline , at an level of 0.05 ( two-tailed t-test ) . R and omization and Treatment The protocol was approved by the institutional review boards of the 17 participating centers . After giving informed consent , 111 eligible patients were r and omly assigned ( 1:1 ) to receive continuous epoprostenol infusion ( Flolan , Glaxo Wellcome , Inc. , Research Triangle Park , North Carolina ) plus conventional therapy or to receive conventional therapy alone . Investigators contacted a central r and omization center to obtain treatment assignment , which was based on a stratified r and omized block design . Assignments were stratified on the basis of vasodilator use at baseline ( yes or no ) and exercise capacity at baseline ( 50 to<200 m or 200 m ) and were r and omized within blocks . Fifty-six patients were assigned to receive epoprostenol plus conventional therapy , and 55 patients were assigned to receive conventional therapy alone . Investigators were not blinded to treatment group assignment ; however , independent blinded observers assessed the primary efficacy measure , exercise capacity . Patients taking calcium-channel blockers at study entry continued to take them during the study period . Adjustments in concomitant medications were allowed during the study on the basis of clinical judgment . Patients in both groups were to receive oral anticoagulants during the study ; 94 of the 111 enrolled patients took warfarin . Venous access for epoprostenol infusion ( in the epoprostenol group only ) was obtained by insertion of a permanent indwelling central venous catheter . Epoprostenol was infused continuously by a portable infusion pump ( CADD-1 Model 5100 HF , SIMS Deltec , St. Paul , Minnesota ) . Patients were instructed in sterile technique , catheter care , and drug preparation and administration . Epoprostenol therapy was initiated at a low dose ( usually 2 ng/kg of body weight per minute ) . During the 12-week study , doses were adjusted on the basis of signs or symptoms consistent with persistent pulmonary hypertension in the absence of intolerable adverse effects ( Figure 1 ) . Figure 1 . Epoprostenol dosing . Outcome Measures The primary measure of efficacy was exercise capacity , as defined by the distance a patient could walk in 6 minutes . Trained observers at each site who were not otherwise involved in patient care administered the 6-minute walk test . All patients wore an ambulatory infusion pump and a hospital gown over their clothes to mask the presence or absence of a long-term indwelling catheter , thereby blinding testers to the patients ' treatment groups . Each patient performed one practice walk test . A st and ardized , unencouraged 6-minute walk test was performed as described elsewhere ( 59 ) at baseline and at 1 , 6 , and 12 weeks . The 6-minute walk test has been shown to provide meaningful outcome data in assessing potential therapy for patients with pulmonary hypertension ( 6 ) . Secondary measures of efficacy were cardiopulmonary hemodynamics measured by performing right-heart catheterization using st and ard techniques at baseline and week 12 ; the Borg Dyspnea Score ( 60 ) , obtained immediately after completion of the 6-minute walk test at baseline and 1 , 6 , and 12 weeks ( 6 , 59 ) ; the Dyspnea-Fatigue Rating , obtained before the 6-minute walk test at baseline and weeks 1 , 6 , and 12 ( 61 ) ; NYHA functional class ( 62 ) , measured at baseline and weeks 1 , 6 , and 12 ; digital ulcer counts , done at baseline and weeks 6 and 12 ; and the severity of the Raynaud phenomenon , RATIONALE Small , open-label studies suggest that combinations of existing therapies may be effective for pulmonary arterial hypertension ( PAH ) . OBJECTIVE To evaluate the safety and efficacy of adding inhaled iloprost , a prostacyclin analog , to the endothelin receptor antagonist bosentan in patients with PAH . METHODS In a r and omized , multicenter , double-blind trial , inhaled iloprost ( 5 mug ) or placebo was added to stable monotherapy with bosentan for 12 wk . Efficacy endpoints included change from baseline in 6-min-walk distance ( 6-MWD ) , modified New York Heart Association ( NYHA ) functional class , hemodynamic parameters , and time to clinical worsening . MEASUREMENTS AND MAIN RESULTS A total of 67 patients with PAH ( 55 % idiopathic PAH , 45 % associated PAH , 94 % NYHA class III , and mean baseline 6-MWD of 335 m ) were r and omized . At Week 12 , patients receiving iloprost had a mean increase in 6-MWD of 30 m ( p = 0.001 ) ; placebo patients had a mean 6-MWD increase of 4 m ( p = 0.69 ) , with a placebo-adjusted difference of + 26 m ( p = 0.051 ) . NYHA status improved by one class in 34 % of iloprost versus 6 % of placebo patients ( p = 0.002 ) . Iloprost delayed the time to clinical worsening ( p = 0.0219 ) . Improvements were noted in postinhalation placebo-adjusted change in mean pulmonary artery pressure (-8 mm Hg ; p < 0.001 ) and pulmonary vascular resistance ( -254 dyn x s x cm(-5 ) ; p < 0.001 ) . Combination therapy was well tolerated . CONCLUSIONS Within the limitations of a relatively small sample size , results of this study demonstrate that the addition of inhaled iloprost in patients with PAH with reduced exercise capacity on bosentan monotherapy is safe and efficacious OBJECTIVES In a r and omized double-blind crossover trial , we compared the efficacy of phosphodiesterase-5 ( PDE-5 ) inhibitor tadalafil with placebo in patients of Eisenmenger Syndrome ( ES ) . The primary end point was the change in 6-minute walk test distance ( 6 MWD ) . Secondary end points were the effect of the drug on systemic oxygen saturation ( SO(2 ) ) , pulmonary vascular resistance ( PVR ) , systemic vascular resistance ( SVR ) , effective pulmonary blood flow ( EPBF ) , and World Health Organization ( WHO ) functional class . BACKGROUND ES is a disorder with limited treatment options . Uncontrolled studies have shown PDE-5 inhibitors to be beneficial in patients of ES . METHODS Twenty-eight symptomatic adult patients of ES with weight ≥30 kg in WHO class II and III were enrolled . Patients were given 40 mg of tadalafil or matching placebo for 6 weeks followed by crossover to the other drug after a washout period of 2 weeks . Assessment of WHO class , exercise capacity by 6 MWD , and various hemodynamic parameters by cardiac catheterization was done at baseline , after 6 weeks and at the end of the study . RESULTS All patients completed the study . There was significant increase in 6 MWD following drug administration compared with baseline ( 404.18 ± 69.54 m vs. 357.75 ± 73.25 m , P < .001 ) . Compared with placebo , tadalafil produced significant decrease in PVR ( -7.32 ± 1.58 , P < .001 ) , result ing in significant increase in EPBF ( 0.12 ± 0.05 , P= .03 ) , SO(2 ) % ( 1.72 ± 0.58 , P= .007 ) , and WHO functional class ( 1.96 ± 0.18 vs. 2.14 ± 0.44 , P= .025 ) , with no significant change in SVR ( P= NS ) . CONCLUSION In this first short-term placebo-controlled trial of tadalafil in patients of ES , the drug was well tolerated and significantly improved exercise capacity , functional class , SO(2 ) , and pulmonary hemodynamics BACKGROUND Treatments for pulmonary arterial hypertension have been mainly studied in patients with advanced disease ( WHO functional class [ FC ] III and IV ) . This study was design ed to assess the effect of the dual endothelin receptor antagonist bosentan in patients with WHO FC II pulmonary arterial hypertension . METHODS Patients with WHO FC II pulmonary arterial hypertension aged 12 years or over with 6-min walk distance of less than 80 % of the normal predicted value or less than 500 m associated with a Borg dyspnoea index of 2 or greater were enrolled in this double-blind , placebo-controlled , multicentre trial . 185 patients were r and omly assigned to receive bosentan ( n=93 ) or placebo ( n=92 ) for the 6-month double-blind treatment period via a central ised integrated voice recognition system . Primary endpoints were pulmonary vascular resistance at month 6 expressed as percentage of baseline and change from baseline to month 6 in 6-min walk distance . Analyses of the primary endpoints were done with all r and omised patients who had a valid baseline assessment and an assessment or an imputed value for month 6 . This trial was registered with Clinical Trials.gov , number NCT00091715 . FINDINGS Analyses were done with 168 patients ( 80 in the bosentan group , 88 in the placebo group ) for pulmonary vascular resistance and with 177 ( 86 and 91 ) for 6-min walking distance . At month 6 , geometric mean pulmonary vascular resistance was 83.2 % ( 95 % CI 73.8 - 93.7 ) of the baseline value in the bosentan group and 107.5 % ( 97.6 - 118.4 ) of the baseline value in the placebo group ( treatment effect -22.6 % , 95 % CI -33.5 to -10.0 ; p<0.0001 ) . Mean 6-min walk distance increased from baseline in the bosentan group ( 11.2 m , 95 % CI -4.6 to 27.0 ) and decreased in the placebo group ( -7.9 m , -24.3 to 8.5 ) , with a mean treatment effect of 19.1 m ( 95 % CI 3.6 - 41.8 ; p=0.0758 ) . 12 ( 13 % ) patients in the bosentan group and eight ( 9 % ) in the placebo group reported serious adverse events , the most common of which were syncope in the bosentan group and right ventricular failure in the placebo group . INTERPRETATION Bosentan treatment could be beneficial for patients with WHO FC II pulmonary arterial hypertension Intravenous epoprostenol is currently FDA approved for management of primary pulmonary hypertension , but it requires intravenous infusion and is associated with adverse effects . The objective of this study was to evaluate the effects of an epoprostenol analog , treprostinil , for management of pulmonary hypertension . Ten tertiary care academic institutions with pulmonary hypertension programs participated in these pilot trials . In the first trial , intravenous epoprostenol and intravenous treprostinil were compared . In the second trial , intravenous treprostinil and subcutaneous treprostinil were compared . In the third trial , subcutaneous treprostinil was compared with placebo infusion during an 8-week period . Intravenous epoprostenol and intravenous treprostinil result ed in a similar reduction in pulmonary vascular resistance acutely ( 22 % and 20 % , respectively ) . Intravenous treprostinil and subcutaneous treprostinil also demonstrated comparable short-term decrease in pulmonary vascular resistance ( 23 % and 28 % , respectively ) . The placebo-controlled 8-week trial demonstrated a mean improvement of 37 ± 17 m as measured by the 6-minute walk distance in patients receiving treprostinil compared with a 6 ± 28 m reduction in those receiving placebo . There were trends toward an improvement in cardiac index and pulmonary vascular resistance index in the treprostinil group . Subcutaneous treprostinil has favorable hemodynamic effects when given acutely and in the short term . Treprostinil can be given safely to an ambulatory patient with a novel subcutaneous delivery pump system Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous prostacyclin has proven to be effective . However , this treatment requires a permanent central venous catheter with the associated risk of serious complications such as sepsis , thromboembolism , or syncope . Treprostinil , a stable prostacyclin analogue , can be administered by a continuous subcutaneous infusion , avoiding these risks . We conducted a 12-week , double-blind , placebo-controlled multicenter trial in 470 patients with pulmonary arterial hypertension , either primary or associated with connective tissue disease or congenital systemic-to-pulmonary shunts . Exercise capacity improved with treprostinil and was unchanged with placebo ; the between treatment group difference in median six-minute walking distance was 16 m ( p = 0.006 ) . Improvement in exercise capacity was greater in the sicker patients and was dose-related , but independent of disease etiology . Concomitantly , treprostinil significantly improved indices of dyspnea , signs and symptoms of pulmonary hypertension , and hemodynamics . The most common side effect attributed to treprostinil was infusion site pain ( 85 % ) leading to premature discontinuation from the study in 8 % of patients . Three patients in the treprostinil treatment group presented with an episode of gastrointestinal hemorrhage . We conclude that chronic subcutaneous infusion of treprostinil is an effective treatment with an acceptable safety profile in patients with pulmonary arterial hypertension OBJECTIVES This study assessed the efficacy and safety of inhaled treprostinil in pulmonary arterial hypertension ( PAH ) patients receiving therapy with either bosentan or sildenafil . BACKGROUND There is no cure for PAH , despite effective treatments , and outcomes remain suboptimal . The addition of inhaled treprostinil , a long-acting prostacyclin analog , might be a safe and effective treatment addition to other PAH-specific oral therapies . METHODS Two hundred thirty-five PAH patients with New York Heart Association ( NYHA ) functional class III ( 98 % ) or IV symptoms and a 6-min walk distance ( 6MWD ) of 200 to 450 m while treated with bosentan ( 70 % ) or sildenafil were r and omized to inhaled treprostinil ( up to 54 mug ) or inhaled placebo 4 times daily . The primary end point was peak 6MWD at 12 weeks . Secondary end points included time to clinical worsening , Borg Dyspnea Score , NYHA functional class , 12-week trough 6MWD , 6-week peak 6MWD , quality of life , and PAH signs and symptoms . The biomarker N-terminal pro-brain natriuretic peptide ( NT-proBNP ) was assessed . RESULTS Twenty-three patients withdrew from the study prematurely ( 13 treprostinil , 10 placebo ) . The Hodges-Lehmann between-treatment median difference in change from baseline in peak 6MWD was 19 m at week 6 ( p = 0.0001 ) and 20 m at week 12 ( p = 0.0004 ) . Hodges-Lehmann between-treatment median difference in change from baseline in trough 6MWD at week 12 was 14 m ( p = 0.0066 ) . Quality of life measures and NT-proBNP improved on active therapy . There were no improvements in other secondary end points , including time to clinical worsening , Borg Dyspnea Score , NYHA functional class , and PAH signs and symptoms . Inhaled treprostinil was safe and well-tolerated . CONCLUSIONS This trial demonstrates that , among PAH patients who remain symptomatic on bosentan or sildenafil , inhaled treprostinil improves exercise capacity and quality of life and is safe and well-tolerated . ( TRIUMPH I : Double Blind Placebo Controlled Clinical Investigation Into the Efficacy and Tolerability of Inhaled Treprostinil Sodium in Patients With Severe Pulmonary Arterial Hypertension ; NCT00147199 ) |
13,641 | 32,315,460 | Subgroup analysis did not change these results .
Evidence of very low quality shows that it is uncertain whether antibiotic prophylaxis reduces the risk of postoperative wound infections after herniorrhaphy surgery .
Evidence of moderate quality shows that antibiotic prophylaxis probably makes little or no difference in preventing wound infections ( i.e. all wound infections , SSSI or DSSI ) after hernioplasty surgery in a low infection risk environment .
Evidence of low quality shows that antibiotic prophylaxis in a high-risk environment may reduce the risk of all wound infections and SSSI , while evidence of very low quality shows that it is uncertain whether antibiotic prophylaxis reduces DSSI after hernioplasty surgery | BACKGROUND Inguinal or femoral hernia is a tissue protrusion in the groin region and has a cumulative incidence of 27 % in adult men and of 3 % in adult women .
As most hernias become symptomatic over time , groin hernia repair is one of the most frequently performed surgical procedures worldwide .
This type of surgery is considered ' clean ' surgery with wound infection rates expected to be lower than 5 % .
For clean surgical procedures , antibiotic prophylaxis is not generally recommended .
However after the introduction of mesh-based hernia repair and the publication of studies that have high wound infection rates the debate as to whether antibiotic prophylaxis is required to prevent postoperative wound infections started again .
OBJECTIVES To determine the effectiveness of antibiotic prophylaxis in reducing postoperative ( superficial and deep ) wound infections in elective open inguinal and femoral hernia repair . | The European Hernia Society ( EHS ) is proud to present the EHS Guidelines for the Treatment of Inguinal Hernia in Adult Patients . The Guidelines contain recommendations for the treatment of inguinal hernia from diagnosis till aftercare . They have been developed by a Working Group consisting of expert surgeons with representatives of 14 country members of the EHS . They are evidence -based and , when necessary , a consensus was reached among all members . The Guidelines have been review ed by a Steering Committee . Before finalisation , feedback from different national hernia societies was obtained . The Appraisal of Guidelines for REsearch and Evaluation ( AGREE ) instrument was used by the Cochrane Association to vali date the Guidelines . The Guidelines can be used to adjust local protocol s , for training purpose s and quality control . They will be revised in 2012 in order to keep them up date d. In between revisions , it is the intention of the Working Group to provide every year , during the EHS annual congress , a short up date of new high-level evidence ( r and omised controlled trials [ RCTs ] and meta-analyses ) . Developing guidelines leads to questions that remain to be answered by specific research . Therefore , we provide recommendations for further research that can be performed to raise the level of evidence concerning certain aspects of inguinal hernia treatment . In addition , a short summary , specifically for the general practitioner , is given . In order to increase the practical use of the Guidelines by consultants and residents , more details on the most important surgical techniques , local infiltration anaesthesia and a patient information sheet is provided . The most important challenge now will be the implementation of the Guidelines in daily surgical practice . This remains an important task for the EHS . The establishment of an EHS school for teaching inguinal hernia repair surgical techniques , including tips and tricks from experts to overcome the learning curve ( especially in endoscopic repair ) , will be the next step . Working together on this project was a great learning experience , and it was worthwhile and fun . Cultural differences between members were easily overcome by educating each other , respecting different views and always coming back to the principles of evidence -based medicine . The members of the Working Group would like to thank the EHS board for their support and especially Ethicon for sponsoring the many meetings that were needed to finalise such an ambitious project A prospect i ve study was carried out to determine the incidence of wound infection following surgery for inguinal hernia repair in a day surgery unit . The study incorporated surveillance for 1 month postoperatively . All patients were contacted by telephone , and reports of possible wound infection investigated via their General Practitioners . Ninety-seven patients were included in the study and the infection rate was 4 % BACKGROUND Inguinal hernia is the commonest type of external hernias . Lichtenstein mesh repair is the most favoured technique of inguinal hernia repair nowadays . It is tension free repair of weakened inguinal wall using polypropylene mesh . The present study was conducted to determine the efficacy of single dose antibiotic with placebo on patients undergoing inguinal hernia mesh repair . METHODS This r and omised controlled trial was carried out in the Department of General Surgery , Ayub Teaching Hospital , Abbottabad from January to December 2011 . The study population included male patients presenting with primary unilateral inguinal hernia , above 18 years of age . Mesh repair was performed in all patients . The patients were r and omly divided into two groups . Patients in group A were given a single dose of antibiotic before inguinal hernia mesh repair and patients in group B were given placebo before inguinal hernia mesh repair . Efficacy of antibiotic and placebo was accessed in terms of surgical site infections ( SSIs ) . RESULTS A total of 166 cases of inguinal hernia mesh repair patients were recorded during the study period . A total of 83 patients were recruited in each group . Surgical site infection was found in 6 ( 7.2 % ) in Group B it was 15 ( 18.1 % ) . The difference being statistically significant ( p = 0.036 ) . CONCLUSION Antibiotic prophylaxis is a preferred option for mesh plasty OBJECTIVE There are controversies about the benefits of prophylactic antibiotics in the prevention of postoperative surgical site infection ( SSI ) in mesh herniorrhaphy for a long time . This study aim ed to evaluate the effectiveness and efficacy of systemic prophylactic cefazolin in prevention of wound infection in various types of hernia repair with mesh material s. METHODS This is a prospect i ve r and omized control study . We evaluated wound infection rates in 395 patients with various kinds of hernia who underwent elective mesh repair using polypropylene mesh from 2007 to 2011 . A total of 237 ( 60.0 % ) patients received prophylactic cefazolin ( study group ) and the remaining 158 ( 40.0 % ) patients did not receive any prophylactic antibiotics ( control group ) . Patients were followed for infection at the following periods after the operation by an independent surgeon : 10 days , 30 days , 12 months , and then annually for at least 2 years . RESULTS Eight ( 2.03 % ) patients had infection in the site of surgery [ 2 ( 1.27 % ) in the control group and 6 ( 2.53 % ) in the study group ] . The distribution of infection was not significantly different between the two groups ( p = 0.364 ) . The superficial infections were managed by drainage and irrigation . One patient from the study group developed deep SSI and was readmitted and subsequently received antibiotic therapy , drainage , and debridement . CONCLUSION Preoperative administration of single-dose cefazolin for prosthetic hernia repairs did not markedly decrease the risk of wound infection . Our results do not support the use of cefazolin as a prophylactic antibiotic for various kinds of abdominal wall hernia repair with mesh A controlled r and omized trial was carried out in 324 patients with inguinal hernia . Efficacy was evaluated of a single injection of cefam and ole ( n = 162 ) administered at operative site during local anesthesia , using an untreated group as control ( n = 162 ) , as prophylaxis against post-operative local infection . Seven patients in the control group developed abscesses at the operative site after discharge , 6 of the 7 during one-month follow up , compared with none in the treated group ( n = 0.07 ) . No side effects were reported due to the antibiotic therapy . The cost of the antibiotic treatment was 10 times less than that for treating the suppurations in the control group In a series of 762 general surgical wounds 376 were selected at r and om to receive three parenteral doses of cephaloridine and 386 remained as untreated controls . In all types of operation , with the exception of wounds in the lower extremities associated with arterial surgery , the rate of wound infection was lowered by the prophylactic use of cephaloridine . The results were statistically significant for total wounds , clean wounds , total contaminated wounds , and contaminated wounds other than in colorectal surgery . We therefore recommend the routine use of three doses of cephaloridine Abstract . Antibiotic prophylaxis is not routinely given for nonimplant , clean operations , although this view has recently been challenged . We have conducted a r and omized multicenter , double-blind prospect i ve trial to compare co-amoxiclav with placebo in 619 patients undergoing open groin hernia repair . Altogether 563 ( 91 % ) patients fulfilled the protocol ; 283 received co-amoxiclav and 280 placebo . There was no difference between the groups in the number of patients receiving local or general anesthetic , the type of repair performed , the use of a subcutaneous fat suture , the type of skin closure used , the use of wound analgesia , or the use of a wound drain . Patients were given a card to return to the hospital in the event of their wound discharging or their needing to see their general practitioner . All patients were review ed at approximately 6 weeks after operation . Fifty ( 8.9 % ) patients sustained a wound infection , 25 in the co-amoxiclav group and 25 in the placebo group . We conclude that antibiotic prophylaxis is of no benefit to patients undergoing open groin hernia repair Objective To assess the value of single-dose , intravenous , prophylactic ampicillin and sulbactam ( AS ) in the prevention of wound infections during open prosthetic inguinal hernia repair by a double-blind , prospect i ve , r and omized trial . Summary Background Data The use of antibiotic prophylaxis during open prosthetic inguinal hernia surgery is controversial , and no prospect i ve trial has been conducted to examine this issue . Methods Patients undergoing unilateral , primary inguinal hernia repair electively with the Lichtenstein technique using polypropylene mesh were r and omized to receive 1.5 g intravenous AS before the incision or an equal volume of placebo according to a predetermined code of which the surgeons were unaware . Patients with recurrent , femoral , bilateral , giant , or incarcerated hernias or any systemic diseases were excluded . Age , sex , body mass index , American Society of Anesthesiologists score , type of hernia , type of anesthesia , duration of surgery , and use of drains were recorded . Infection was defined according to the criteria of Centers for Disease Control . Patients were evaluated 1 week , 1 month , 6 months , and 1 year after surgery by an independent surgeon . All complications were recorded . Results were assessed using chi-square , Fisher ’s exact , and Student t tests as appropriate . Results Between September 1996 and July 1998 , 280 patients ( 140 AS , 140 placebo group ) entered the protocol . Four patients from the AS group and seven from the placebo group were excluded because of inadvertent antibiotic administration or follow-up problems . Groups were well matched for all the variables studied and postoperative complications , excluding wound infections , which occurred at a rate of 0.7 % in the AS group and 9 % in the placebo group ( P = .00153 ) . Twelve patients in the placebo group developed wound infections , requiring five repeat hospital admissions in three patients . These three patients suffered deep infections reaching the graft , which result ed in graft loss in two . The single infected patient in the AS group had his graft removed as well because of deep persistent infection . Conclusions This study documented a significant ( 10-fold ) decrease in overall wound infections when single-dose , intravenous AS was used during Lichtenstein hernia repair . Deep infections and wound infection-related readmissions were also reduced by the use of AS . Proponents of mesh repairs may therefore be advised to use prophylactic single-dose intravenous antibiotic coverage in the light of the results of this trial . AS proved to be an effective antimicrobial agent BACKGROUND Prophylactic antibiotics are recommended for clean-contaminated and selected contaminated surgery . In clean surgery antibiotics are suggested if the operation involves the insertion of prosthetic devices and a potential infection is expected to cause serious morbidity or mortality . Inguinal hernia repair is a clean operation , infections are rare ; they can usually be cured without removing the prosthesis and recurrence is uncommon even after removal of the mesh . Aim of the study is to evaluate whether the lack of antimicrobial prophylaxis increases the risk of postoperative infections in patients treated for groin hernia , compared to those treated with prophylaxis . METHODS One hundred and forty-eight patients underwent inguinal hernia repair with mesh : 64 patients ( 43 % ) received 2 g cefotaxime by intravenous bolus about 30 minutes before the operation , 84 patients ( 57 % ) did not receive any antimicrobic prophylaxis . Mean follow-up was 13 months ( range 1 - 31 months ) for both groups . RESULTS We did not observe any major complication . Among both groups , no patient had developed infection at one week and one month after surgery . CONCLUSIONS In personal experience , any advantage in terms of prevention of infections with antibiotic prophylaxis in patients operated on for groin hernia has been observed . A review of the literature showed no general agreement on this subject with different risk of infections in different trials . A new prospect i ve r and omized trial is necessary to clarify this topic A study was made of the risk factors causing a high incidence of surgical wound infections in clean operations . Identification of these factors in the preoperative stage allows the patients to be divided into two categories : a high risk ( about 10 % of patients for surgery ) and low risk . By giving antibiotic prophylaxis only to patients at high risk , the incidence of postoperative infections can be reduced , decreasing the number of extra days in hospital and consequently lowering costs . This is a new approach to the problem of surgical wound infections since not only is it based on the usual classification of operations into clean , clean-contaminated , contaminated and dirty , but it also takes into account the defensive capacity of the target of the infection : the patient Objective : To assess the long-term crossover ( CO ) rate in men undergoing watchful waiting ( WW ) as a primary treatment strategy for their asymptomatic or minimally symptomatic inguinal hernias . Background : With an average follow-up of 3.2 years , a r and omized controlled trial comparing WW with routine repair for male patients with minimally symptomatic inguinal hernias led investigators to conclude that WW was an acceptable option [ JAMA . 2006;295(3):285–292 ] . We now analyze patients in the WW group after an additional 7 years of follow-up . Methods : At the conclusion of the original study , 254 men who had been assigned to WW consented to longer-term follow-up . These patients were contacted yearly by mail question naire . Nonresponders were contacted by phone or e-mail for additional data collection . Results : Eighty-one of the 254 men ( 31.9 % ) crossed over to surgical repair before the end of the original study , December 31 , 2004 , with a median follow-up of 3.2 ( range : 2–4.5 ) years . The patients have now been followed for an additional 7 years with a maximum follow-up of 11.5 years . The estimated cumulative CO rates using Kaplan-Meier analysis was 68 % . Men older than 65 years crossed over at a considerably higher rate than younger men ( 79 % vs 62 % ) . The most common reason for CO was pain ( 54.1 % ) . A total of 3 patients have required an emergency operation , but there has been no mortality . Conclusions : Men who present to their physicians because of an inguinal hernia even when minimally symptomatic should be counseled that although WW is a reasonable and safe strategy , symptoms will likely progress and an operation will be needed eventually Mesh prosthesis , local anesthesia , and ambulatory care have been widely introduced in recent decades in the treatment of inguinal hernia . The use of antibiotic prophylaxis during open inguinal hernia repair has been controversial . No prospect i ve trial has been conducted to assess the role of antibiotic prophylaxis in patients operated on for inguinal hernia under the above-mentioned conditions . A prospect i ve , r and omized , double-blinded trial was initiated to assess the efficacy of antibiotic prophylaxis in the prevention of wound infection during open mesh inguinal hernia repair under local anesthesia on an ambulatory basis . Ninety-nine consecutive hernia repairs were r and omized to receive 1 g of parenteral Cefazolin preoperatively or a placebo . No wound infections existed in the therapeutic group ( 0/50 ) . Four infections appeared in the control group ( 4/49 ) , and the study was suspended for ethical reasons when differences reached values close to statistical significance ( P=0.059 ) . We conclude that a single dose of intravenous Cefazolin decreases the risk of wound infection during open mesh inguinal hernia repair under local anesthesia on an ambulatory basis Objective : To determine whether the use of prophylactic antibiotics is effective in the prevention of postoperative wound infection after Lichtenstein open mesh inguinal hernia repair . Summary Background Data : A recent Cochrane meta- analysis ( 2003 ) concluded that “ antibiotic prophylaxis for elective inguinal hernia repair can not be firmly recommended or discarded . ” Methods : Patients with a primary inguinal hernia scheduled for Lichtenstein repair were r and omized to a preoperative single dose of 1.5 g intravenous cephalosporin or a placebo . Patients with recurrent hernias , immunosuppressive diseases , or allergies for the given antibiotic were excluded . Infection was defined using the Centers for Disease Control and Prevention criteria . Results : We included 1040 patients in the study between November 1998 and May 2003 . According to the intention-to-treat principle , 1008 patients were analyzed . There were 8 infections ( 1.6 % ) in the antibiotic prophylaxis group and 9 ( 1.8 % ) in the placebo group ( P = 0.82 ) . There was 1 deep infection in the antibiotic prophylaxis group and 2 in the placebo group ( P = 0.57 ) . Statistical analysis showed an absolute risk reduction of 0.19 % ( 95 % confidence interval , −1.78%–1.40 % ) and a number needed to treat of 520 for the total number of infections . For deep infection , the absolute risk reduction is 0.20 % ( 95 % confidence interval , −0.87%–0.48 % ) with a number needed to treat of 508 . Conclusions : A low percentage ( 1.7 % ) of wound infection after Lichtenstein open mesh inguinal ( primary ) hernia repair was found , and there was no difference between the antibiotic prophylaxis or placebo group . The results show that , in Lichtenstein inguinal primary hernia repair , antibiotic prophylaxis is not indicated in low-risk patients Abstract Although antibiotic prophylaxis is not explicitly indicated for hernia repair and breast surgery , its use for these clean procedures is widely adopted , albeit to a different extent in different countries , often on the personal decision of the individual surgeon . The present study was carried out to compare the efficacy of a single pre-operative dose of piperacillin-tazobactam with placebo in preventing surgical wound infections and to determine the main risk factors associated with infections following two main elective surgical clean procedures such as hernia repair and breast surgery . A total of 501 patients undergoing elective inguinal/femoral hernia repair or breast surgery were enrolled in this prospect i ve r and omized clinical study . Patients were r and omly assigned to receive preoperative antibiotic prophylaxis or placebo . One dose of piperacillin-tazobactam 2.250 g or placebo was administered i.v . 30 minutes prior to the surgical procedure . Using statistical univariate analysis , the following variables were correlated with a higher infection risk : age > 40 years , concomitant disease , WBC < 3500 , surgical wound size > 9 cm , use of drainages , non-prophylaxis . Using multivariate analysis , no antibiotic pre-operative prophylaxis , concurrent chronic diseases , especially diabetes ( risk 15 times higher ) , and length of intervention > 45 min ( risk 6 times higher ) were independent predictors of infection . Finally , patients with postoperative infections had a significantly longer hospitalisation . One pre-operative dose of piperacillin-tazobactam 2.250 g is more effective than placebo in preventing postoperative infections in breast surgery and hernia repair Hernia repair is one of the so-called clean operations . Many surgeons , however , use antibiotics , especially in the mesh repair era , without strong evidence to support this policy . We conducted a single-centre prospect i ve r and omised trial with a view to clarify this issue on a scientific basis . From January 2000 all patients undergoing elective inguinal hernia repair using a tension-free polypropylene mesh technique , provided they fulfilled predetermined criteria , were r and omised to have a single dose of amoxicillin and clavoulanic acid or placebo in a double-blind manner . The main end point was to detect any difference in infectious complication rates - with specific interest to wound infection rates - between the two groups . Between January 2000 and June 2004 , 386 patients entered the study ( 364 men and 22 women , median age 63 years , range 15 - 90 years ) and were r and omised to have antibiotic prophylaxis ( group A , n = 193 ) or placebo ( group B , n = 193 ) . The two groups were comparable regarding demographic data . In total , 19 ( 5 % ) cases with infectious complications were detected . Fourteen of these were wound infections ( 3.7 % ) . There were five cases of wound infection in group A and nine in group B ( p = 0.4 , Fisher 's exact test ) . All wound infections were treated with antibiotics . The wound was opened in some cases . Mesh removal was not required in any of the cases . From the results of this study it does not appear that antibiotic prophylaxis offers any benefits in the elective mesh inguinal hernia repair A question naire survey was sent to a r and om sample of the Spanish network of National Health System public acute-care hospitals . Of responding institutions ( representing 25 % of Spanish hospital beds ) , nearly 75 % had active surveillance programs for the prevention and control of surgical-site infections ( SSIs ) , but only 20 % performed postdischarge surveillance . Overall , perioperative antibiotic prophylaxis ( PAP ) was used in 84 % of all surgical procedures . For 77 % of procedures , there were written guidelines for the choice and use of PAP . Cefazolin was the most commonly used antibiotic ( 38 % ) . Duration of PAP was shorter than 24 hours in 75 % of procedures , and only a single dose was given in 52 % of procedures . PAP was commonly used in breast ( 52 % ) and inguinal hernia repair ( 69 % ) procedures , as well as in laparoscopic abdominal surgery ( 86 % ) . In summary , the use of PAP in Spanish hospitals is adequate , but improvements can be made in the frequency of prolonged PAP and in the use of broad-spectrum antibiotics . Surveillance systems for SSI , including postdischarge follow-up , also should be improved We compared the effects of single dose ( 750 milligrams ) prophylactic cefam and ole delivered directly into the operative wound with local anesthesia ( n = 162 ) with a control group ( no antibiotics ) ( n = 162 ) in a r and omized trial . No adverse effects were observed . There were seven wound abscesses in the untreated group compared with none in the group receiving antibiotic prophylaxis ( p = 0.007 ) . Six of the seven abscesses occurred as late as one month after the patient was discharged from the hospital . The costs of antibiotics used were ten times less than the costs of treatment of wound complications in the control group Purpose In this double-blind prospect i ve r and omized trial , our objective was to investigate the effect of antibiotic prophylaxis in patients undergoing elective inguinal hernia surgery with mesh repair in a large-volume tertiary referral trauma center . Methods Eligible patients were assigned r and omly to either an antibiotic prophylaxis group or a control group . Patients in the prophylaxis group were given 1 g cefazolin by IV bolus injection whereas the placebo control group received an equal volume of sterile saline preoperatively . A Lichtenstein repair was done in all cases . The patients were examined for surgical site infection ( SSI ) and other postoperative local complications before discharge , and reexamined 3 , 5 , 7 , and 30 days after discharge . Results Groups were well matched for age , sex , coexisting diseases , ASA scores , type of hernia , type of anesthesia , duration of surgery . Incidence of infection was 7 % in the control group ( 7/100 ) and 5 % in the prophylaxis group ( 5/100 ) ( P = 0.38 ) . All the infections were superficial and responded well to drainage and proper antibiotic therapy . All other postoperative complications were similar in the two groups . Conclusions In our setting s antibiotic prophylaxis has no significant effect on the incidence of SSI in elective repair of inguinal hernias with mesh . The most effective way to reduce the incidence of infection in prosthetic repair may be a specific center for treatment of abdominal wall hernias We assessed the efficacy of perioperative antibiotic prophylaxis for surgery in a r and omized , double-blind trial of 1218 patients undergoing herniorrhaphy or surgery involving the breast , including excision of a breast mass , mastectomy , reduction mammoplasty , and axillary-node dissection . The prophylactic regimen was a single dose of cefonicid ( 1 g intravenously ) administered approximately half an hour before surgery . The patients were followed up for four to six weeks after surgery . Blinding was maintained until the last patient completed the follow-up and all diagnoses of infection had been made . The patients who received prophylaxis had 48 percent fewer probable or definite infections than those who did not ( Mantel-Haenszel risk ratio , 0.52 ; 95 percent confidence interval , 0.32 to 0.84 ; P = 0.01 ) . For patients undergoing a procedure involving the breast , infection occurred in 6.6 percent of the cefonicid recipients ( 20 of 303 ) and 12.2 percent of the placebo recipients ( 37 of 303 ) ; for those undergoing herniorrhaphy , infection occurred in 2.3 percent of the cefonicid recipients ( 7 of 301 ) and 4.2 percent of the placebo recipients ( 13 of 311 ) . There were comparable reductions in the numbers of definite wound infections ( Mantel-Haenszel risk ratio , 0.49 ) , wounds that drained pus ( risk ratio , 0.43 ) , Staphylococcus aureus wound isolates ( risk ratio , 0.49 ) , and urinary tract infections ( risk ratio , 0.40 ) . There were also comparable reductions in the need for postoperative antibiotic therapy , non-routine visits to a physician for problems involving wound healing , incision and drainage procedures , and readmission because of problems with wound healing . We conclude that perioperative antibiotic prophylaxis with cefonicid is useful for herniorrhaphy and certain types of breast surgery Objectives Assessment of the usefulness of antibiotic prophylaxis in inguinal hernioplasty . Material s and methods This prospect i ve r and omized double blind study was conducted on 98 patients . Group A ( 50 patients ) received a single dose of intravenous amoxicillin and clavulanic acid , and Group P ( 48 patients ) received an equal volume of normal saline placebo by intravenous bolus 30 min before the induction of anesthesia . Hernioplasty was performed with polypropylene mesh . Skin was closed using skin staples that were removed after complete wound healing . The surgical site infection was diagnosed according to APIC , CDC criteria ( http://www.apic.org ) . Results The mean operative time was 38.8 ± 10.8 min in group A versus 40.9 ± 11.1 min in group P ( P = 0.34 ) . The mean hospitalization time was 1.3 ± 0.463 days in group A versus 1.25 ± 0.438 days in group P ( P = 0.58 ) . Four patients ( 2 % ) in group A and 6 patients ( 2.88 % ) in group P had wound infections ( P = 0.47 ) . Group A had 3 superficial infections and 1 deep infection while group P had 5 superficial infections and 1 deep infection . Antibiotic treatment of the wound infection was successful in all patients . Wound culture showed Staphylococcus aureus infection in 1 patient each group , Streptococcus pyogenes in 1 group A patient and Pseudomonas aeruginosa in 1 group P patient . Cultures in other patients in both groups were reported to be sterile . Conclusion Prophylactic antibiotic usage in patients undergoing tension free inguinal hernioplasty did not show any statistically significant beneficial effects in reduction of surgical site infection OBJECTIVE Infection is one of possible complications after prosthetic material hernia repair surgery . Antibiotic prophylaxis is applied routinely in China , but its effect is still controversial . The present study aims to offer direct clinical evidence on prevention of infection after tension-free inguinal hernia repair . METHODS A total of 1,200 cases with primary inguinal hernia treated in 6 hospitals in Shaanxi Province were enrolled in this study . They were r and omly divided into three groups ( n = 400 per group ) : placebo control group , Cefazolin group and Levofloxacin group after tensionfree inguinal hernia repair using polypropylene mesh . Hernia type , age , gender , weight and complications were recorded . The surgical-site infection was diagnosed according to APIC , CDC criteria ( http://www.apic . org ) . Infections were evaluated every other day in the first week , and then at 14 days , 21 days and 30 days following surgery . RESULTS Two cases from the placebo group , 3 from the Cefazolin group and 3 from the Levofloxacin group failed to follow-up . Six patients ( 2 non-following the protocol , 2 severe depression , and 2 laparoscopic surgery ) from the placebo group , 14 ( 8 nonreceiving trial medication , 5 laparoscopic surgery , and 1 failure to tolerance ) from the Cefazolin group , and 12 ( 2 combination of antibiotic usage , 5 laparoscopic surgery and 5 failure to tolerance ) from the Levofloxacin group were excluded . The data of the 1,160 cases were statistically analyzed in the incidence rates of surgical-site infection and complications after inguinal hernia repair . Surgical-site infection including wound infection , cellulitis or mesh-related infection was found in 20 cases ( 5.1 % ) of the control group , 15 ( 3.92 % ) of the Cefazolin group and 17 ( 4.42 % ) of the Levofloxacin group , and the difference among the three groups was not statistically significant ( χ2 = 0.438 , p = 0.803 ) . There was also no significant difference in post-surgery complications including seroma ( p = 0.6366 ) , urinary retention ( p = 0.8136 ) , fat liquefaction ( p = 0.8061 ) , pulmonary infection ( p = 0.1911 ) , and urinary tract infection ( p = 0.8144 ) among the three groups . CONCLUSIONS Prophylactic use of Cefazolin or Levofloxacin did not significantly decrease the risk of wound infection in these patients undergoing inguinal hernia repair . The present results do not support the administration of antibiotic prophylaxis for tension-free inguinal hernia repair . * The authors contributed equally to this work Background There is ambiguity about the use of antibiotic prophylaxis in inguinal mesh hernioplasty . We have tried to assess the efficacy of antibiotic prophylaxis in this procedure . Material s and methods A r and omized double blind placebo controlled study was conducted which included 55 patients who underwent an inguinal mesh hernioplasty over a 2 year period . The patients were evaluated for the status of the suture line as well as the presence of wound infection . Results Out of 55 patients 29 were r and omized to the antibiotic arm and 26 to the placebo group . The groups were well matched for all variables studied excluding wound infections , which occurred at a rate of 10.34 % ( n = 3 ) in the antibiotic group and 15.38 % ( n = 4 ) in the placebo arm , ( p > 0.01 ) . Conclusion This study did not document any statistically significant difference observed between those who received antibiotics and those receiving placebo in terms of any of the prognostic end points evaluated for Lichtenstein mesh hernioplasty To study the role of prophylactic antibiotics in open inguinal hernia repair . A total of 200 patients were included , they were r and omised in two groups . Group 1 was given prophylactic dose of inj amoxy-clav while group 2 was given placebo only . Results were compared and Data analysed using the Chi-square test . Complications in both the groups were compared . Rate of serous discharge and seroma formation was 1 % and 22 % respectively in group 1 while 2 % and 26 % in group 2 also the rate of erythema and stitch abscess were 1 % and none in group 1 and 2 % and 1 % in group 2 respectively . On statistical analysis these differences were not significant . Addition of prophylactic antibiotics in elective open inguinal hernia repair has no significant benefit over placebo although larger studies are required to prepare some uniform guidelines BACKGROUND In recent years , use of prosthetic material for inguinal hernia repair has increased dramatically . Tension-free repairs have gained popularity not only for recurrent or complicated hernias , but for primary hernia repairs as well . Although routine use of prophylactic antibiotics is not recommended in the Philippines for open nonimplant herniorrhaphy , there is little direct clinical evidence on which to base recommendations when implantable mesh is used . STUDY DESIGN We conducted a prospect i ve , r and omized , double-blind , placebo-controlled trial comparing wound infection rates in 360 patients ( 180 received prophylactic antibiotics , 180 received a placebo ) undergoing primary inguinal hernia repair electively using polypropylene mesh . Age , gender , American Society of Anesthesiologists class , type of hernia , type of anesthesia , and duration of operation were recorded . Infections were evaluated 1 week , 2 weeks , and 1 month after operation by an independent surgeon . All complications were recorded . Results were assessed using chi-square , Fisher 's exact test , and Student 's t-tests as appropriate . RESULTS Groups were well matched for all preoperative variables studied , including comorbid conditions . Six patients from the antibiotic group and four from the placebo group failed to followup after the second week . Superficial surgical site infection developed in 3 patients ( 1.7 % ) from the antibiotic group and 6 ( 3.3 % ) from the placebo group ( p = 0.50 ) . One from each group developed deep surgical site infection . Both patients were readmitted and underwent repeated debridement , which eventually result ed in graft loss . CONCLUSIONS Preoperative administration of single-dose antibiotic for tension-free inguinal mesh herniorrhaphy did not markedly decrease risk of wound infection in this patient population . Our results do not support use of antibiotic prophylaxis for tension-free mesh herniorrhaphy OBJECTIVE --To assess the effect of a programme of postoperative community surveillance on the rate of detection of wound complications after operation for inguinal hernia . DESIGN -- Prospect i ve audit of wound complications including complications recorded in case notes and those discovered by community surveillance . SETTING --Academic surgical unit of three consultant surgeons . PATIENTS --510 patients undergoing elective inguinal hernia repair between June 1985 and August 1989 . RESULTS --The wound infection rate recorded in the hospital notes was 3 % compared with 9 % when additional information was obtained from community surveillance . Wound complications were detected in 143 ( 28 % ) patients by community surveillance compared with a complication rate of 7 % in the case records for the same patients . CONCLUSIONS --Wound complications are common after clean surgery in patients discharged home early . Complication rates are a reflection not only of the st and ards of surgical practice but also the rigour with which they are sought . Before national comparative audit data are published the method of collection must be st and ardised . For short stay surgery this should include meaningful community surveillance The effect of topical ampicillin sodium and polyglycolic acid and silk sutures on the recurrence of an existing hernia or an incisional hernia and on infection rates in clean abdominal wounds ( herniotomies and simple cholecystectomies ) was studied in a triple-blind , r and omized trial with 398 consecutive patients . One infection , three suture sinuses , and two incisional hernias occurred among 113 patients with cholecystectomies , while the corresponding rates in 285 patients with hernia repairs were 11 infections , no suture sinuses , and three recurrent hernias . No effect of ampicillin could be demonstrated , nor was any difference between polyglycolic acid and silk sutures shown . No interaction between the antibiotic and suture material was found , and no side effects were observed . Wound infection was significantly more frequent in patients with postoperative seromas or hematomas BACKGROUND Identification of subgroups of patients at high and low risk for global infectious complications ( GIC ) after inguinal hernia repair without mesh . METHODS A data base of 1254 patients who underwent inguinal hernia repair without mesh , issued from 3 prospect i ve multicenter r and omized trials , has been established ( group A ) . After multivariate analysis , a score for GIC was calculated and tested using data from a similar prospect i ve r and omized multicenter study ( group B ) . RESULTS A risk score for GIC was constructed : -4.7 + ( 0.95 x age > or = 75 years ) + ( 1.1 obesity ) + ( 2.1 x urinary catheter ) . In case of score less than -4.2 ( low-risk group ) , the GIC rate was 2.7 % ; therefore , in case of score more than -4.2 ( high-risk score ) , the GIC rate was 14.3 % ( P < .001 ) . In the low-risk group , the administration of antibiotic prophylaxis did not reduce the infectious complication rate , while in high-risk group the administration of antibiotic prophylaxis significantly reduced the rates of surgical site infection , GIC , and urinary infection by 72 % , 67 % , and 76.8 % , respectively . CONCLUSIONS This study demonstrates the efficacy of antibiotic prophylaxis in inguinal hernia surgery in the subgroup of high-risk patients The role of prophylactic antibiotics in mesh repair of inguinal hernia is unclear . A Cochrane meta- analysis in 2005 concluded that " antibiotic prophylaxis for elective inguinal hernia repair can not be firmly recommended or discarded " and " further studies are needed , particularly on the use for mesh repair . " So , we design ed a study to define the role of prophylactic antibiotics in mesh repair of inguinal hernia . We conducted a prospect i ve , r and omized , double-blind , trial comparing wound infection rates in 450 patients ( 225 received intravenous Cefazolin , 225 received a placebo ) undergoing primary inguinal hernia repair electively using polypropylene mesh . 334 patients who completed a followup period of one month were analyzed . Age , American Society of Anesthesiologists class , type of hernia , type of anesthesia , grade of surgeon , pre and postoperative hospital stay and duration of operation were recorded . CDC criteria was used to define wound infection . Groups were well matched for all preoperative variables studied . The overall infection rate was 8.7 % ( 29 out of 334 ) . The incidence of wound infection in antibiotic group was 7 % and 10.5 % in control group . One from each group developed deep surgical site infection . Most of the infections occurred between the 7th and 12th post-operative day after discharge from the hospital . Antibiotic prophylaxis was associated with decreased incidence of wound infection when compared to control group , but the difference was not statistically significant . Based on our results we do not recommend the routine use of antibiotic prophylaxis in elective mesh repair of inguinal hernias BACKGROUND The efficacy of antibiotic prophylaxis for the prevention of surgical-site infection ( SSI ) after open tension-free inguinal hernia repair remains controversial . METHODS A double-blind , r and omized , placebo-controlled trial was conducted . Patients who underwent elective open mesh-plug hernia repair were eligible for r and omization . In the antibiotic prophylaxis group , 1.0 g cefazolin was intravenously administrated 30 minutes before the incision . In the placebo group , an equal volume of sterile saline was administered . The primary end point was the incidence of SSI . RESULTS A total of 200 patients were enrolled . SSI developed in 2 of 100 patients ( 2 % ) in the antibiotic prophylaxis group and 13 of 100 patients ( 13 % ) in the placebo group , indicating a significant difference between the 2 groups ( relative risk ratio , 0.25 ; 95 % confidence interval , 0.070 to 0.92 ; P = .003 ) . Other complications occurred in 23 patients : 7 ( 7 % ) in the antibiotic prophylaxis group and 16 ( 16 % ) in the placebo group ( P = .046 ) . CONCLUSIONS This study indicates that antibiotic prophylaxis is effective for the prevention of SSI after open mesh-plug hernia repair |
13,642 | 22,827,803 | Conclusions The scientific evidence is insufficient to determine whether the accuracy of single reading + CAD is at least equivalent to that obtained in st and ard practice , i.e. double reading where two breast radiologists independently read the mammographic images | Background In accordance with European guidelines , mammography screening comprises independent readings by two breast radiologists ( double reading ) .
CAD ( computer-aided detection ) has been suggested to complement or replace one of the two readers ( single reading + CAD).The aim of this systematic review is to address the following question : Is the reading of mammographic x-ray images by a single breast radiologist together with CAD at least as accurate as double reading ? | Mammography is the basic imaging modality for early detection of breast cancer . The aim of this prospect i ve study was to evaluate the impact of different mammogram reading strategies on the diagnostic yield in a consecutive patient population referred for digital mammography to a hospital . First , the effect of using computer‐aided detection ( CAD ) software on the performance of mammogram readers was studied . Furthermore , the impact of employing technologists as either prereaders or double readers was assessed , as compared to the conventional strategy of single reading by a radiologist . Digital mammograms of 1,048 consecutive patients were evaluated by a radiologist and 3 technologists with and without the use of CAD software . ROC analysis was used to study the effects of the different strategies . In the conventional strategy , an overall area under the curve ( AUC ) of 0.92 was found , corresponding to a sensitivity of 84 % and specificity of 94 % . When applying CAD software , the AUCs were similar before and after CAD for all readers ( mean of 0.95 ) . Employing technologists in prereading and double reading of mammograms result ed in a mean AUC of 0.91 and 0.96 , respectively . In the prereading strategy , the corresponding sensitivity and specificity were 81 and 96 % ; in the double reading strategy they were 96 and 79 % , respectively . Concluding , in this clinical population , systematic application of CAD software by either radiologist or technologists failed to improve the diagnostic yield . Furthermore , employing technologists as double readers of mammograms was the most effective strategy in improving breast cancer detection in daily clinical practice . © 2009 OBJECTIVE The purpose of our study was to perform a prospect i ve assessment of the impact of a CAD system in a screen-film mammography screening program during a period of 3 years . MATERIAL S AND METHODS Our study was carried out on a population of 21,855 asymptomatic women ( 45 - 65 years ) . Mammograms were processed in a CAD system and independently interpreted by one of six radiologists . We analyzed the following parameters : sensitivity of radiologist 's interpretation ( without and with CAD ) , detection increase , recall rate and positive predictive value of biopsy , CAD 's marks , radiologist 's false negatives and comparative analysis of carcinomas detected and non-detected by CAD . RESULTS Detection rate was 4.3‰. CAD supposed an increase of 0.1‰ in detection rate and 1 % in the total number of cases ( p<0.005 ) . The impact on recall rate was not significant ( 0.4 % ) and PPV of percutaneous biopsy was unchanged by CAD ( 20.23 % ) . CAD 's marks were 2.7 per case and 0.7 per view . Radiologist 's false negatives were 13 lesions which were initially considered as CAD 's false positives . CONCLUSIONS CAD supposed a significant increase in detection , without modifications in recall rates and PPV of biopsy . However , better results could have been achieved if radiologists had considered actionable those cases marked by CAD but initially misinterpreted The aim of this study was to determine the tumour detection rate and false positive rate of a new mammographic computer-aided detection system ( CAD ) in order to assess its clinical usefulness . The craniocaudal and oblique images of 150 suspicious mammograms from 150 patients that were histologically proven to be malignant were analysed using the Second Look CAD ( CADx Medical Systems , Quebec , Canada ) . Cases were selected r and omly using the clinic 's internal tumour case sample r. Correct marking of the malignant lesion in at least one view was scored as a true positive . Marks not at the location of the malignant lesion were scored as false positives . In addition , mammograms with histologically proven benign masses ( n=50 ) and microcalcifications ( n=50 ) , as well as 100 non-suspicious mammograms , were scanned in order to determine the value of false-positive marks per image . The 150 mammograms included 94 lesions that were suspicious due to masses , 26 due to microcalcifications and 30 showed both signs of malignancy . The overall sensitivity was 90.0 % ( 135 of 150 ) . Sensitivity on subsets of the data was 88.7 % ( 110 of 124 ) for suspicious masses ( MA ) and 98.2 % ( 55 of 56 ) for microcalcifications . Eight of 14 false-negative cases were large lesions . The overall false-positive rate was observed as 0.28 and 0.97 marks per image of microcalcifications and masses , respectively . The lowest false-positive rates for microcalcifications and MA were observed in the cancer subgroup , whereas the highest false-positive rates were scored in the benign but mammographically suspicious subgroups , respectively . The new CAD system shows a high tumour detection rate , with approximately 1.3 false positive marks per image . These results suggest that this system might be clinical ly useful as a second reader of mammograms . The system performance was particularly useful for detecting microcalcifications OBJECTIVE The purpose of this study was to prospect ively assess the usefulness of computer-aided detection ( CAD ) in the interpretation of screening mammography and to provide the true sensitivity and specificity of this technique in a clinical setting . SUBJECTS AND METHODS Over a 26-month period , 5,016 screening mammograms were interpreted without , and subsequently with , the assistance of the iCAD MammoReader detection system . Data collected for actionable findings included dominant feature ( calcification , mass , asymmetry , architectural distortion ) , detection method ( radiologist only , CAD only , or both radiologist and CAD ) , BI-RADS assessment code , associated histopathology for those undergoing biopsy , and tumor stage for malignant lesions . The study population was cross-checked against an independent reference st and ard to identify false-negative cases . RESULTS Of the 5,016 cases , the recall rate increased from 12 % to 14 % with the addition of CAD . Of the 107 ( 2 % ) patients who underwent biopsy , 101 ( 94 % ) were prompted by the radiologist and six ( 6 % ) were prompted by CAD . Of the 124 biopsies performed on actionable findings in the 107 patients , findings in 79 ( 64 % ) were benign and in 45 ( 36 % ) were in situ or invasive carcinoma . Three study participants who were not recalled by the radiologist with the assistance of CAD developed cancer within 1 year of the screening mammogram and were considered to be false-negative cases . The radiologist detected 43 ( 90 % ) of the 48 total malignancies and 45 ( 94 % ) of the 48 malignancies with the assistance of CAD . CAD missed eight cancers that were detected by the radiologist , which presented as architectural distortions ( n = 3 ) , irregular masses ( n = 4 ) , and a circumscribed mass ( n = 1 ) . CAD detected two in situ cancers as a faint cluster of calcifications that had not been perceived by the radiologist and one mass that was dismissed by the radiologist , accounting for at least a 4.7 % increase in cancer detection rate . Sensitivity of screening mammography with the use of CAD ( 94 % ) represented an absolute and relative 4 % increase over the sensitivity of the radiologist alone ( 90 % ) . Specificity of screening mammography with and without the use of CAD was 99 % . CONCLUSION Routine use of CAD while interpreting screening mammograms significantly increases recall rates , has no significant effect on positive predictive value for biopsy , and can increase cancer detection rate by at least 4.7 % and sensitivity by at least 4 % . This study provides " true " values for sensitivity and specificity for use of CAD in interpretation of screening mammography as measured prospect ively in the context of a working clinical setting In March 1981 a r and omized single-view mammographic screening for breast cancer was started in the south of Stockholm . The screened population in the first round numbered 40,318 women , and 20,000 women served as a well-defined control group . The age groups represented were 40–64 years , and 80.7 % of the invited women participated in the study . The first round disclosed 128 breast cancers ( 113 invasive and 15 noninvasive ) , or 4.0 per 1,000 women . Mean tumour size was 14.1 mm and axillary lymph node metastases were found in 21.8 % . Fifty-five per cent of the tumours were small ( ⩽10 mm ) or non-invasive , and 71 % were stage I.Participation rates are high in all Swedish trials . The present results differ only slightly from other screening programs ; the percentages of patients with axillary metastases and stage II tumours are similar in the Stockholm , Malmö and Kopparberg/Östergötl and studies . Comparisons of cancer prevalence in the various Swedish screening trials show that , in comparable age groups , there are some differences , even when the differences in the natural cancer incidence are taken into account . A decreased mortality was found recently in a Swedish trial in ages above 50 years but not below . In the Stockholm study more than one-third of the participants were aged 40–49 years OBJECTIVE This study prospect ively evaluated a computer-aided detection ( CAD ) device used with diagnostic and screening mammography by assessing cancers detected ; tumor sizes , histology , and stage ; positive predictive value ( PPV ) of biopsy recommendation ; and recall rates before and after CAD introduction . SUBJECTS AND METHODS Interpretations of 9,520 consecutive mammograms were recorded without and then with CAD for a 28-month period . Cancer detections based on initial radiologist review and additional detections based on CAD findings were noted . Recall rates , tumor size and histology , and PPV of biopsy recommendation before and after the introduction of CAD were compared . RESULTS Cancers detected only with CAD assistance were 9.6 % of all cancers ( 10 of 104 ) ; screening-detected cancers increased 13.3 % with CAD assistance ( four in addition to 30 screening-detected cancers ) . The 95 % one-sided confidence boundary using binomial distribution is consistent with at least 5.3 % for all cancers and 5.1 % for nonpalpable cancers . The greatest impact was on ductal carcinoma in situ , for which CAD increased cancer detection by 14.2 % ( three added to 21 ) . Similar percentages of cancers were detected only with CAD assistance in both screening ( 11.4 % ; 4 of 35 ) and diagnostic ( 9.5 % ; six of 63 ) studies . Additional cancers were detected using CAD in patients with implants and previous lumpectomy . The additional cancers detected with CAD were smaller ( p = 0.01 for all cancers , p = 0.03 for nonpalpable invasive cancer ) . The screening recall rate increased from 6.2 % to 7.8 % after CAD , with a decrease in the biopsy rate and a nonsignificant increase in the biopsy PPV from 21.9 % to 26.3 % . CONCLUSION CAD result ed in detection of more cancers in screening and diagnostic patients , with an increased recall rate but no deterioration in PPV of biopsy . Additional cancers detected were significantly smaller BACKGROUND The sensitivity of screening mammography for the detection of small breast cancers is higher when the mammogram is read by two readers rather than by a single reader . We conducted a trial to determine whether the performance of a single reader using a computer-aided detection system would match the performance achieved by two readers . METHODS The trial was design ed as an equivalence trial , with matched-pair comparisons between the cancer-detection rates achieved by single reading with computer-aided detection and those achieved by double reading . We r and omly assigned 31,057 women undergoing routine screening by film mammography at three centers in Engl and to double reading , single reading with computer-aided detection , or both double reading and single reading with computer-aided detection , at a ratio of 1:1:28 . The primary outcome measures were the proportion of cancers detected according to regimen and the recall rates within the group receiving both reading regimens . RESULTS The proportion of cancers detected was 199 of 227 ( 87.7 % ) for double reading and 198 of 227 ( 87.2 % ) for single reading with computer-aided detection ( P=0.89 ) . The overall recall rates were 3.4 % for double reading and 3.9 % for single reading with computer-aided detection ; the difference between the rates was small but significant ( P<0.001 ) . The estimated sensitivity , specificity , and positive predictive value for single reading with computer-aided detection were 87.2 % , 96.9 % , and 18.0 % , respectively . The corresponding values for double reading were 87.7 % , 97.4 % , and 21.1 % . There were no significant differences between the pathological attributes of tumors detected by single reading with computer-aided detection alone and those of tumors detected by double reading alone . CONCLUSIONS Single reading with computer-aided detection could be an alternative to double reading and could improve the rate of detection of cancer from screening mammograms read by a single reader . ( Clinical Trials.gov number , NCT00450359 . PURPOSE To prospect ively determine the effect of a commercially available computer-aided detection ( CAD ) system on interpretations of screening mammograms . MATERIAL S AND METHODS Institutional review board approval was granted ; informed consent and HIPAA compliance were waived . A total of 21 349 screening mammograms obtained in 18 096 women were interpreted first without and then with review of CAD images to determine the effect of CAD analysis on the screening breast cancer detection rate , recall rate , and positive predictive value ( PPV ) for biopsy . The percentage of total cancers detected by the radiologists independent of CAD and the percentage correctly marked by the CAD system were determined . RESULTS On the basis of pre-CAD interpretations , 2101 patients were recalled for diagnostic evaluation , 256 biopsies were performed , and 105 breast cancers were diagnosed . The breast cancer detection rate per 1000 screening mammograms was 4.92 ( 105 of 21 349 mammograms ) , the recall rate was 9.84 % ( 2101 of 21 349 mammograms ) , and the PPV for biopsy was 41.0 % ( 105 of 256 biopsies ) . After CAD image review , 199 additional patients were recalled , 21 additional biopsies were performed , and eight additional cancers were detected . The effect was a 7.62 % ( eight of 105 ) increase in the number of breast cancers detected , an increase in the recall rate to 10.77 % ( 2300 of 21 349 mammograms ) , and a slight decrease in the PPV to 40.8 % ( 113 of 277 biopsies ) . Radiologists detected 92.9 % ( 105 of 113 cancers ) of the total cancers , and CAD correctly marked 76.1 % ( 86 of 113 cancers ) . CONCLUSION The use of CAD improved the detection of breast cancer , with an acceptable increase in the recall rate and a minimal increase in the number of biopsies with benign results RATIONALE AND OBJECTIVES The aim of this study was to investigate the effects of relative sensitivity ( reader without computer-aided detection [ CAD ] vs st and -alone CAD ) and reading mode on reader performance when using CAD software . MATERIAL S AND METHODS Two sets of 100 images ( low-contrast and high-contrast sets ) were created by adding low-contrast or high-contrast simulated masses to r and om locations in 100 normal mammograms . This produced a relative sensitivity , substantially less for the low-contrast set and similar for the high-contrast set . Seven readers review ed every image in each set and specified location and probability scores using three reading modes ( without CAD , second read with CAD , and concurrent read with CAD ) . Reader detection accuracy was analyzed using areas under free-response receiver operating characteristic curves , sensitivity , and the number of false-positive findings per image . RESULTS For the low-contrast set , average differences in areas under free-response receiver operating characteristic curves , sensitivity , and false-positive findings per image without CAD were 0.02 , 0.12 , and 0.11 , respectively , compared to second read and 0.05 , 0.17 , and 0.09 ( not statistically significant ) , respectively , compared to concurrent read . For the high-contrast set , average differences were 0.002 ( not statistically significant ) , 0.04 , and 0.05 , respectively , compared to second read and -0.004 ( not statistically significant ) , 0.04 , and 0.08 ( not statistically significant ) , respectively , compared to concurrent read ( all differences were statistically significant except as noted ) . Differences were greater in the low-contrast set than the high-contrast set . Differences between second read and concurrent read were not significant . CONCLUSIONS Relative sensitivity is a critical factor that determines incremental improvement in reader performance when using CAD and appears to be more important than reading mode . Relative sensitivity may determine the clinical usefulness of CAD in different clinical applications and for different types of users PURPOSE To retrospectively evaluate the role of computer-aided detection ( CAD ) in reducing the rate of false-negative ( FN ) findings on screening mammograms considered normal at initial double reading . MATERIAL S AND METHODS At the authors ' institution , independent prospect i ve double readings in which the second reader is not blinded to results of the first reading are performed routinely for all mammograms . When cancer is diagnosed , prior mammograms also are review ed with double reading to determine cancer visibility . Findings are categorized as ( a ) no evidence of cancer on any prior screening mammogram and patient presents more than 1 year after prior screening , ( b ) no evidence of cancer on any prior screening mammogram and patient presents with symptoms within 1 year after prior screening ( year-interval occult false-negative ) , or ( c ) cancer visible . The clinical director separately evaluates each case in the same way . In 2000 , 519 histologically proved breast cancers were diagnosed , including 132 for which patients sought a second opinion and FN findings were not tracked . Prior screening mammograms were available in 318 of the other 387 cases . Five radiologists in two reading sessions independently review ed current and prior mammograms to categorize visible cancers as either threshold or actionable FN findings . Visible cancers deemed actionable by at least three of five readers were analyzed with a commercially available CAD system . FN rates were calculated prior to and after CAD analysis . RESULTS Twenty-seven occult and 71 visible cancers were found ( total FN findings , 98 ) . Three of five readers considered 52 ( 73 % ) of 71 visible cancers actionable . The CAD system correctly marked 37 ( 71 % ) of these 52 on prior screening mammograms ( 19 [ 65 % ] of 29 masses , seven [ 88 % ] of eight microcalcifications , seven [ 78 % ] of nine architectural distortions , and four [ 67 % ] of six masses with microcalcifications ) . The FN rate was 98 ( 31 % ) of 318 before CAD and 61 ( 19 % ) of 318 after CAD . CONCLUSION In this retrospective review of this small subset of cancers , it appears that CAD has the potential to decrease the FN rate at double reading by more than one-third ( from 31 % to 19 % ) . The CAD system correctly marked 37 ( 71 % ) of 52 actionable findings read as negative in previous screening years Purpose : To evaluate the effect of computer-aided detection ( CAD ) on the reader 's performance . Material and Methods : Four screening radiologists , two novice radiologists , and two residents with no prior experience in CAD read films of 200 women without and with CAD . The films , including 16 screen-detected cancers and 35 cancers “ missed ” on prior screening , were divided into two rollers : A ( free time schedule ) and B ( prompted time schedule ) . Reading times were noted . Individual readings without and with CAD were compared , sensitivities and specificities were calculated . Results : The sensitivity of CAD was 70.6 % and specificity 15.8 % . In 408 cancer readings , the screeners found 10 and other readers 7 new cancers with the aid of CAD . The screeners changed their opinion four times and others six times from true positive to false negative when CAD was negative . CAD output produced 12 versus 13 new false-positive findings respectively after 2352 readings . CAD did not significantly affect the reader 's sensitivities/specificities regardless of the time limit ( P = not significant ) . The use of CAD increased mean time for roller reading from 56 to 63 min ( P = 0.053 ) . Conclusion : Screening radiologists benefited slightly more from CAD than other readers did , but no statistical significant difference was found in personal readings without and with CAD Purpose : To evaluate a system of computer-assisted diagnosis ( CAD ) in mammography . Material and Methods : A sample of 120 sets of two-view mammograms was examined by an expert screener , a screening radiologist , a clinical radiologist , and a CAD system . The screening and clinical radiologists examined the mammograms twice , first without and then with the help of CAD . The sample consisted of first-round screening films from a two-round population -based screening , and comprised : 32 women in whom breast cancer was detected at the first screening ; 10 with cancer detected during the screening interval ; 32 with cancer detected at the second screening ; and 46 with normal mammograms at both screenings . Results : The expert screener , the screening radiologist , the clinical radiologist , and the CAD system detected respectively 44 , 41 , 34 and 37 cancers . Their respective specificities were 80 % , 83 % , 100 % and 22 % . With the help of CAD , the screening radiologist detected 1 additional cancer and the clinical radiologist detected 3 ; their respective specificities were 80 % and 100 % . Conclusion : The sensitivity of the CAD system was satisfactory . The two radiologists helped by CAD achieved a modest increase in sensitivity with unaffected specificity . However , the CAD system by itself had a very low specificity and it needs improvement before it can be useful in mammographic screening STUDY OBJECTIVE --To determine whether mortality from breast cancer could be reduced by repeated mammographic screening . DESIGN --Birth year cohorts of city population separately r and omised into study and control groups . SETTING --Screening clinic outside main hospital . PATIENTS --Women aged over 45 ; 21,088 invited for screening and 21,195 in control group . INTERVENTIONS --Women in the study group were invited to attend for mammographic screening at intervals of 18 - 24 months . Five rounds of screening were completed . Breast cancer was treated according to stage at diagnosis . END POINT -- Mortality from breast cancer . MEASUREMENTS AND MAIN RESULTS --All women were followed up and classed at end point as alive without breast cancer , alive with breast cancer , dead from breast cancer , or dead from other causes . Cause of death was taken from national mortality registry and for patients with breast cancer was vali date d independently . Mean follow up was 8.8 years . Altogether 588 cases of breast cancer were diagnosed in the study group and 447 in the control group ; 99 v 94 women died of all causes and 63 v 66 women died of breast cancer ( no significant difference ; relative risk 0.96 ( 95 % confidence interval 0.68 to 1.35 ) ) . In the study group 29 % more women aged less than 55 died of breast cancer ( 28 v 22 ; relative risk 1.29 ( 0.74 to 2.25 ) ) . More women in the study group died from breast cancer in the first seven years ; after that the trend reversed , especially in women aged greater than or equal to 55 at entry . Overall , women in the study group aged greater than or equal to 55 had a 20 % reduction in mortality from breast cancer ( 35 v 44 ; relative risk 0.79 ( 0.51 to 1.24 ) ) . OTHER FINDINGS --In the study group 100 ( 17 % ) cancers appeared in intervals between screenings and 107 ( 18 % ) in non-attenders ; 51 of these women died from breast cancer . Cancers classed as stages II-IV comprised 33 % ( 190/579 ) of cancers in the study group and 52 % ( 231/443 ) in the control group . CONCLUSIONS --Invitation to mammographic screening may lead to reduced mortality from breast cancer , at least in women aged 55 or over PURPOSE To determine the false-negative rate in screening mammography , the capability of computer-aided detection ( CAD ) to identify these missed lesions , and whether or not CAD increases the radiologists ' recall rate . MATERIAL S AND METHODS All available screening mammograms that led to the detection of biopsy-proved cancer ( n = 1,083 ) and the most recent corresponding prior mammograms ( n = 427 ) were collected from 13 facilities . Panels of radiologists evaluated the retrospectively visible prior mammograms by means of blinded review . All mammograms were analyzed by a CAD system that marks features associated with cancer . The recall rates of 14 radiologists were prospect ively measured before and after installation of the CAD system . RESULTS At retrospective review , 67 % ( 286 of 427 ) of screening mammography-detected breast cancers were visible on the prior mammograms . At independent , blinded review by panels of radiologists , 27 % ( 115 of 427 ) were interpreted as warranting recall on the basis of a statistical evaluation index ; and the CAD system correctly marked 77 % ( 89 of 115 ) of these cases . The original attending radiologists ' sensitivity was 79 % ( 427 of [ 427 + 115 ] ) . There was no statistically significant increase in the radiologists ' recall rate when comparing the values before ( 8.3 % ) with those after ( 7.6 % ) installation of the CAD system . CONCLUSION The original attending radiologists had a false-negative rate of 21 % ( 115 of [ 427 + 115 ] ) . CAD prompting could have potentially helped reduce this false-negative rate by 77 % ( 89 of 115 ) without an increase in the recall rate A r and omised controlled trial to investigate the efficacy of mass screening with single-view mammography in reducing mortality from breast cancer was started in Sweden in 1977 . 162 981 women aged 40 years or more and living in the counties of Kopparberg and Ostergötl and were enrolled in the study and divided at r and om into 2 groups . Each woman in the study group was offered screening every 2 or 3 years depending on age . Women in the control group were not offered screening . This report is confined to the 134 867 women aged 40 - 74 years at date of entry . The results to the end of 1984 show a 31 % reduction in mortality from breast cancer and a 25 % reduction in the rate of stage II or more advanced breast cancers in the group invited to screening . 7 years after the start of the study the excess of stage I cancers in the study group largely outweighs the deficit of advanced cancers PURPOSE To evaluate prospect ively the recall and cancer detection rates with and without computer-aided detection ( CAD ) in the United Kingdom National Health Service Breast Screening Programme . MATERIAL S AND METHODS The study had appropriate ethics committee approval . Informed consent was not required ; however , patients were informed that their mammograms might be used in research efforts , and all patients agreed to participate . Mammograms obtained in 6111 women ( mean age , 58.4 years ) undergoing routine screening every 3 years were analyzed with a CAD system . Mammograms were independently double read . Twelve readers participated . Readers recorded an initial evaluation , viewed the CAD prompts , and recorded a final evaluation . Recall to assessment was decided after arbitration . Sensitivities were calculated for single reading , single reading with CAD , and double reading , as a proportion of the total number of cancers detected by using double reading with CAD . RESULTS A total of 62 cancers were detected in 61 women . CAD prompted 51 ( 84 % ) of 61 radiographically detected cancers . Of 12 cancers missed on single reading , nine were correctly prompted ; however , seven prompts were overruled by the reader . Sensitivity of single reading was 90.2 % ( 95 % confidence interval [ CI ] : 83.0 % , 95.0 % ) , single reading with CAD was 91.5 % ( 95 % CI : 85.0 % , 96.0 % ) , and double reading without CAD was 98.4 % ( 95 % CI : 91.0 % , 100 % ) . Cancer detection rate was 1 % . Recall to assessment rate was 6.1 % , with an increase of 5.8 % because of CAD . Average time required , per reader , to read a case was 25 seconds without CAD and 45 seconds with CAD . CONCLUSION CAD increases sensitivity of single reading by 1.3 % , whereas double reading increases sensitivity by 8.2 % PURPOSE To evaluate the mammographic features of breast cancer that favor lesion detection with single reading and computer-aided detection ( CAD ) or with double reading . MATERIAL S AND METHODS The Computer Aided Detection Evaluation Trial II study was approved by the ethics committee , and all participants provided written informed consent . A total of 31,057 women were recruited from three screening centers between September 2006 and August 2007 . They were r and omly allocated to the double reading group , the single reading with CAD group , or the double reading and single reading with CAD group at a ratio of 1:1:28 , respectively . In this study , cancers in the women whose mammograms were read with both single reading with CAD and double reading were retrospectively review ed . The original mammograms were obtained for each case and review ed by two of three experienced breast radiologists in consensus . The method of detection was noted . The size and predominant mammographic feature of the cancer were recorded , as was the breast density . CAD marking data were review ed to determine if the cancer had been correctly marked . RESULTS A total of 227 cancers were detected in 28,204 women . A total of 170 cases were recalled with both reading regimens . Lesion types were masses ( 66 % ) , microcalcifications ( 25 % ) , parenchymal deformities ( 6 % ) , and asymmetric densities ( 3 % ) . The ability of the reading regimens to correctly prompt the reader to recall cases varied significantly by lesion type ( P < .001 ) . More parenchymal deformities were recalled with double reading , whereas more asymmetric densities were recalled with single reading with CAD . There was no difference in the ability of either reading regimen to prompt the reader to correctly recall masses or microcalcifications . CAD correctly prompted 100 % of microcalcifications , 87 % of mass lesions , 80 % of asymmetric densities , and 50 % of parenchymal deformities . CAD correctly marked 93 % of spiculated masses compared with 80 % of ill-defined masses ( P = .054 ) . There was a significant trend for cancers detected with double reading to occur only in women with a denser mammographic background pattern ( P = .02 ) . Size had no effect on lesion detection . CONCLUSION Readers using either single reading with CAD or double reading need to be aware of the strengths and weaknesses of reading regimens to avoid missing the more challenging cancer cases To compare double reading plus arbitration for discordance , ( currently best practice , ( BP ) ) with computer-aided-detection (CAD)-assisted single reading ( CAD-R ) for detection of invasive cancers detected within BreastScreen Australia . Secondarily , to examine characteristics of cancers detected/rejected using each method . Mammograms of 157 r and omly selected double-read invasive cancers were mixed 1:9 with normal cancers ( total 1569 ) , all detected in a BreastScreen service . Cancers were detected by two readers or one reader ( C2 and C1 cancers , ratio 70:30 % ) in the program . The 1569 film-screen mammograms were read by two radiologists ( reader A ( RA ) and reader B(RB ) ) , with findings recorded before and after CAD . Discordant findings with BP were resolved by arbitration . We compared CAD-assisted reading ( CAD-RA , CAD-RB ) with BP , and CAD and arbitration contribution to findings . We correlated cancer size , sensitivity and mammographic density with detection methods . BP sensitivity 90.4 % compared with CAD-RA sensitivity 86.6 % ( P = 0.12 ) and CAD-RB 94.3 % ( P = 0.14 ) . CAD-RB specificity was less than BP ( P = 0.01 ) . CAD sensitivity was 93 % , but readers rejected most positive CAD prompts . After CAD , reader 's sensitivity increased 1.9 % and specificity dropped 0.2 % and 0.8 % . Arbitration decreased specificity 4.7 % . Receiving operator curves analysis demonstrated BP accuracy better than CAD-RA , borderline significance ( P = 0.07 ) , but not CAD-RB . Secondarily , cancer size was similar for BP and CAD-R. Cancers recalled after arbitration ( P = 0.01 ) and CAD-R ( P = 0.10 ) were smaller . No difference in cancer size or sensitivity between reading methods was found with increasing breast density . CAD-R and BP sensitivity and cancer detection size were not significantly different . CAD-R specificity was significantly lower for one reader PURPOSE To estimate the long-term ( 29-year ) effect of mammographic screening on breast cancer mortality in terms of both relative and absolute effects . MATERIAL S AND METHODS This study was carried out under the auspices of the Swedish National Board of Health and Welfare . The board determined that , because r and omization was at a community level and was to invitation to screening , informed verbal consent could be given by the participants when they attended the screening examination . A total of 133 065 women aged 40 - 74 years residing in two Swedish counties were r and omized into a group invited to mammographic screening and a control group receiving usual care . Case status and cause of death were determined by the local trial end point committees and , independently , by an external committee . Mortality analysis was performed by using negative binomial regression . RESULTS There was a highly significant reduction in breast cancer mortality in women invited to screening according to both local end point committee data ( relative risk [ RR ] = 0.69 ; 95 % confidence interval : 0.56 , 0.84 ; P < .0001 ) and consensus data ( RR = 0.73 ; 95 % confidence interval : 0.59 , 0.89 ; P = .002 ) . At 29 years of follow-up , the number of women needed to undergo screening for 7 years to prevent one breast cancer death was 414 according to local data and 519 according to consensus data . Most prevented breast cancer deaths would have occurred ( in the absence of screening ) after the first 10 years of follow-up . CONCLUSION Invitation to mammographic screening results in a highly significant decrease in breast cancer-specific mortality . Evaluation of the full impact of screening , in particular estimates of absolute benefit and number needed to screen , requires follow-up times exceeding 20 years because the observed number of breast cancer deaths prevented increases with increasing time of follow-up PURPOSE To retrospectively determine if the use of a computer-aided detection ( CAD ) system can improve the performance of single reading of screening mammograms to match that of double reading in the United Kingdom . MATERIAL S AND METHODS Local research ethics committee approval was obtained ; informed consent was not required . This study included a sample of 10 267 mammograms obtained in women aged 50 years or older who underwent routine screening at one of two breast screening centers in 1996 . Mammograms that were double read in 1996 were r and omly allocated to be re-read by eight different radiologists using CAD . The cancer detection and recall rates from double reading and single reading with CAD were compared . Statistical significance and confidence intervals were calculated with the McNemar test to account for the matched nature of the data . RESULTS Single reading with CAD led to a cancer detection rate that was significantly ( P = .02 ) higher than that achieved with double reading : 6.5 % more cancers were detected by means of single reading with CAD than by means of double reading . However , the recall rate was higher for single reading with CAD than for double reading ( 8.6 % vs 6.5 % , respectively ; P < .001 ) . This was equivalent to relative increases of 15 % and 32 % in the cancer detection and recall rates , respectively . CONCLUSION Single reading with CAD leads to an improved cancer detection rate and an increased recall rate OBJECTIVE This study was conducted to prospect ively assess the effect of computer-aided detection ( CAD ) on screening outcomes in a regional mammography program . MATERIAL S AND METHODS Between January 1 , 1998 , and December 31 , 2000 , 27,274 consecutive screenings were performed . Radiologists ' performance before CAD ( n = 7,872 ) and with CAD ( n = 19,402 ) was determined by annual audits . All positive biopsy results were review ed ; histopathology was review ed and confirmed . Outcomes ( recall , biopsy , and cancer detection rates ) with CAD ( 1999 , 2000 ) were compared with historical control data ( 1998 ) . RESULTS With CAD , increases were seen in recall rate ( 8.1 % , from 7.7 % to 8.3 % ) , biopsy rate ( 6.7 % , from 1.4 % to 1.5 % ) , and cancer detection rate ( 16.1 % , from 3.7 per 1,000 to 4.3 per 1,000 ) . Detection rate of invasive cancers of 1.0 cm or less increased 164 % ( from 0.508 to 1.34 per 1,000 screens ; p = 0.069 ) . Detection rate of in situ cancers declined 6.7 % ( from 1.27 to 1.19 per 1,000 ; p = 0.849 ) . In multivariable analysis of invasive cancers , early stage ( stage I ) was strongly associated with detection by CAD ( odds ratio = 4.13 , p = 0.025 ) . Mean age at screening detection of cancer was 5.3 years younger in the CAD group than in the pre-CAD group ( p = 0.060 ) . CONCLUSION Increased detection rate , younger age at diagnosis , and significantly earlier stage of invasive cancer detection are consistent with a positive screening impact of CAD . Audit results were positive but generally not statistically significant due to sample size limitations . Our findings support the hypothesis that screening with CAD significantly improves detection of the specific cancer morphologies that CAD algorithms were design ed to detect OBJECTIVE The purpose of this study was to evaluate the performance and potential contribution of computer-aided detection ( CAD ) to independent double reading of paired screen-film and full-field digital screening mammograms . MATERIAL S AND METHODS The cases of 3,683 women who underwent both screen-film mammography and full-field digital mammography ( FFDM ) with independent double reading for each technique were followed for 2 years to include cancers detected in the interval between screening rounds and cancers detected at the next screening round . Fifty-five biopsy-proven cancers were diagnosed . The baseline screening mammograms of the 55 cancers were defined as having positive findings if at least one of two independent readers scored it 2 or higher on a 5-point rating scale . The baseline mammograms of interval ( n = 10 ) or secondround ( n = 16 ) cancers were retrospectively classified as overlooked ( n = 2 ) , minimal sign actionable ( n = 8) , minimal sign nonactionable ( n = 5 ) , and normal ( n = 11 ) . The baseline mammograms of these cases of cancer were evaluated with a CAD system , and the CAD results were compared ( McNemar 's test for paired proportions ) with the findings at prospect i ve independent double reading of mammograms obtained with each technique . RESULTS For FFDM , CAD sensitivity was 95 % ( 37/39 ) compared with 64 % ( 25/39 ) for double reading ( p = 0.006 ) , and for screen-film mammography , CAD sensitivity was 85 % ( 33/39 ) compared with 77 % ( 30/39 ) for prospect i ve double reading ( p = 0.57 ) of radiographically visible lesions in baseline mammograms . CAD correctly marked five ( 13 % ) of 39 cancers on screen-film mammography and 14 ( 36 % ) of 39 cancers on FFDM not detected at prospect i ve independent double reading . CONCLUSION CAD showed the potential to increase the cancer detection rate for FFDM and for screen-film mammography in breast cancer screening performed with independent double reading Making a diagnosis is the bread and butter of clinical practice , but in light of the number of tests now available to clinician , diagnosing illness has become a complicated process . Guidelines for making an evidence -based diagnosis abound , but those making recommendations about diagnostic tests or test strategies must realize that clinicians require support to make diagnostic decisions that they can easily implement in daily practice . The Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) Working Group has developed a rigorous , transparent , and increasingly adopted approach for grading the quality of research evidence and strength of recommendations to guide clinical practice . This editorial summarizes GRADE 's process for developing recommendations for tests ( 1 ) . Clinicians are trained to use tests for screening and diagnosis ; identifying physiologic derangements ; establishing a prognosis ; and monitoring illness and treatment response by assessing signs and symptoms , imaging , biochemistry , pathology , and psychological testing techniques ( 2 ) . Sensitivity , specificity , positive predictive value , likelihood ratios , and diagnostic odds ratios are among the challenging terms that diagnostic studies typically deliver to clinicians , and all have to do with diagnostic accuracy . Not only do clinicians have difficulties remembering the definitions and calculations for these terms , application of the concepts to individual patients is often complicated . Many clinicians order a test despite uncertainty about how to interpret the result , and they also contribute to testing errors by incorrectly ordering tests ( 3 , 4 ) . GRADE 's framework for developing recommendations for diagnostic management studies is based on what is needed for practical clinical applicationthat is , how to weigh the benefits and harms of ordering and using a diagnostic test in caring for patients ( 1 ) . The approach begins with specifying the PICO : the relevant population ( P ) , diagnostic intervention or test ( I ) ( including its purpose , such as triage , replacement , or an add-on test ) , comparison test ( C ) , and patient-important outcomes ( O ) related to the use of a test for a focused clinical question . If a test fails to improve patient-important outcomes , there is no reason to use it , whatever its accuracy . For example , the results of genetic testing for Huntington chorea , an untreatable condition , may provide either welcome reassurance that a patient will not have the condition or the ability to plan for his future knowing that he will sadly fall victim ( 1 ) . Here , the ability to plan is analogous to an effective treatment , and the benefits of planning need to be balanced against the downsides of receiving an early diagnosis ( 5 - 7 ) . The best evidence of test performance comes from large r and omized trials of diagnostic strategies that directly measure patient-important outcomes ( 1 ) . However , these trials are few and far between : An informal review of the Cochrane data base of r and omized trials revealed < 100 such studies . Therefore , most recommendations about diagnostic testing are based on an implicit 2-step process of how the accuracy of a test indirectly changes patient-important outcomes . In the first step , a diagnostic-test accuracy study ( Figure ) , patients may receive both a new test and a reference test ( i.e. , the best available method for detecting the target condition ) . Investigators can then calculate the accuracy of the test compared with the reference test ( first step ) . In the second step , judgments about the patient importance of test accuracy are based on the consequences of being correctly or incorrectly classified as having or not having the disease . These include the benefits and harms of receiving treatment or follow-up tests for those correctly classified as having the disease , reassurance or receipt of other follow-up tests for those correctly classified as not having the disease , receipt of unnecessary treatment or additional tests for those incorrectly classified as having the disease , delayed or no treatment for those incorrectly classified as not having the disease , and any adverse effects of the diagnostic test ( e.g. , from invasive tests ) . Those making recommendations about diagnostic tests must then compare patient-important outcomes ( and costs ) in all patients receiving the new test with all patients receiving the old , or comparator , test . For the first step ( i.e. , assessing test accuracy ) , there are well-described method ological criteria for assessing risk for bias in an estimate of test accuracy , ideally based on a systematic review of relevant studies . For instance , studies of diagnostic test accuracy with a low risk for bias enroll consecutive patients for whom there is legitimate diagnostic uncertaintythat is , the type of patients to whom clinicians would apply the test in the course of regular clinical practice . If studies fail this criterion ( e.g. , only enroll patients with severe disease and healthy controls ) , the apparent accuracy of a test is likely to be misleadingly high ( 8 , 9 ) . The second step shown in the Figure is , in most situations , based on judgments of test accuracy as a surrogate for patient-important outcomes . The key issue about these judgments is that they should be made transparent to those using the recommendations . For example , in the diagnosis of suspected acute urolithiasis , well- design ed studies demonstrate fewer false-negative results with noncontrast helical computed tomography ( CT ) than with intravenous pyelography ( IVP ) ( 10 ) . However , those ureteric stones that CT detects but IVP misses are smaller and therefore are more likely to spontaneously pass . Before r and omized trials evaluating outcomes in patients treated for smaller stones , evidence from observational studies was of lower quality . Thus , it remained uncertain how patients were affected by missed cases and follow-up of incidental findings unrelated to renal calculi with CT . Recommendations about using one test ( IVP ) over the other ( helical CT ) were based on judgments of how the cases that were detected or missed would fare with or without treatment ( 11 ) . These judgments were likely to be based on indirect evidence and would be less certain than judgments based on direct evidence from a r and omized trial comparing the 2 tests . The GRADE approach requires making these judgments about the relation between accuracy and patient-important outcomes transparent . The example of IVP versus helical CT for patients with suspected acute shows exemplifies how the quality of evidence for an accurate test would be down grade d because of the lack of direct evidence on patient-important outcomes . Uncertainty about patient-important consequences and associated uncertainty about benefits and harms would probably have result ed in weak GRADE recommendations about the use of IVP compared with helical CT . Those making recommendations using the GRADE approach should also explicitly consider judgments and evidence about the values and preferences that patients attach to important consequences , as described more fully elsewhere ( 1 ) . Acknowledgments : This work was partially funded by a The human factor , mobility and Marie Curie Actions Scientist Reintegration European Commission Grant ( IGR 42192 ) GRADE to Dr. Schnemann PURPOSE To prospect ively assess the effect of computer-aided detection ( CAD ) on the interpretation of screening mammograms in a community breast center . MATERIAL S AND METHODS Over a 12-month period , 12,860 screening mammograms were interpreted with the assistance of a CAD system . Each mammogram was initially interpreted without the assistance of CAD , followed immediately by a reevaluation of areas marked by the CAD system . Data were recorded to measure the effect of CAD on the recall rate , positive predictive value for biopsy , cancer detection rate , and stage of malignancies at detection . RESULTS When comparing the radiologist 's performance without CAD with that when CAD was used , the authors observed the following : ( a ) an increase in recall rate from 6.5 % to 7.7 % , ( b ) no change in the positive predictive value for biopsy at 38 % , ( c ) a 19.5 % increase in the number of cancers detected , and ( d ) an increase in the proportion of early-stage ( 0 and I ) malignancies detected from 73 % to 78 % . CONCLUSION The use of CAD in the interpretation of screening mammograms can increase the detection of early-stage malignancies without undue effect on the recall rate or positive predictive value for biopsy PURPOSE To prospect ively assess the effect of computer-aided detection ( CAD ) on screening mammogram interpretation in an academic medical center to determine if the outcome is different than that previously reported for community practice s. MATERIAL S AND METHODS Institutional review board approval was granted , and informed consent was waived . During a 19-month period , 8682 women ( median age , 54 years ; range , 33 - 95 years ) underwent screening mammography . Each mammogram was interpreted by one of seven radiologists , followed by immediate re-evaluation of the mammogram with CAD information . Each recalled case was classified as follows : radiologist perceived the finding and CAD marked it , radiologist perceived the finding and CAD did not mark it , or CAD prompted the radiologist to perceive the finding and recall the patient . Lesion type was also recorded . Recalled patients were tracked to determine the effect of CAD on recall and biopsy recommendation rates , positive predictive value ( PPV ) of biopsy , and cancer detection rate . A 95 % confidence interval was calculated for cancer detection rate . Pathologic examination was performed for all cancers . RESULTS Of 8682 patients , 863 ( 9.9 % ) with 960 findings were recalled for further work-up ( Breast Imaging Reporting and Data System category 0 ) . After further diagnostic imaging , it was recommended that biopsy or aspiration be performed for 181 of 960 findings ( 19 % ) ; 165 interventions were confirmed to have been performed . Twenty-nine cancers were found in this group , with a PPV for biopsy of 18 % ( 29 of 165 findings ) and a cancer detection rate of 3.3 per 1000 screening mammograms ( 29 of 8682 patients ) . CAD-prompted recalls contributed 8 % ( 73 of 960 findings ) of total recalled findings and 7 % ( two of 29 lesions ) of cancers detected . Of 29 cancers ( 59 % ) , 17 manifested as masses and 12 ( 41 % ) were microcalcifications . Ten ( 34 % ) cancers were ductal carcinoma in situ , and the remaining cancers had an invasive component . Both cancers found with CAD manifested as masses , and both were invasive ductal carcinoma . CONCLUSION Prospect i ve clinical use of CAD in a university hospital setting result ed in a 7.4 % increase ( from 27 to 29 ) in cancers detected . Both cancers were nonpalpable masses |
13,643 | 28,648,414 | High Ki-67 was strongly associated with worse clinical outcomes .
High Ki-67 expression in localized PCa is a factor of poor prognosis for DSS , biochemical failure-free survival , DFS , DM , and OS after curative-intent treatments . | BACKGROUND Ki-67 for quantifying tumor proliferation is widely used .
In localized prostate cancer ( PCa ) , despite a suggested predictive role of Ki-67 for outcomes after therapies , it has not been incorporated into clinical practice .
Herein , we conduct a systematic review and meta- analysis of the literature reporting the association of Ki-67 and disease outcomes in PCa treated radically . | Accurate prognostic parameters in prostate biopsies are needed to better counsel individual patients with prostate cancer . We evaluated the prognostic impact of morphologic and immunohistochemical parameters in preoperative prostate cancer biopsies . A consecutive series of prostate biopsies of 279 men ( 72 % with clinical stage T1c and 23 % with T2 ) who subsequently underwent radical prostatectomy was prospect ively analysed for Gleason score , number and percentage of positive cores ( NPC , PPC ) , total percentage of biopsy tissue with tumour ( TPT ) , maximum tumour percentage per core ( MTP ) , and expression of Ki67 , Bcl‐2 and p53 . All biopsy features were significantly associated with at least one feature of the radical prostatectomy specimen . pT stage was independently predicted by PSA , seminal vesicle invasion by Ki67 LI , positive margins by PSA and MTP , large tumour diameter by PSA and PPC , and Gleason score by biopsy Gleason score , MTP , and Ki67 LI , respectively . Biopsy Gleason score , NPC ( 1 vs. > 1 ) , TPT ( < 7 vs. ≥7 % ) , and Ki67 LI ( < 10 vs. ≥10 % ) were significant predictors of biochemical recurrence after radical prostatectomy ( p < 0.01 , each ) . KI67 LI was the only independent prognostic factor in case of a low TPT ( < 7 % ) or low Gleason score ( < 7 ) , the hazard ratio being 6.76 and 6.44 , respectively . In summary , preoperative Gleason score , NPC , TPT and Ki67 LI significantly predict the risk of recurrence after radical prostatectomy , and Ki67 is an independent prognosticator in biopsies with low‐volume or low‐ grade prostate cancer . Analysis of Ki67 LI in these biopsies may help to better identify patients with clinical ly insignificant prostate cancer . © 2008 Wiley‐Liss , BACKGROUND Appropriate timing of and rogen deprivation treatment ( ADT ) for prostate cancer is controversial . Our aim was to determine whether immediate ADT extends survival in men with node-positive prostate cancer who have undergone radical prostatectomy and pelvic lymphadenectomy compared with those who received ADT only once disease progressed . METHODS Eligible patients from 36 institutes in the USA were r and omly assigned in 1988 - 93 to receive immediate ADT ( n=47 ) or to be observed ( n=51 ) , with ADT to be given on detection of distant metastases or symptomatic recurrences . Patients were followed up every 3 months for the first year and every 6 months thereafter . The primary endpoint was progression-free survival ; secondary endpoints were overall and disease-specific survival . Analysis was by intention to treat . To ensure that the treatment groups were comparable , we did a retrospective central pathology review of slides and re grade d the Gleason scores for available sample s. This trial pre date s the requirement for clinical trial registration . FINDINGS At median follow-up of 11.9 years ( range 9.7 - 14.5 for surviving patients ) , men assigned immediate ADT had a significant improvement in overall survival ( hazard ratio 1.84 [ 95 % CI 1.01 - 3.35 ] , p=0.04 ) , prostate-cancer-specific survival ( 4.09 [ 1.76 - 9.49 ] , p=0.0004 ) , and progression-free survival ( 3.42 [ 1.96 - 5.98 ] , p<0.0001 ) . Of 49 histopathology slides received ( 19 immediate ADT , 30 observation ) , 16 were down grade d from the original Gleason score ( between groups < or = 6 , 7 , and > or = 8) and five were up grade d. We recorded similar proportions of score changes in each group ( p=0.68 ) , and no difference in score distribution by treatment ( p=0.38 ) . After adjustment for score , associations were still significant between treatment and survival ( overall , p=0.02 ; disease-specific , p=0.002 ; progression-free survival , p<0.0001 ) . INTERPRETATION Early ADT benefits patients with nodal metastases who have undergone prostatectomy and lymphadenectomy , compared with those who receive deferred treatment . The beneficial effects of early ADT , rather than an imbalance in risk factors , are likely to explain the differences in outcomes between treatments BACKGROUND Local failure after radical prostatectomy ( RP ) is common in patients with cancer extending beyond the capsule . Three prospect ively r and omized trials demonstrated an advantage for adjuvant radiotherapy ( ART ) compared with a wait- and -see ( WS ) policy . OBJECTIVE To determine the efficiency of ART after a 10-yr follow-up in the ARO 96 - 02 study . DESIGN , SETTING , AND PARTICIPANTS After RP , 388 patients with pT3 pN0 prostate cancer ( PCa ) were r and omized to WS or three-dimensional conformal ART with 60 Gy . The present analysis focuses on intent-to-treat patients who achieved an undetectable prostate-specific antigen after RP ( ITT2 population ) --that is , 159 WS plus 148 ART men . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point of the study was progression-free survival ( PFS ) ( events : biochemical recurrence , clinical recurrence , or death ) . Outcomes were compared by log-rank test . Cox regression analysis served to identify variables influencing the course of disease . RESULTS AND LIMITATIONS The median follow-up was 111 mo for ART and 113 mo for WS . At 10 yr , PFS was 56 % for ART and 35 % for WS ( p<0.0001 ) . In pT3b and R1 patients , the rates for WS even dropped to 28 % and 27 % , respectively . Of all 307 ITT2 patients , 15 died from PCa , and 28 died for other or unknown reasons . Neither metastasis-free survival nor overall survival was significantly improved by ART . However , the study was underpowered for these end points . The worst late sequelae in the ART cohort were one grade 3 and three grade 2 cases of bladder toxicity and two grade 2 cases of rectum toxicity . No grade 4 events occurred . CONCLUSIONS Compared with WS , ART reduced the risk of ( biochemical ) progression with a hazard ratio of 0.51 in pT3 PCa . With only one grade 3 case of late toxicity , ART was safe . PATIENT SUMMARY Pre caution ary radiotherapy counteracts relapse after surgery for prostate cancer with specific risk factors BACKGROUND Optimum management of clinical ly localised prostate cancer presents unique challenges because of the highly variable and often indolent natural history of the disease . To predict disease aggressiveness , clinicians combine clinical variables to create prognostic models , but the models have limited accuracy . We assessed the prognostic value of a predefined cell cycle progression ( CCP ) score in two cohorts of patients with prostate cancer . METHODS We measured the expression of 31 genes involved in CCP with quantitative RT-PCR on RNA extracted from formalin-fixed paraffin-embedded tumour sample s , and created a predefined score and assessed its usefulness in the prediction of disease outcome . The signature was assessed retrospectively in a cohort of patients from the USA who had undergone radical prostatectomy , and in a cohort of r and omly selected men with clinical ly localised prostate cancer diagnosed by use of a transurethral resection of the prostate ( TURP ) in the UK who were managed conservatively . The primary endpoint was time to biochemical recurrence for the cohort of patients who had radical prostatectomy , and time to death from prostate cancer for the TURP cohort . FINDINGS After prostatectomy , the CCP score was useful for predicting biochemical recurrence in the univariate analysis ( hazard ratio for a 1-unit change [ doubling ] in CCP 1·89 ; 95 % CI 1·54 - 2·31 ; p=5·6 × 10(-9 ) ) and the best multivariate analysis ( 1·77 , 1·40 - 2·22 ; p=4·3 × 10(-6 ) ) . In the best predictive model ( final multivariate analysis ) , the CCP score and prostate-specific antigen ( PSA ) concentration were the most important variables and were more significant than any other clinical variable . In the TURP cohort , the CCP score was the most important variable for prediction of time to death from prostate cancer in both univariate analysis ( 2·92 , 2·38 - 3·57 , p=6·1 × 10(-22 ) ) and the final multivariate analysis ( 2·57 , 1·93 - 3·43 ; p=8·2 × 10(-11 ) ) , and was stronger than all other prognostic factors , although PSA concentration also added useful information . Heterogeneity in the hazard ratio for the CCP score was not noted in any case for any clinical variables . INTERPRETATION The results of this study provide strong evidence that the CCP score is a robust prognostic marker , which , after additional validation , could have an essential role in determining the appropriate treatment for patients with prostate cancer . FUNDING Cancer Research UK , Queen Mary University of London , Orchid Appeal , US National Institutes of Health , and Koch Foundation |
13,644 | 27,273,468 | The common biological complication reported included peri-implant mucositis , mucosal enlargement , bone loss , pain , and implant loss .
CONCLUSIONS This review provides robust evidence favoring dental implant therapy in elderly patients as a predictable long-term treatment option , in terms of implant survival , clinical ly acceptable PI-MBL changes , and minimal complications .
Therefore , age alone should not be a limiting factor for dental implant therapy | OBJECTIVE This systematic review was conducted to evaluate the outcome of dental implant therapy in elderly patients ( ≥65 years ) . | Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more PURPOSE The aim of this study was to report a clinical comparative assessment of crestal bone level change around single implants in fresh extraction sockets in the esthetic zone of the maxilla either immediately loaded or loaded after a delay . MATERIAL S AND METHODS Forty patients were included in a prospect i ve , r and omized study . All patients required 1 tooth extraction ( ie , 1 tooth with a hopeless prognosis ) and were r and omized into either the test group or the control group . Implants were positioned immediately after tooth extraction and were loaded immediately in the test group ( 20 implants ) and after 3 months in the control group ( 20 implants ) . The implant site was prepared , with at least 4 mm of sound apical bone below the implant apex , and the coronal margin of the implant was placed at the buccal level of the bone crest . All implants were 13 mm long ; 30 implants had a diameter of 5 mm , and 10 had a diameter of 3.75 mm . Radiographic examinations were made at baseline , at 6 months , and at 24 months . To compare the mean values between test and control group , a paired t test was performed ( considered statistically significant at P < .05 ) . RESULTS After a 24-month follow-up period , a cumulative survival rate of 100 % was reported for all implants . The control group result ed in a mean mesial bone loss of 1.16 + /- 0.32 mm and a mean distal bone loss of 1.17 + /- 0.41 ( mean bone loss , 1.16 + /- 0.51 mm ) . The test group result ed in a mesial bone loss of 0.93 + /- 0.51 mm and a distal bone loss of 1.1 + /- 0.27 mm ( mean bone loss , 1.02 + /- 0.53 mm ) . No statistically significant difference between control and test groups ( P > .05 ) was found . CONCLUSION The success rate and radiographic results of immediate restorations of dental implants placed in fresh extraction sockets were comparable to those obtained in delayed loading group PURPOSE The aim of this prospect i ve study was to evaluate the concept of intraoral welding as a suitable technique for the fabrication of a restoration for the edentulous atrophic maxilla on the day of placement of axial and tilted implants . MATERIAL S AND METHODS Thirty patients received three axial and four tilted implants in the edentulous maxilla . Immediately after implant placement , definitive abutments were connected to the implants and then a titanium bar was welded to them using an intraoral welding unit . This framework was used as a support for the definitive restoration , which was attached on the day of implant placement . Mean marginal bone loss and radiographically detectable alteration of the welded framework were assessed using periapical radiographs immediately after surgery and at 6 , 12 , 24 , and 36 months after placement . RESULTS Sixteen men and 14 women with an average age of 58.1 years ( SD 13.6 ) were consecutively treated with 210 immediately loaded implants . No fractures or radiographically detectable alterations of the welded frameworks were evident . A 100 % prosthetic success rate was seen at 36 months . Three ( 1.4 % ) implants had serious biologic complications , result ing in success rates of 97.8 % for axial implants and 99.2 % for tilted implants . The accumulated mean marginal bone loss was 0.92 mm ( SD 0.75 ; n = 90 ) for axial implants and 1.03 mm ( SD 0.69 ; n = 120 ) for tilted implants . The average pocket probing depths were 1.87 mm ( SD 0.98 ; n = 90 ) for the axial implants and 1.95 mm ( SD 0.81 ; n = 120 ) for the tilted implants . CONCLUSIONS It is possible on the day of implant placement surgery to successfully rehabilitate the edentulous atrophic maxilla with a fixed , definitive restoration supported by an intraorally welded titanium framework attached to axial and tilted implants PURPOSE To evaluate aged partially and fully edentulous patients who received dental implants and were maintained over time . Further , to determine how the partially and edentulous ageing population s ( 65 and above ) with dental implants maintain bone levels , proper oral hygiene , and perceive benefits of dental implants . MATERIAL S AND METHODS Since 1995 , patients receiving dental implants have been prospect ively entered into an Access-based computerized program ( Triton Tacking System ) . Patient demographics ( age , sex ) , bone quality , quantity , implant location , and type of surgery have been continuously entered into the data base . The data base was queried for patients receiving implants ( first stage ) between 66 and 93 years of age . Thirty-one patients were within this age group . Twenty-five patients returned to the clinic for periodontal and dental implant evaluation . The Periodontal Index was used to evaluate selected teeth in terms of probing depth , bleeding on probing , plaque accumulation , and mobility . Using NIH Image J , radiographs taken at second stage and last examination were measured for changes in interproximal bone levels . Once identified , each patient anomalously filled out an abbreviated quality of health life form . Due to small sample size , descriptive statistics were used to compare clinical findings . RESULTS Fifteen males ranging from 78 to 84 ( mean age 84 years ) years and 16 females from 66 to 93 ( mean age 83 years ) ( age range 66 - 93 ) were contacted by phone or mail and asked to return to our office for a re-examination . For this group , the first dental implants were placed in 1996 ( n = initial two implants ) and continuously recorded through 2013 ( n = last seven implants ) . Thirty-one patients received a total of 84 implants . Two patients were edentulous , and the remaining were partially edentulous . Four implants were lost . Between implant placement and 6- to 7-year interval , 13 patients with 40 implants had a cumulative survival rate of 94.6 % . Of the original group ( n = 33 ) , three were deceased , two were in nursing homes , and three could not be located . CONCLUSIONS Aged patients receiving dental implants had excellent implant survival rates , low periodontal disease index scores with minimal changes in interproximal bone levels . Results from this study indicate that patients with advanced age , in reasonably good health , have excellent implant survival rates , excellent quality of life scores , and can be maintained in good oral health OBJECTIVE To evaluate prospect ively clinical and radiographic outcomes of 6- or 10 mm-long implants with moderately rough surface ( SLA ( ® ) ) loaded within 7 weeks from installation and supporting single crowns in the posterior regions in the course of 5 years of loading . MATERIAL AND METHODS Sixty implants with a moderately rough surface , 30 tests ( 6 mm long , 4.1 mm in diameter ) and 30 controls ( 10 mm long , 4.1 mm in diameter ) , were placed in posterior regions in 45 patients . After 6 weeks , impressions were taken and the implants were restored with a single fixed prosthesis made with gold-palladium alloy and porcelain . Survival rate and marginal bone loss were evaluated yearly . The clinical crown/implant ratio was calculated . RESULTS During the follow-up period , five implants , four tests and one control , were lost . Of the four test implants , one was lost before loading , two between the 2nd and the 3rd years , and one during the 4th year of the follow-up period . The control implant was lost during the first year of function . Consequently , after 5 years of follow-up , a survival rate of 86.7 % and 96.7 % was observed at the test and control sites , respectively . CONCLUSION The results of this study showed that 6-mm-long implants supporting single crowns loaded within 7 weeks from installation lose a small amount of marginal bone during 5 years of functional loading , similar to that of 10-mm-long implants . However , a higher degree of implant loss was recorded at the short implants , probably due to the fracturing of the surrounding bone BACKGROUND The placement of an implant into a fresh extraction socket has been identified as a reliable technique , allowing a reduction in the time needed for prosthetic rehabilitation . This treatment modality is widely reported in the scientific literature ; however , the long-term outcomes and the need for guided bone regeneration ( GBR ) are still topics of debate . The aim of this prospect i ve study is to evaluate the clinical and radiologic findings from the 10-year follow-up of immediately placed implants , with and without the GBR procedure . METHODS A total of 159 implants in 91 patients are included in this study ; 101 implants required a GBR procedure simultaneously with placement . All implants were used to support a single crown restoration . The clinical /radiographic measurements were repeated each year up to the 10-year follow-up . At the 10-year follow-up visit , the papilla index and the apico-coronal location of mid-buccal soft tissue positions were recorded . RESULTS The 10-year cumulative success rate was 91.8 % ( 87.9 % in the non-GBR group and 94.1 % in the GBR group ) . The clinical attachment level ( CAL ) measurements were stable throughout the study , and 82 % of the implants showed marginal bone loss ( MBL ) of 0.6 to 1.5 mm at the 10-year visit ; moreover , these two parameters did not show significant differences between the GBR and non-GBR groups . Seventy percent of the implant sites showed acceptable outcomes in terms of interproximal papilla . The facial gingival level was more apical in the non-GBR group than in the GBR group ( P < 0.05 ) . CONCLUSIONS The present prospect i ve clinical study shows that implants placed in fresh extraction sockets had a high cumulative success rate , namely 91.8 % after 10 years . No differences were detected in survival and success rate of implants whether GBR procedures were performed or not . The CAL , MBL , and marginal level of soft tissue measurements were stable throughout the 10-year evaluation OBJECTIVES The purpose of the present clinical study was to report on the clinical performance of screw-cylinder implants with special consideration of the survival rate of short implants . MATERIAL AND METHODS In this prospect i ve study with consecutive patient recruitment , Camlog screw-cylinder implants with a particle-blasted and acid-etched microstructured surface and a triple-cam tube-in-tube implant-abutment connection have been used only . Two groups of implants were evaluated : implants of 9 and 11 mm in length were considered short , those of 13 and 16 mm were considered long . Besides clinical and radiographic parameters , data of complications , patients ' subjective evaluation of treatment outcome , general medical history and smoking habits were recorded . RESULTS Three hundred and thirty-three Camlog screw-cylinder implants were inserted in 133 patients . One hundred and twenty-nine patients were available for follow-up , representing 325 implants . The median observation period was 33 months ( Q(25 % ) 26 ; Q(75 % ) 38 ) . After a maximum observation period of 55 months , the Kaplan-Meier-survival analysis revealed no significant difference between the mean survival probabilities of 98.3 % ( n=59 , patient-related ) of short implants , and of 95.7 % of long implants ( n=70 , patient-related ) ( P=0.162 ) . No significant difference was found between implant survival rates considering maxilla ( 98.7 % ) and m and ible ( 98.2 % ) . A stratified analysis of short implants revealed a significant influence of premature cover screw exposures ( P=0.02 ) and smoking ( P=0.008 ) on implant survival . These influences were not found significant for long implants . CONCLUSIONS The prognosis of short Camlog implants is comparable with that of long implants . Therefore , their clinical use instead of performance of sophisticated vertical augmentation procedures before installation of long implants might be considered as alternative treatment option . In smokers , the use of short implants should be considered cautiously , however . The risk of premature cover screw exposure should be minimized PURPOSE This 15-year prospect i ve study evaluated the success rate and preservation of the gingival margin of single implants placed in a flapless procedure loaded immediately after extraction or after a healing period . MATERIAL S AND METHODS Immediate flapless implant placement was performed in patients who fulfilled specified inclusion criteria . Implants were either immediately restored with a provisional crown or left unloaded ( received healing abutment only ) . Implant success and gingival margin levels were evaluated after implant placement and after 1 to 15 years . RESULTS A total of 305 healthy nonsmoking subjects ( 90 men , 215 women ) were treated with 430 immediate implants during a 15-year period ( December 1994 to December 2009 ) and monitored for 1 to 15 years . Two hundred seventy-five implants received an immediate provisional crown , and 155 received a healing abutment . The implant survival rate was 93.03 % ( ± 3.74 % ) . The immediate provisional helped to maintain the original gingival margin , although the implant survival rate was higher for implants that were not immediately restored ( 96.78 % ) than for the implants that were immediately restored with a provisional ( 90.9 % ) . CONCLUSIONS This 15-year prospect i ve study showed a favorable implant success rate related to the flapless immediate implant placement protocol with healing abutment placement or an immediate provisional crown to replace a single missing tooth PURPOSE To compare immediately loaded post-extractive single implants using a definitive abutment versus provisional abutment later replaced by custom-made abutment . MATERIAL S AND METHODS In two private clinics , 28 patients in need of one single post-extractive implant in the maxilla or m and ible from the left second premolar to the right second premolar area were r and omised shortly before tooth extraction to provisional abutment ( PA ) and definitive abutment ( DA ) groups . Three patients had to be excluded for buccal wall fracture after tooth extraction . In the PA group , implants were immediately restored using a platform-switched provisional titanium abutment and definitive platform-switched titanium abutments were used in the DA group . In both groups , a non-occluding provisional single crown was provided . Implants were definitively restored after 4 months . In the PA group , the abutment was removed and the impression was made directly on the implant platform . In the DA group an impression of the abutment was made using a retraction cord . Outcome measures were : implant failures ; complications ; and marginal peri-implant bone level changes . Patients were followed up to 1 year after loading . RESULTS Twelve patients were r and omised to the DA group and 13 patients to the PA group . At the 12-month follow-up , no implant failed . One biological complication occurred in the DA group and one mechanical complication occurred in the PA group . All complications were successfully treated . One year after loading , implants in the DA group lost an average of 0.11 mm ( SD : 0.06 ) of periimplant bone and implants in PA group about 0.58 mm ( SD : 0.11 ) . At the 12-month follow-up , there was a statistically significant difference in bone level change between groups ( mean difference : 0.48 mm , CI 95 % 0.40 ; 0.55 , P < 0.0001 ) . CONCLUSIONS Within the limits of this study , the non-removal of abutments placed at the time of surgery result ed in the maintenance of 0.5 mm more bone levels around immediately restored postextractive single implants than repeated abutment removal , although this amount of bone maintenance may not have a clinical impact . Conflicts of interest notification : Dr Tommaso Gr and i and Dr Paolo Guazzi serve as consultants for JDentalCare . This study was completely self-financed and no funding was sought or obtained , not even in the form of free material PURPOSE The aim of this prospect i ve comparative study was to assess whether age has influence on peri-implant health in patients treated with m and ibular two-implant overdentures during a 10-year evaluation period . MATERIAL S AND METHODS A prospect i ve study was carried out with two groups of edentulous patients , viz a younger ( n = 52 ; mean age 45 years , 35 - 50 years ) and an older ( n = 53 ; mean age 68 years , 60 - 80 years ) group . In all patients , two dental implants were placed in the interforaminal region of the m and ible and after a 3-month healing period overdentures were fabricated . Clinical and radiographic parameters were evaluated immediately after completion of the prosthetic treatment , and after 1 , 5 and 10 years . Implant loss , plaque index , gingival index , bleeding index , and probing depth were assessed as clinical parameters . Peri-implant bone loss was assessed on dental radiographs made with a st and ardized long-cone technique with a direction device . RESULTS Implant survival after 10 years was 97.1 % and 93.4 % in the younger and older group , respectively . Ten-year scores of plaque , gingiva , and bleeding were between 0 and 1 for both groups ( possible scores 0 - 3 ) , and mean probing depth was 3 mm in both groups . Mean peri-implant bone loss after 10 years was 1.2 and 1.4 mm in the younger and older patients , respectively . No significant differences were observed between the groups . CONCLUSION Clinical performance of m and ibular two-implant overdentures is equally successful in younger and older patients PURPOSE The aim of this study was to evaluate the survival and success of screw-retained versus cement-retained implant restorations in immediately loaded implants at 8-year follow-up . MATERIAL S AND METHODS Patients who were scheduled for full-arch ceramic prosthetic restorations were divided into two groups by r and omization : in one group , prosthetic frameworks were screwed onto implants ( screw-retained group , SRG ) , and in the second group , the frameworks were cemented on abutments ( cement-retained group , CRG ) . Dental implants were placed both in post extraction and in healed sites . A temporary full-arch prosthesis was placed immediately after implant placement . Intraoral digital radiographic examinations ( evaluating marginal bone levels ) were made at baseline , 6 months , and each year after implant placement . RESULTS In 28 patients , 24 full arches and 192 implants were placed in the maxilla and 10 full arches and 80 implants in the m and ible ( 17 rehabilitations in each group ) . After an 8-year follow-up period , a survival rate of 99.27 % was reported for all implants . Within the first year after implant placement , bone loss was recorded as follows : the CRG showed mean bone levels of -1.23 ± 0.45 mm , while the SRG showed mean bone levels of -1.01 ± 0.33 mm . After a 3-year follow-up , a slight increase was found ( 0.30 ± 0.25 mm in CRG and 0.45 ± 0.29 mm in SRG ) . After that point , marginal bone levels remained stable over time , up to the 8-year follow-up . No statistically significant differences were found between groups ( P > .05 ) . CONCLUSION Definitive cement- and screw-retained ceramic restorations are highly predictable , biocompatible , and esthetically pleasing , and the two groups presented no statistically significant differences in bone loss This prospect i ve study evaluated the long-term performance of tapered screw implants placed in patients with a variety of potentially compromising clinical variables . Sixty patients were treated with 218 implants ; each case included one or more potential risk factors associated with increased rates of implant failure , peri-implant bone loss or clinical complications in the dental literature : short implants ( 23 % ) , comorbid conditions ( 25 % ) , maxillary implants ( 61 % ) , immediate loading ( 88.5 % ) , placement into extraction sockets ( 91 % ) , and partial edentulism ( 97 % ) . The implants were restored with a variety of prostheses . Marginal bone changes were calculated utilizing periapical radiographs taken at placement and at all subsequent appointments utilizing a st and ardized paralleling device and a 1-mm measurement grid . Mean clinical follow-up was 67.5 ( range : 1 - 94 ) months for implants and 60 ( range : 15 - 74 ) months for prostheses . Four implants failed to integrate and were immediately replaced by wide-diameter implants . Eight prostheses sustained porcelain fracture ( n = 7 ) or cement failure ( n = 1 ) and were replaced . No peri-implant marginal bone loss was observed for 98 % of the implants ; the remaining 2 % exhibited 1 mm of bone loss . Cumulative survival rates were 98.2 % for implants and 96.3 % for prostheses after 5 years of clinical loading . Concerns that tapered implant design s may be more prone to crestal bone loss than cylinder design s are unsupported by the results of this study . Tapered implants maintained integration and marginal bone levels despite the presence of one or more potentially compromising variables The type of attachment that is used in implant-supported m and ibular overdentures may influence the retention and stability of the prosthesis and , thus , masticatory function . In this within-subject cross-over clinical trial , we examined the hypothesis that greater retention and stability of the overdenture improve the masticatory function . Eighteen edentulous subjects received 2 oral implants , a new overdenture , and , successively , 3 different suprastructure modalities : magnet , ball , and bar-clip . Masticatory performance , masticatory efficiency , and swallowing threshold were measured . The masticatory function significantly improved after implant treatment with each of the 3 attachments . We observed small differences in masticatory function among the 3 attachment types : slightly better masticatory performance with ball and bar-clip than with magnet attachments . The number of chewing cycles until swallowing hardly decreased after implant treatment . We conclude that significantly better masticatory performance , combined with a slightly smaller number of chewing cycles after implant treatment , results in smaller food particles being swallowed BACKGROUND Immediate occlusal implant loading has been documented as a viable treatment option for various indications . However , most of the available studies reported on the short-term outcome of this treatment modality . PURPOSE The purpose of this prospect i ve clinical study was to document , on a long-term basis , the outcome of immediate occlusally loaded Brånemark System Mk IV TiUnite ( Nobel Biocare AB , Göteborg , Sweden ) implants placed to support fixed reconstructions in various regions of the jaws . MATERIAL S AND METHODS Thirty-eight patients received a total of 51 fixed prosthetic reconstructions , all of which were connected on the day of implant insertion . Twenty restorations replaced single teeth , 30 were fixed partial dentures , and 1 was a full-arch fixed lower restoration . These prostheses were supported by 102 Brånemark System Mk IV TiUnite implants ( 38 maxillary and 64 m and ibular ) , the majority of which were placed in posterior regions ( 88 % ) and mainly in soft bone ( 76 % ) . Resonance frequency measurements and marginal periimplant soft tissue evaluations were conducted during the course of the study . Furthermore , radiographic examinations were performed at the time of prosthesis delivery and at the 1- and 6-month and 1- , 2- , 3- , and 4-year follow-up visits . This report summarizes the results after 4 years of loading . RESULTS Three maxillary implants were removed , although stable , in one patient at the 8-week follow-up owing to postoperative infection in the adjacent guided bone regeneration area . No implants were lost further on . This result ed in a cumulative implant success rate of 97.1 % after 4 years of prosthetic loading . The mean marginal bone remodeling after 4 years of function was 1.3 + /- SD 0.9 mm . At 4 years , absence of marginal plaque and bleeding on probing was reported for 87 % and 69 % of the sites , respectively , thereby remaining unchanged since the 1-year follow-up . On average , the interproximal soft tissue fill increased for both mesial and distal papillae from scores of 1.4 + /- 1.1 and 1.0 + /- 1.1 , respectively , at the preoperative assessment to 2.0 + /- 0.8 and 1.7 + /- 0.8 , respectively , at the 4-year assessment . CONCLUSION The applied immediate loading protocol , in combination with a slightly tapered implant design and a modified implant surface texture , was shown to be a successful treatment alternative in regions exhibiting soft bone PURPOSE The aim of this study was to evaluate the survival rate of immediately provisionalized implants with up to 5 years follow-up . MATERIAL S AND METHODS The study consisted of 226 patients , 113 consecutive patients with immediately provisionalized dental implants ( cases ) and 113 r and omly selected , age- , gender- , and implant position-matched controls with conventional late implant loading . Survival rate and incidence of complications were recorded . RESULTS Follow-up ranged from 6 to 60 months . Smoking was reported by 20.8 % of patients . Maxillary incisors and m and ibular lateral incisors were the most common areas for implant placement . Conventionally loaded implants were narrower ( p = .03 ) and shorter ( p = .001 ) . Immediate implantation into a fresh extraction socket was performed in 69 % of the cases and in 36.3 % of the controls ( p = .001 ) . Implant survival rate was 96.5 % . Of the eight failed implants , six were immediately provisionalized and two were conventionally loaded . No statistically significant difference was found in survival rates between groups ( p > 0.05 ) . Five of the failed implants ( case group ) were immediately loaded implants placed in fresh extraction sockets . CONCLUSION Immediate implant provisionalization achieved similar high success rates compared with the conventional , delayed approach . As immediate implant provisionalization is mainly desired in the anterior region , the high success rates are encouraging STATEMENT OF PROBLEM Numerous studies have demonstrated the feasibility and predictability of immediate implant loading or immediate implant restoration . However , most of these studies report primarily short-term outcomes . PURPOSE The purpose of this prospect i ve clinical study was to document the 5-year outcome of immediate occlusally loaded implants with an oxidized , microtextured surface placed to support fixed prostheses in various regions of the jaws . MATERIAL AND METHODS Thirty-eight patients received a total of 51 implant-supported fixed prostheses , 29 m and ibular and 22 maxillary , the day of implant insertion . Thirty were fixed partial dentures ( FPDs ) , 20 replaced single teeth , and 1 was a fixed m and ibular complete denture . The restorations were supported by 102 slightly tapered , screw-type implants , the majority of which were placed in posterior regions ( 88 % ) and primarily in soft bone quality ( 76 % ) . Patients with ongoing signs of parafunctional habits were not included . All implants were placed using conventional flap procedures . Treatment with local regenerative procedures in connection with implant placement was accepted within the study design . Resonance frequency implant stability measurements and marginal periimplant soft tissue evaluations were conducted . Radiographic examinations were performed at the time of prosthesis insertion , at 1- and 6-month follow-ups , and annually at the 1- through 5-year follow-up visits . This report presents the results after 5 years of loading , summarized with descriptive statistics . RESULTS Three maxillary implants were removed , although stable , in 1 patient at the 8-week follow-up due to postoperative infection in the adjacent guided bone regeneration ( GBR ) area . No additional implants were lost . This result ed in a cumulative implant success rate of 97.1 % after 5 years of prosthetic loading . The mean marginal bone remodeling ( SD ) after 5 years of function was 1.54 ( 0.99 ) mm . At the 5-year examination , absence of marginal plaque and absence of bleeding on probing was reported for 75 % and 74 % of the sites , respectively , and remained generally unchanged from the 1-month follow-up . CONCLUSIONS The 5-year follow-up data indicate that an immediate loading protocol using a slightly tapered implant design with an oxidized , microtextured surface is a successful treatment alternative in regions exhibiting soft bone quality |
13,645 | 29,473,462 | Conclusions Mortality , both short and long term , and the occurrence of ventricular arrhythmias in patients with acute myocardial infa rct ion seem to be negatively associated with hypokalemic serum potassium concentration . | Background Challenging clinical practice guidelines that recommend serum potassium concentration between 4.0–5.0 mEq/L or ≥4.5 mEq/L in patients with acute myocardial infa rct ion , recent studies found increased mortality risks in patients with a serum potassium concentration of ≥4.5 mEq/L. Studies investigating consequences of hypokalemia after acute myocardial infa rct ion revealed conflicting results .
Therefore , the aim of this systematic review and meta- analysis was to combine evidence from previous studies on the association of serum potassium concentration with both short and long-term mortality as well as the occurrence of ventricular arrhythmias . | Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND Atrial fibrillation is the most common sustained arrhythmia in the elderly . Serum potassium is associated with ventricular arrhythmias and cardiac arrest . Little is known about the association of serum potassium with atrial fibrillation . The objective of this study was to investigate the association of serum potassium and the risk of atrial fibrillation in a population based setting . METHODS The study was performed within the prospect i ve population -based Rotterdam Study . The study population consisted of 4059 participants without atrial fibrillation at baseline for whom baseline levels of serum potassium were measured . Atrial fibrillation was ascertained from centre visit ECG assessment s as well as medical records . RESULTS During a mean follow up of 11.8 years ( SD=5.2 yr ) , 474 participants developed atrial fibrillation . Participants with hypokalemia ( < 3.5 mmol/l ) had a higher risk of atrial fibrillation ( HR : 1.63 , 95%CI : 1.03 - 2.56 ) than those with normokalemia ( 3.5 - 5.0 mmol/l ) . This association was independent of age , sex , serum magnesium , and other potential confounders . Especially in participants with a history of myocardial infa rct ion , those with hypokalemia had a higher risk of atrial fibrillation than those with normokalemia ( HR : 3.81 , 95%-CI : 1.51 - 9.61 ) . CONCLUSIONS In this study low serum levels of potassium were associated with a higher risk of atrial fibrillation Background : In acute coronary syndrome ( ACS ) , potassium levels < 3.5 mEq/L are associated with ventricular arrhythmias . Current guidelines therefore recommend a potassium target > 4.0 mEq/L in ACS . Our study evaluated the association between potassium levels , cardiac arrhythmias , and cardiovascular death in patients with non-ST-segment elevation myocardial infa rct ion or unstable angina . Methods : Potassium levels were measured in 6515 patients prior to r and omization to receive either ranolazine or a placebo in the MERLIN-TIMI 36 trial . A seven-day continuous electrocardiographic assessment was obtained to determine the incidence of non-sustained ventricular tachycardia ( NSVT ) and ventricular pauses . The association between potassium levels and cardiovascular death was evaluated using a Cox proportional hazards regression model with multivariable adjustment . Results : NSVT lasting for at least eight consecutive beats occurred more frequently at potassium levels < 3.5 mEq/L than at potassium levels ⩾5 mEq/L ( 10.1 vs. 4.5 % , p=0.03 for trend ) , whereas the inverse pattern was observed for ventricular pauses > 3 s , which occurred more frequently at potassium levels ⩾5 mEq/L than at potassium levels < 3.5 mEq/L ( 5.9 vs. 2.0 % , p=0.03 for trend ) . There was a U-shaped relationship between the potassium level at admission and both early and late risk of cardiovascular death . Compared with patients with potassium levels of 3.5 to < 4 mEq/L , a potassium level < 3.5 mEq/L was associated with an increased risk of cardiovascular death at day 14 ( 2.4 vs. 0.8 % , HRadj 3.1 , p=0.02 ) and at one year ( 6.4 vs. 3.0 % , HRadj 2.2 , p=0.01 ) . The risk of cardiovascular death at one year was also significantly increased at potassium levels ⩾4.5 mEq/L and a similar trend was noted at potassium levels ⩾5 mEq/L. Conclusions : The lowest risk of cardiovascular death was observed in patients with admission potassium levels between 3.5 and 4.5 mEq/L. Both lower and higher levels of potassium were associated with tachyarrhythmias and bradyarrhythmias , suggesting a potential mechanistic explanation for the increased risk of cardiovascular death at the extremes of potassium homeostasis Abstract Abnormal serum potassium levels are associated with an increased risk of ventricular arrhythmias and mortality in patients with acute myocardial infa rct ion ( AMI ) . The aim of the present study was to evaluate whether different levels of serum potassium , within the normal range , are associated with worse outcomes . The present study comprised 1277 patients with AMI and normal-range admission potassium levels ( 3.5–5.2 mEq/L ) , who were enrolled and prospect ively followed up in the Acute Coronary Syndrome Israeli Survey between 2010 and 2013 . Patients were divided into 4 quartiles based on admission potassium levels ; “ normal-low ” ( K ≥ 3.5 and K ⩽ 3.9 ) , “ normal-moderate ” ( K > 3.9 and K ⩽ 4.18 ) , “ normal-high ” ( K > 4.18 and K ⩽ 4.45 ) , and “ normal-very high ” ( K > 4.45 and K ⩽ 5.2 ) . We analyzed the association between admission serum potassium levels and 7 days in-hospital complication rates , and 30-day and 1-year all-cause mortality rates . Patients with “ normal-very high ” potassium displayed increased frequency of baseline clinical risk factors and experienced a higher rate of acute kidney injury during hospitalization compared with the “ normal-low ” group ( 7.7 % vs 2.4 % ; P = 0.002 ) . However , the rate of in-hospital ventricular arrhythmias was similar across the range of admission potassium levels ( overall P = 0.26 ) , Multivariate analysis showed that compared with “ low-normal ” potassium values , patients with “ normal-very high ” potassium levels experienced increased risk for 30-days ( adjusted hazard ratio 2.88 , 95 % confidence interval 1.05–7.87 , P = 0.039 ) and 1-year all-cause mortality ( adjusted hazard ratio 1.98 , 95 % confidence interval 1.05–3.75 , P = 0.034 ) . In patients admitted with AMI , admission serum potassium levels of 4.45 to 5.2 mEq/L are not associated with in-hospital ventricular arrhythmias , but are associated with increased short and long-term mortality OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity Aims In the Ongoing Telmisartan Alone and in Combination with Ramipril Trial ( ONTARGET ) , dual agent renin-angiotensin-aldosterone system ( RAAS ) blockade with angiotensin-converting-enzyme inhibitors ( ACEIs ) and angiotensin receptor blockers ( ARBs ) did not reduce the risk of renal and cardiovascular outcomes compared with the single use of either agent . Dual therapy however increased the incidence of hyperkalemia . We examined risk factors for hyper- and hyokalemia and hypothesized that both would be associated with worse cardiovascular and renal outcomes . Methods A post-hoc analysis of the ONTARGET trial comparing dual therapy ( ramipril and telmisartan ) vs monotherapy ( ramipril or telmisartan ) was performed . The association between serum potassium at week 6 on cardiovascular and renal outcomes during the 56 months follow-up was assessed by multivariate Cox analysis . The main cardiovascular outcome was the composite of cardiovascular death , myocardial infa rct ion , stroke , or hospitalization for heart failure . The renal outcome was defined as the composite of a doubling of serum creatinine or chronic dialysis . Results Six weeks after r and omization , hyperkalemia developed in 210 ( 2.7 % ) patients on dual therapy vs 264 ( 1.6 % ) patients on monotherapy ( p < 0.001 vs dual therapy ) . Hypokalemia developed in 87 ( 1.1 % ) patients on dual therapy vs 200 ( 1.2 % ) patients on monotherapy . Serum potassium was nonlinearly associated with cardiovascular and renal events with a nadir between 4.0–5.0 mmol/l for cardiovascular and 4.0–4.5 mmol/l for renal events such that subjects above or below these values exhibited higher risks . This association was independent of age , gender , diabetes , estimated glomerular filtration rate , systolic blood pressure and diuretic use . Conclusions With the pre caution s stipulated by the protocol of the ONTARGET trial , hypokalemia and hyperkalemia were infrequent events . Nevertheless , both high and low serum potassium were associated with an increased risk of cardiovascular and renal disease STUDY OBJECTIVES Although controversial , hypokalemia ( LK ) in patients with acute myocardial infa rct ion ( MI ) is thought to predict increased in-hospital morbidity , particularly cardiac arrhythmias , and mortality . Also , the mechanism of low serum potassium in the setting of MI has not been delineated . We evaluated the frequency , attributes , and outcome , and speculated on the mechanism of LK in patients with MI . DESIGN This was a prospect i ve cross-sectional study of 517 consecutive patients with MI admitted to the coronary care unit ( CCU ) . Serum potassium was measured in the emergency department and repeatedly thereafter throughout hospitalization , and was used in the analysis , along with a large array of clinical and laboratory variables . RESULTS The patients were allocated to a LK and a normokalemic ( NK ) cohort , based on the emergency department serum potassium measurement . The 41 patients with LK ( 3.16+/-0.24 mEq/L ; 7.9 % of total ) were comparable on admission in their baseline assessment to the 476 patients with normal serum potassium ( 4.28+/-0.56 mEq/L ) , except for lower emergency department magnesium ( 1.48+/-0.15 mg/dL vs. 1.96+/-0.26 mg/dL ; p = 0.0005 ) and earlier presentation after onset of symptoms ( 3.0+/-4.1 h vs. 4.4+/- 6.2 h ; p = 0.05 ) . There was a poor correlation between serum potassium and magnesium on admission ( r = 0.14 ) . Peak creatine kinase ( CK ) and myocardial isomer of CK were higher in the LK patients ( 3,870+/-3 , 840 IU/L vs. 2,359+/-2,653 IU/L [ p = 0.018 ] and 358+/-312 IU/L vs. 228 + /- 258 IU/L [ p = 0.013 ] , respectively ) . Management of the two cohorts was the same , except for a higher rate of use of magnesium ( 14.6 % vs. 4.6 % ; p = 0.007 ) , serum potassium supplements ( 90.2 % vs 43 . 1 % ; p = 0.000005 ) , and antiarrhythmic drugs ( 78.0 % vs 50.4 % ; p = 0 . 0007 ) in the LK patients . No difference was detected between the LK and NK patients in total mortality ( 24.4 % vs. 18.3 % ; p = 0.34 ) , cardiac mortality ( 17.1 % vs. 15.3 % ; p = 0.52 ) , atrial fibrillation ( 14.6 % vs 13.9 % ; p = 0.89 ) , and ventricular tachycardia ( 22.0 % vs. 16.0 % ; p = 0.32 ) , but ventricular fibrillation ( VF ) occurred more often ( 24.4 % vs 13.0 % ; p = 0.04 ) in the LK patients . However , proportions of VF occurring in the emergency department , CCU , or wards in the two cohorts were not different , but they were higher during the time interval prior to emergency department admission in LK patients ( 17.1 % vs 2.1 % ; p = 0.00001 ) . CONCLUSIONS LK is seen in approximately 8 % of patients with MI in the emergency department ; LK is associated with low emergency department magnesium , and low serum potassium levels in the CCU and throughout hospitalization . LK has no relationship to preadmission use of diuretics , it is associated with early presentation to the emergency department , and it is not a predictor of increased morbidity or mortality Low plasma potassium and magnesium concentrations have been advanced as risk factors for ventricular fibrillation ( VF ) . For potassium , this assertion is based almost exclusively on retrospective data ; for magnesium the evidence shows an association with ventricular arrhythmias but no direct association with VF . We studied the relationship between these electrolytes and VF prospect ively . Plasma potassium and serum magnesium concentrations were measured on admission to our coronary care unit . Drug therapy , time from onset of symptoms , ECG , enzyme changes and clinical status were all recorded . VF was confirmed by analysis of 24 h monitoring tapes . Mean plasma potassium in the 21 patients with VF who had measurements prior to their arrhythmia was 3.49 + /- 0.54 mmol/l , lower than that of the 1165 patients without VF ( mean K 3.88 + /- 0.57 mmol/l , p < 0.05 ) . Plasma potassium concentrations in the 17 patients with myocardial infa rct ion and VF were lower ( mean 3.58 + /- 0.41 mmol/l ) than in those without VF ( n = 417 , mean 3.89 + /- 0.61 mmol/l ) ( p < 0.05 ) . Mean serum magnesium in the 12 patients with VF , measured prior to their arrhythmia ( all with myocardial infa rct ion ) was 0.80 + /- 0.07 mmol/l , which was not different from the mean for patients without VF ( n = 781 , 0.82 + /- 0.09 mmol/l ) or from the mean of 0.81 + /- 0.08 mmol/l for those with infa rct ion but not VF ( n = 331 ) . Low plasma potassium concentrations are associated with increased risk of ventricular fibrillation , but low serum magnesium concentrations are not Eighteen patients with essential hypertension were treated in a single‐blind , crossover study with pindolol and with propranolol . The two drugs were compared because of known differences between them on renin secretion . We noted that plasma renin activity and plasma aldosterone concentration were suppressed by propranolol but not by pindolol . Blood pressure was reduced about equally by both drugs . Serum potassium levels rose in 17 patients on pindolol ( p < 0.001 ) and in 14 patients on propranolol ( p = 0.008 ) . Our data suggest that serum potassium elevations induced by beta blockade do not depend on the renin‐angiotensin‐aldosterone system . Alternative possibilities are discussed |
13,646 | 27,643,388 | By comparison , short-term ( up to 12 weeks ) , but not longer-term effectiveness was demonstrated for both pharmacological and psychological interventions .
CONCLUSIONS Collaborative care interventions have newly emerged as multidisciplinary care delivery models , which may result in more long-term depression remission .
This review also up date s previous findings of modest evidence for the effectiveness of both pharmacological and psychological interventions for threshold depression in cancer patients .
Research design s focusing on combined treatments and delivery systems may best further the limited evidence -base for the management of depression in cancer | BACKGROUND Previous systematic review s have found limited evidence for the effectiveness of pharmacological and psychological interventions for the management of depression in patients with cancer .
This paper provides the first meta- analysis of newer collaborative care interventions , which may include both types of treatment , as well as integrated delivery and follow-up . | BACKGROUND The management of depression in patients with poor prognosis cancers , such as lung cancer , creates specific challenges . We aim ed to assess the efficacy of an integrated treatment programme for major depression in patients with lung cancer compared with usual care . METHODS Symptom Management Research Trials ( SMaRT ) Oncology-3 is a parallel-group , multicentre , r and omised controlled trial . We enrolled patients with lung cancer and major depression from three cancer centres and their associated clinics in Scotl and , UK . Participants were r and omly assigned in a 1:1 ratio to the depression care for people with lung cancer treatment programme or usual care by a data base software algorithm that used stratification ( by trial centre ) and minimisation ( by age , sex , and cancer type ) with allocation concealment . Depression care for people with lung cancer is a manualised , multicomponent collaborative care treatment that is systematic ally delivered by a team of cancer nurses and psychiatrists in collaboration with primary care physicians . Usual care is provided by primary care physicians . The primary outcome was depression severity ( on the Symptom Checklist Depression Scale [ SCL-20 ] , range 0 - 4 ) averaged over the patient 's time in the trial ( up to a maximum of 32 weeks ) . Trial statisticians and data collection staff were masked to treatment allocation , but patients and clinicians could not be masked to the allocations . Analyses were by intention to treat . This trial is registered with Current Controlled Trials , number IS RCT N75905964 . FINDINGS 142 participants were recruited between Jan 5 , 2009 , and Sept 9 , 2011 ; 68 were r and omly allocated to depression care for people with lung cancer and 74 to usual care . 43 ( 30 % ) of 142 patients had died by 32 weeks , all of which were cancer-related deaths . No intervention-related serious adverse events occurred . 131 ( 92 % ) of 142 patients provided outcome data ( 59 in the depression care for people with lung cancer group and 72 in the usual care group ) and were included in the intention-to-treat primary analysis . Average depression severity was significantly lower in patients allocated to depression care for people with lung cancer ( mean score on the SCL-20 1·24 [ SD 0·64 ] ) than in those allocated to usual care ( mean score 1·61 [ SD 0·58 ] ) ; difference -0·38 ( 95 % CI -0·58 to -0·18 ) ; st and ardised mean difference -0·62 ( 95 % CI -0·94 to -0·29 ) . Self-rated depression improvement , anxiety , quality of life , role functioning , perceived quality of care , and proportion of patients achieving a 12-week treatment response were also significantly better in the depression care for people with lung cancer group than in the usual care group . INTERPRETATION Our findings suggest that major depression can be treated effectively in patients with a poor prognosis cancer ; integrated depression care for people with lung cancer was substantially more efficacious than was usual care . Larger trials are now needed to estimate the effectiveness and cost-effectiveness of this care programme in this patient population , and further adaptation of the treatment will be necessary to address the unmet needs of patients with major depression and even shorter life expectancy . FUNDING Cancer Research UK and Chief Scientist Office of the Scottish Government In the context of chronic physical illness , such as breast cancer , depression is associated with increased morbidity , longer periods of hospitalization , and greater overall disability . Prompt diagnosis and effective treatment is , therefore , essential . Several small studies have established the efficacy of tricyclic antidepressants ( TCAs ) in this setting , and the selective serotonin reuptake inhibitors ( SSRIs ) would appear to be an alternative therapeutic option because of their established efficacy and better tolerability profile . This was a multicenter , double-blind , parallel-group study in which 179 women with breast cancer were r and omized to treatment with either the SSRI paroxetine ( 20–40mg/day ) , or the TCA , amitriptyline ( 75–150mg/day ) . After 8-weeks treatment , depressive symptomatology had improved markedly and to a similar extent in both groups on the Montgomery Asberg Depression Rating Scale . Clinical global impression ( CGI ) Global improvement and Patient global evaluation scales indicated that patients were minimally to much improved at study endpoint ; a change from moderately/mildly ill to borderline ill on the CGI severity of Illness scale . A steady improvement in quality of life was also observed in both groups . There were no clinical ly significant differences between the groups . In total , 47 ( 53.4 % ) patients in the paroxetine group and 53 ( 59.6 % ) patients in the amitriptyline group had adverse experiences , the most common of which were the well-recognized side-effects of the antidepressant medications or chemotherapy . Anticholinergic effects were almost twice as frequent in the amitriptyline group ( 19.1 % ) compared with paroxetine ( 11.4 % ) . This study has demonstrated that paroxetine is a suitable alternative to amitriptyline for the treatment of depression in patients with breast cancer Little has been done to study the effectiveness of antidepressants in controlling anxiety/depression in a population of cancer patients . A double‐blind placebo‐controlled study was therefore design ed to assess the effectiveness of 20 mg fluoxetine . Of 115 cancer patients who fulfilled entry criteria for levels of distress , 45 patients were r and omized to a fluoxetine treatment group ( FA ) and 46 patients to a placebo group ( PA ) after a 1‐week placebo period design ed to exclude placebo responders . The Montgomery and Asberg Depression Scale ( MADRS ) , the Hamilton Anxiety Scale ( HAS ) , the Hospital Anxiety and Depression Scale ( HADS ) , the Revised Symptom Checklist ( SCL90‐R ) and the Spitzer Quality of Life Index ( SQOLI ) were used to assess the efficacy of fluoxetine . The response rate , defined by a HADS score lower than 8 after 5 weeks of treatment , was not significantly higher in the FA group ( 11 % ) compared to the PA group ( 7 % ) . Compared to the PA group , patients in the FA group showed a significantly greater decrease in SCL90‐R mean total score after 5 weeks , but not a greater decrease in HADS mean score . No difference between the two groups was found in observer‐reported assessment s ( MADRS , HAS and SQOLI ) . Significantly more drop‐outs were observed in the FA group ( n=15 ) than in the PA group ( n=7 ) , although the frequencies of side‐effects were not significantly different BACKGROUND There is a lack of trials of psychodynamic treatments of depression in breast cancer patients . The purpose of this trial was to determine the efficacy of short-term psychodynamic psychotherapy ( STPP ) in non-metastatic breast cancer patients diagnosed with depression , one of the most frequent mental comorbidities of breast cancer . PATIENTS AND METHODS In a multicenter prospect i ve trial , 157 breast cancer patients with comorbid depression were r and omized to either individual STPP ( intervention group , N=78 ) or ' treatment as usual ' ( control group , TAU , N=79 ) . As our primary outcome measure , we hypothesized a higher rate of remission defined as no diagnosis of depression ( Structured Clinical Interview for DSM-IV ) and reduction in depression score by at least 2 points ( Hospital Anxiety and Depression Scale , HADS-D ) in STPP versus TAU at treatment termination . Secondary outcomes mainly refer to quality of life ( QoL ) . RESULTS In the intention to treat ( ITT ) analysis , 44 % of the STPP group achieved highly significantly more remission than TAU ( 23 % ) . STPP treatment ( OR=7.64 ; P<0.001 ) was the strongest predictor for remission post-treatment ; time was also significant ( OR=0.96 ; P<0.05 ) . A high effect favoring STPP ( d=0.82 ) was observed for the HADS-D score post-treatment ( secondary outcome ) . Regarding further secondary outcomes ( QoL ) , analyses of covariance yielded main effects for group ( favoring STPP with an effect size of at least d=0.5 ) for global QoL , role , emotional and social functioning , pain , treatment side-effects , breast symptoms and upset by hair loss . CONCLUSIONS STPP is an effective treatment of a broad range of depressive conditions in breast cancer patients improving depression and functional QoL. Findings are limited by the drop-out rate ( ∼1/3 ) and delayed post-treatment assessment s. Future trials may consider stepped-care approaches , tailored to patients ' needs and requirements in the acute treatment phase OBJECTIVE Head and neck cancer ( HNC ) patients have a high incidence of cancer-related posttraumatic stress disorder ( PTSD ) and other anxiety and depressive disorders . We report the results from the first pilot r and omized controlled trial in which the efficacy of an early cognitive-behavioral therapy ( CBT ) program was compared with a non-directive supportive counseling ( SC ) intervention in reducing PTSD , general anxiety and depressive symptoms , and improving perceived quality of life in newly diagnosed , distressed HNC patients undergoing radiotherapy . PATIENTS AND METHODS Thirty-five HNC patients ( mean age=54.8 years ; 80 % males ) with elevated levels of PTSD , depression or anxiety were r and omized to seven individual sessions of a multi-modal CBT or non-directive SC , concurrent with patients ' radiotherapy . The SC intervention provided non-directive counseling support . PTSD , anxiety and depressive symptoms ( primary outcomes ) , and cancer-related appraisal s and quality of life ( secondary outcomes ) were assessed pre-intervention ( baseline ) , 1 month , 6 months and 12 months post-intervention by diagnostic clinical interviews and vali date d self-report question naires . RESULTS The CBT and SC interventions were found to be equal in their effects in reducing PTSD and anxiety symptoms both in the short and longer term . However , up to 67 % of patients in the CBT program no longer met clinical or sub- clinical PTSD , anxiety and /or depression by 12 months post-treatment compared with 25 % of patients who received SC . CONCLUSION Findings indicate that the early provision of psychotherapy has utility in reducing PTSD , anxiety and depressive symptoms , and preventing chronic psychopathology in distressed HNC patients Background Depression is common among older cancer patients , but little is known about the optimal approach to caring for this population . This analysis evaluates the effectiveness of the Improving Mood-Promoting Access to Collaborative Treatment ( IMPACT ) program , a stepped care management program for depression in primary care patients who had an ICD-9 cancer diagnosis . Methods Two hundred fifteen cancer patients were identified from the 1,801 participants in the parent study . Subjects were 60 years or older with major depression ( 18 % ) , dysthymic disorder ( 33 % ) , or both ( 49 % ) , recruited from 18 primary care clinics belonging to 8 health-care organizations in 5 states . Patients were r and omly assigned to the IMPACT intervention ( n = 112 ) or usual care ( n = 103 ) . Intervention patients had access for up to 12 months to a depression care manager who was supervised by a psychiatrist and a primary care provider and who offered education , care management , support of antidepressant management , and brief , structured psychosocial interventions including behavioral activation and problem-solving treatment . Results At 6 and 12 months , 55 % and 39 % of intervention patients had a 50 % or greater reduction in depressive symptoms ( SCL-20 ) from baseline compared to 34 % and 20 % of usual care participants ( P = 0.003 and P = 0.029 ) . Intervention patients also experienced greater remission rates ( P = 0.031 ) , more depression-free days ( P < 0.001 ) , less functional impairment ( P = 0.011 ) , and greater quality of life ( P = 0.039 ) at 12 months than usual care participants . Conclusions The IMPACT collaborative care program appears to be feasible and effective for depression among older cancer patients in diverse primary care setting Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND Major depressive disorder severely impairs the quality of life of patients with medical disorders such as cancer , but evidence to guide its management is scarce . We aim ed to assess the efficacy and cost of a nurse-delivered complex intervention that was design ed to treat major depressive disorder in patients who have cancer . METHODS We did a r and omised trial in a regional cancer centre in Scotl and , UK . 200 out patients who had cancer with a prognosis of greater than 6 months and major depressive disorder ( identified by screening ) were eligible and agreed to take part . Their mean age was 56.6 ( SD 11.9 ) years , and 141 ( 71 % ) were women . We r and omly assigned 99 of these participants to usual care , and 101 to usual care plus the intervention , with minimisation for sex , age , diagnosis , and extent of disease . The intervention was delivered by a cancer nurse at the centre over an average of seven sessions . The primary outcome was the difference in mean score on the self-reported Symptom Checklist-20 depression scale ( range 0 to 4 ) at 3 months after r and omisation . Analysis was by intention to treat . This trial is registered as IS RCT N84767225 . FINDINGS Primary outcome data were missing for four patients . For 196 patients for whom we had data at 3 months , the adjusted difference in mean Symptom Checklist-20 depression score , between those who received the intervention and those who did not , was 0.34 ( 95 % CI 0.13 - 0.55 ) . This treatment effect was sustained at 6 and 12 months . The intervention also improved anxiety and fatigue but not pain or physical functioning . It cost an additional pound sterling 5278 ( US$ 10 556 ) per quality -adjusted life-year gained . INTERPRETATION The intervention-Depression Care for People with Cancer-offers a model for the management of major depressive disorder in patients with cancer and other medical disorders who are attending specialist medical services that is feasible , acceptable , and potentially cost effective One hundred and fifty‐two women undergoing mastectomy were r and omly assigned to routine care or routine care plus monitoring by a specialist nurse . The nurse detected and referred 76 % of her patients for psychiatric help . Only 15 % of the routine care subjects that warranted help were referred . Twelve to eighteen months after surgery , morbid anxiety and depression were less common in the monitored ( 5 % and 5 % ) than in the control ( 30 % and 50 % ) group . This difference appeared to be due primarily to psychiatric treatment which included antidepressant medication , anxiolytic drugs , and supportive psychotherapy . Few affective disorders remitted without such treatment . In a further study , the effects of antidepressant medication plus cognitive therapy and cognitive therapy alone were compared . Both treatments alleviated depression in the short term but the improvement was sustained in the long term only in those given combined treatment CONTEXT Few depressed older adults receive effective treatment in primary care setting s. OBJECTIVE To determine the effectiveness of the Improving Mood-Promoting Access to Collaborative Treatment ( IMPACT ) collaborative care management program for late-life depression . DESIGN R and omized controlled trial with recruitment from July 1999 to August 2001 . SETTING Eighteen primary care clinics from 8 health care organizations in 5 states . PARTICIPANTS A total of 1801 patients aged 60 years or older with major depression ( 17 % ) , dysthymic disorder ( 30 % ) , or both ( 53 % ) . INTERVENTION Patients were r and omly assigned to the IMPACT intervention ( n = 906 ) or to usual care ( n = 895 ) . Intervention patients had access for up to 12 months to a depression care manager who was supervised by a psychiatrist and a primary care expert and who offered education , care management , and support of antidepressant management by the patient 's primary care physician or a brief psychotherapy for depression , Problem Solving Treatment in Primary Care . MAIN OUTCOME MEASURES Assessment s at baseline and at 3 , 6 , and 12 months for depression , depression treatments , satisfaction with care , functional impairment , and quality of life . RESULTS At 12 months , 45 % of intervention patients had a 50 % or greater reduction in depressive symptoms from baseline compared with 19 % of usual care participants ( odds ratio [ OR ] , 3.45 ; 95 % confidence interval [ CI ] , 2.71 - 4.38 ; P<.001 ) . Intervention patients also experienced greater rates of depression treatment ( OR , 2.98 ; 95 % CI , 2.34 - 3.79 ; P<.001 ) , more satisfaction with depression care ( OR , 3.38 ; 95 % CI , 2.66 - 4.30 ; P<.001 ) , lower depression severity ( range , 0 - 4 ; between-group difference , -0.4 ; 95 % CI , -0.46 to -0.33 ; P<.001 ) , less functional impairment ( range , 0 - 10 ; between-group difference , -0.91 ; 95 % CI , -1.19 to -0.64 ; P<.001 ) , and greater quality of life ( range , 0 - 10 ; between-group difference , 0.56 ; 95 % CI , 0.32 - 0.79 ; P<.001 ) than participants assigned to the usual care group . CONCLUSION The IMPACT collaborative care model appears to be feasible and significantly more effective than usual care for depression in a wide range of primary care practice CONTEXT Pain and depression are 2 of the most prevalent and treatable cancer-related symptoms , yet they frequently go unrecognized , undertreated , or both . OBJECTIVE To determine whether central ized telephone-based care management coupled with automated symptom monitoring can improve depression and pain in patients with cancer . DESIGN , SETTING , AND PATIENTS R and omized controlled trial conducted in 16 community-based urban and rural oncology practice s involved in the Indiana Cancer Pain and Depression ( INCPAD ) trial . Recruitment occurred from March 2006 through August 2008 and follow-up concluded in August 2009 . The participating patients had depression ( Patient Health Question naire-9 score > or = 10 ) , cancer-related pain ( Brief Pain Inventory [ BPI ] worst pain score > or = 6 ) , or both . INTERVENTION The 202 patients r and omly assigned to receive the intervention and 203 to receive usual care were stratified by symptom type . Patients in the intervention group received central ized telecare management by a nurse-physician specialist team coupled with automated home-based symptom monitoring by interactive voice recording or Internet . MAIN OUTCOME MEASURES Blinded assessment at baseline and at months 1 , 3 , 6 , and 12 for depression ( 20-item Hopkins Symptom Checklist [ HSCL-20 ] ) and pain ( BPI ) severity . RESULTS Of the 405 participants enrolled in the study , 131 had depression only , 96 had pain only , and 178 had both depression and pain . Of the 274 patients with pain , 137 patients in the intervention group had greater improvements in BPI pain severity over the 12 months of the trial whether measured as a continuous severity score or as a categorical pain responder ( > or = 30 % decrease in BPI ) than the 137 patients in the usual-care group ( P < .001 for both ) . Similarly , of the 309 patients with depression , the 154 patients in the intervention group had greater improvements in HSCL-20 depression severity over the 12 months of the trial whether measured as a continuous severity score or as a categorical depression responder ( > or = 50 % decrease in HSCL ) than the 155 patients in the usual care group ( P < .001 for both ) . The st and ardized effect size for between-group differences at 3 and 12 months was 0.67 ( 95 % confidence interval [ CI ] , 0.33 - 1.02 ) and 0.39 ( 95 % CI , 0.01 - 0.77 ) for pain , and 0.42 ( 95 % CI , 0.16 - 0.69 ) and 0.41 ( 95 % CI , 0.08 - 0.72 ) for depression . CONCLUSION Central ized telecare management coupled with automated symptom monitoring result ed in improved pain and depression outcomes in cancer patients receiving care in geographically dispersed urban and rural oncology practice s. TRIAL REGISTRATION clinical trials.gov Identifier : NCT00313573 BACKGROUND Medical conditions are often complicated by major depression , with consequent additional impairment of quality of life . We aim ed to compare the effectiveness of an integrated treatment programme for major depression in patients with cancer ( depression care for people with cancer ) with usual care . METHODS SMaRT Oncology-2 is a parallel-group , multicentre , r and omised controlled effectiveness trial . We enrolled out patients with major depression from three cancer centres and their associated clinics in Scotl and , UK . Participants were r and omly assigned in a 1:1 ratio to the depression care for people with cancer intervention or usual care , with stratification ( by trial centre ) and minimisation ( by age , primary cancer , and sex ) with allocation concealment . Depression care for people with cancer is a manualised , multicomponent collaborative care treatment that is delivered systematic ally by a team of cancer nurses and psychiatrists in collaboration with primary care physicians . Usual care is provided by primary care physicians . Outcome data were collected up until 48 weeks . The primary outcome was treatment response ( ≥50 % reduction in Symptom Checklist Depression Scale [ SCL-20 ] score , range 0 - 4 ) at 24 weeks . Trial statisticians and data collection staff were masked to treatment allocation , but participants could not be masked to the allocations . Analyses were by intention to treat . This trial is registered with Current Controlled Trials , number IS RCT N40568538 . FINDINGS 500 participants were enrolled between May 12 , 2008 , and May 13 , 2011 ; 253 were r and omly allocated to depression care for people with cancer and 247 to usual care . 143 ( 62 % ) of 231 participants in the depression care for people with cancer group and 40 ( 17 % ) of 231 in the usual care group responded to treatment : absolute difference 45 % ( 95 % CI 37 - 53 ) , adjusted odds ratio 8·5 ( 95 % CI 5·5 - 13·4 ) , p<0·0001 . Compared with patients in the usual care group , participants allocated to the depression care for people with cancer programme also had less depression , anxiety , pain , and fatigue ; and better functioning , health , quality of life , and perceived quality of depression care at all timepoints ( all p<0·05 ) . During the study , 34 cancer-related deaths occurred ( 19 in the depression care for people with cancer group , 15 in the usual care group ) , one patient in the depression care for people with cancer group was admitted to a psychiatric ward , and one patient in this group attempted suicide . None of these events were judged to be related to the trial treatments or procedures . INTERPRETATION Our findings suggest that depression care for people with cancer is an effective treatment for major depression in patients with cancer . It offers a model for the treatment of depression comorbid with other medical conditions . FUNDING Cancer Research UK and Chief Scientist Office of the Scottish Government Depression is a major complication of cancer . The efficacy and safety of mianserin were evaluated in a r and omized placebo‐controlled trial of 73 depressed women with cancer . According to RDC diagnosis , all patients showed situational major depression . Both groups were well matched for cancer localization , clinical stages , Karnofsky scores , duration of depression , baseline values on the Hamilton Depression Rating Scale ( HDRS ) , Zung Self‐Rating Depression Scale ( ZSRDS ) , and Clinical Global Impression of Illness Severity ( CGI‐S ) , and for type of depression , whether dominantly depressive or depressive‐anxious . Between days 7–21 , there were significantly fewer dropouts with mianserin ( 7 ) than with placebo ( 15 ) . When compared with placebo , there were significant improvements for mianserin for HDRS on days 7 , 21 and 28 , for ZSRDS on days 7 and 28 , and for CGI‐S on days 7 , 14 , 21 and 28 . According to Clinical Global Impression of Illness Improvement ( CGI‐I ) there were significantly more responders with mianserin ( 28 ) than with placebo ( 18 ) . The efficacy index for mianserin was significantly greater than for placebo on days 21 and 28 . At the end of the trial the scores for HDRS sleep disturbance factor and HDRS anxiety‐somatization factor were significantly reduced for mianserin than for placebo . There were no significant differences in side‐effects between treatment groups . It is concluded that mianserin is superior to placebo in reducing the severity and duration of depression which is present especially in patients with advanced cancer . The fact that side‐effects were not a problem with mianserin and that mianserin treatment was safe when used in association with other anticancer drugs suggests that mianserin can be prescribed routinely for alleviating depression in cancer patients In a pilot study , 55 low-income Latina patients with breast or cervical cancer and comorbid depression were r and omly assigned to receive collaborative care as part of the Multifaceted Oncology Depression Program or usual care . Relative to patients in the usual care condition , patients receiving collaborative care were more likely to show > or=50 % improvement in depressive symptoms as measured by the Personal Health Question naire ( OR=4.51 , 95 % CI=1.07 - 18.93 ) . Patients in the collaborative care program were also more likely to show improvement in emotional well-being ( increase of 2.15 ) as measured by the Functional Assessment of Cancer Therapy Scale than were those receiving usual care ( decrease of 0.50 ) ( group difference=2.65 , 95 % CI : 0.18 - 5.12 ) . Despite health system , provider , and patient barriers to care , these initial results suggest that patients in public sector oncology clinics can benefit from onsite depression treatment Abstract Background : This study aims to evaluate the effects of Group Cognitive Behavioral Therapy ( GCBT ) in treating major depression in Chinese women with breast cancer . Methods : Sixty-two breast cancer patients diagnosed with major depression were r and omly assigned to GCBT group ( N = 31 ) or a waiting list control group provided with an educational booklet ( N = 31 ) . The primary outcome measure was the 17-Item Hamilton Depression Rating Scale ( 17-HAMD ) . The second outcome measures were Self-Rating Anxiety Scale , Functional Assessment of Cancer Therapy – Breast and Self-Esteem Scale ( SES ) . Assessment s were carried out at completion of the study and six-month afterwards . Results : Patients in the GCBT group had a significant reduction in the 17-HAMD mean score by 9 points ( p < 0.001 ) , more than any reduction among patients in the control group from baseline to the end of therapy and a significant 7 points ( p < 0.001 ) more reduction from baseline to six-month follow-up . GCBT also yielded significantly greater improvement than the control group with regard to quality of life ( QoL ; p < 0.01 ) and self-esteem ( p < 0.05 ) . No significant differences were found between groups on improving anxiety ( p > 0.05 ) . Conclusion : The results of this trial suggest that GCBT is effective for treating major depression , as well as for improving QoL and self-esteem in breast cancer patients . Trial Registration : Chictr.org OBJECTIVE Major depression is the most common psychiatric disorder among breast cancer patients and is associated with substantial impairment . Although some research has explored the utility of psychotherapy with breast cancer patients , only 2 small trials have investigated the potential benefits of behavior therapy among patients with well-diagnosed depression . METHOD In a primarily Caucasian , well-educated sample of women ( age = 55.4 years , SD = 11.9 ) diagnosed with breast cancer and major depression ( n = 80 ) , this study was a r and omized clinical trial testing the efficacy of 8 sessions of behavioral activation treatment for depression ( BATD ) compared to problem-solving therapy . Primary outcome measures assessed depression , environmental reward , anxiety , quality of life , social support , and medical outcomes . RESULTS Across both treatments , results revealed strong treatment integrity , excellent patient satisfaction with treatment protocol s , and low patient attrition ( 19 % ) . Intent-to-treat analyses suggested both treatments were efficacious , with both evidencing significant pre-post treatment gains across all outcome measures . Across both treatments , gains were associated with strong effect sizes , and based on response and remission criteria , a reliable change index , and numbers-needed-to-treat analyses , approximately ¾ of patients exhibited clinical ly significant improvement . No significant group differences were found at posttreatment . Treatment gains were maintained at 12-month follow-up , with some support for stronger maintenance of gains in the BATD group . CONCLUSIONS BATD and problem-solving interventions represent practical interventions that may improve psychological outcomes and quality of life among depressed breast cancer patients . Study limitations and future research directions are discussed This is a 4 week , r and omized , double-blind , placebo-controlled study to examine the effects of methylpheni date as add-on therapy to mirtazapine compared to placebo for treatment of depression in terminally ill cancer patients . It involved 88 terminally ill cancer patients from University of Malaya Medical Centre , Kuala Lumpur , Malaysia . They were r and omized and treated with either methylpheni date or placebo as add on to mirtazapine . The change in Montgomery-Åsberg Depression Rating Scale ( MADRS ) score from baseline to day 3 was analyzed by linear regression . Changes of MADRS and Clinical Global Impression-Severity Scale ( CGI-S ) over 28 days were analyzed using mixed model repeated measures ( MMRM ) . Secondary analysis of MADRS response rates , defined as 50 % or more reduction from baseline score . A significantly larger reduction of Montgomery-Åsberg Depression Rating Scale ( MADRS ) score in the methylpheni date group was observed from day 3 ( B=4.14 ; 95 % CI=1.83 - 6.45 ) . Response rate ( defined as 50 % or more reduction from baseline MADRS score ) in the methylpheni date treated group was superior from day 14 . Improvement in Clinical Global Impression-Severity Scale ( CGI-S ) was greater in the methylpheni date treated group from day 3 until day 28 . The drop-out rates were 52.3 % in the methylpheni date group and 59.1 % in the placebo group ( relative risk=0.86 , 95%CI=0.54 - 1.37 ) due to cancer progression . Nervous system adverse events were more common in methylpheni date treated subjects ( 20.5 % vs 9.1 % , p=0.13 ) . In conclusions , methylpheni date as add on therapy to mirtazapine demonstrated an earlier antidepressant response in terminally ill cancer patients , although at an increased risk of the nervous system side effects PURPOSE This report up date s the Cancer Care Ontario Program in Evidence -Based Care guideline for the management of depression in adult patients with cancer . This guideline covers pharmacologic , psychological , and collaborative care interventions , with a focus on integrating practical management tools to assist clinicians in delivering appropriate treatments for depression in patients with cancer . METHODS Recommendations were developed by synthesizing information from extant guidelines and review s and search ing for r and omized controlled trials from the date of data base inception ( 1964 for MEDLINE and 1974 for EMBASE ) to January 2015 . Quality assessment of guidelines and systematic review s were conducted by using the Appraisal of Guidelines for Research and Evaluation II ( AGREE II ) , Assessment of Multiple Systematic Review s ( AMSTAR ) , and Cochrane Risk of Bias tools . Final recommendations were developed through a st and ardized Program in Evidence -Based Care multidisciplinary expert and knowledge user review process . RESULTS Two high- quality relevant clinical practice guidelines , eight pharmacologic trials , nine psychological trials , and eight collaborative care intervention trials composed the evidence base upon which the recommendations were developed . Eight specific recommendations were made to establish a st and ard of care for the management of depression in patients with cancer . The recommendations and practical management tools were review ed as being well organized and helpful , although systemic barriers to implementation were identified . CONCLUSION This up date d guideline supports the previous general recommendation that patients with cancer who have depression may benefit from psychological and /or pharmacologic interventions , without evidence for the superiority of any specific treatment over another . New recommendations for a collaborative care model that incorporates a stepped care approach suggest that multidisciplinary mental health care restructuring may be required for optimal management of depression BACKGROUND Major depressive disorder ( MDD ) is a common and debilitating illness in patients with cancer . However , the optimal treatment of depression in these patients remains uncertain , with limited evidence to support the use of pharmacologic therapy . We conducted a pilot study to evaluate the feasibility of an antidepressant clinical trial in the oncology population and the process of symptom-oriented selection of antidepressants ( citalopram or mirtazapine ) in patients with cancer and MDD . METHODS This was a single center , two-arm , nonr and omized , open-label , nine-week pilot study of mirtazapine or citalopram in cancer patients with MDD . The primary endpoint was the feasibility to recruit and to retain patients . Secondary outcomes included changes in Patient Health Question naire-9 ( PHQ-9 ) ( depression ) , Functional Assessment of Cancer Therapy-General ( FACT-G ) ( quality of life ) , Functional Assessment of Chronic Illness Therapy-Fatigue ( FACIT-Fatigue ) ( fatigue ) , and Pittsburgh Sleep Quality Index ( PSQI ) ( sleep ) . We conducted descriptive statistics and responder analyses . RESULTS Of 21 patients , 18 ( 86 % ) successfully completed the study . An average of 2.8 subjects were enrolled per month . Mean scores on the PHQ-9 improved overall by 6.4 points ( 95 % confidence interval [ CI ] 3.6 - 9.2 ) . Additionally , mean FACT-G , FACIT-Fatigue , and PSQI scores improved in both study arms . CONCLUSION Conducting antidepressant clinical trials is challenging in the oncology population . We approached but did not meet our feasibility goals . Depression and quality of life ( QOL ) scores improved with both mirtazapine and citalopram , but evidence -based pharmacologic treatments for depression in cancer patients are needed PURPOSE To determine the prevalence of psychiatric disorders during hospitalization for hematopoietic stem-cell transplantation ( SCT ) and to estimate their impact on hospital length of stay ( LOS ) . PATIENTS AND METHODS In a prospect i ve inpatient study conducted from July 1994 to August 1997 , 220 patients aged 16 to 65 years received SCT for hematologic cancer at a single institution . Patients received a psychiatric assessment at hospital admission and weekly during hospitalization until discharge or death , yielding a total of 1,062 psychiatric interviews performed . Psychiatric disorders were determined on the basis of the Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition . Univariate and multivariate linear regression analyses were used to identify variables associated with LOS . RESULTS Overall psychiatric disorder prevalence was 44.1 % ; an adjustment disorder was diagnosed in 22.7 % of patients , a mood disorder in 14.1 % , an anxiety disorder in 8.2 % , and delirium in 7.3 % . After adjusting for admission and in-hospital risk factors , diagnosis of any mood , anxiety , or adjustment disorder ( P = .022 ) , chronic myelogenous leukemia ( P = .003 ) , Karnofsky performance score less than 90 at hospital admission ( P = .025 ) , and higher regimen-related toxicity ( P < .001 ) were associated with a longer LOS . Acute lymphoblastic leukemia ( P = .009 ) , non-Hodgkin 's lymphoma ( P = .04 ) , use of peripheral-blood stem cells ( P < .001 ) , second year of study ( P < .001 ) , and third year of study ( P < .001 ) were associated with a shorter LOS . CONCLUSION Our data indicate high psychiatric morbidity and an association with longer LOS , underscoring the need for early recognition and effective treatment PURPOSE To determine the effectiveness of the Alleviating Depression Among Patients With Cancer ( ADAPt-C ) collaborative care management for major depression or dysthymia . PATIENTS AND METHODS Study patients included 472 low-income , predominantly female Hispanic patients with cancer age > or= 18 years with major depression ( 49 % ) , dysthymia ( 5 % ) , or both ( 46 % ) . Patients were r and omly assigned to intervention ( n = 242 ) or enhanced usual care ( EUC ; n = 230 ) . Intervention patients had access for up to 12 months to a depression clinical specialist ( supervised by a psychiatrist ) who offered education , structured psychotherapy , and maintenance/relapse prevention support . The psychiatrist prescribed antidepressant medications for patients preferring or assessed to require medication . RESULTS At 12 months , 63 % of intervention patients had a 50 % or greater reduction in depressive symptoms from baseline as assessed by the Patient Health Question naire-9 ( PHQ-9 ) depression scale compared with 50 % of EUC patients ( odds ratio [ OR ] = 1.98 ; 95 % CI , 1.16 to 3.38 ; P = .01 ) . Improvement was also found for 5-point decrease in PHQ-9 score among 72.2 % of intervention patients compared with 59.7 % of EUC patients ( OR = 1.99 ; 95 % CI , 1.14 to 3.50 ; P = .02 ) . Intervention patients also experienced greater rates of depression treatment ( 72.3 % v 10.4 % of EUC patients ; P < .0001 ) and significantly better quality -of-life outcomes , including social/family ( adjusted mean difference between groups , 2.7 ; 95 % CI , 1.22 to 4.17 ; P < .001 ) , emotional ( adjusted mean difference , 1.29 ; 95 % CI , 0.26 to 2.22 ; P = .01 ) , functional ( adjusted mean difference , 1.34 ; 95 % CI , 0.08 to 2.59 ; P = .04 ) , and physical well-being ( adjusted mean difference , 2.79 ; 95 % CI , 0.49 to 5.1 ; P = .02 ) . CONCLUSION ADAPt-C collaborative care is feasible and results in significant reduction in depressive symptoms , improvement in quality of life , and lower pain levels compared with EUC for patients with depressive disorders in a low-income , predominantly Hispanic population in public sector oncology clinics PURPOSE To determine whether fluoxetine improves overall quality of life ( QOL ) in advanced cancer patients with symptoms of depression revealed by a simple survey . PATIENTS AND METHODS One hundred sixty-three patients with an advanced solid tumor and expected survival between 3 and 24 months were r and omly assigned in a double-blinded fashion to receive either fluoxetine ( 20 mg daily ) or placebo for 12 weeks . Patients were screened for at least minimal depressive symptoms and assessed every 3 to 6 weeks for QOL and depression . Patients with recent exposure to antidepressants were excluded . RESULTS The groups were comparable at baseline in terms of age , sex , disease distribution , performance status , and level of depressive symptoms . One hundred twenty-nine patients ( 79 % ) completed at least one follow-up assessment . Analysis using generalized estimating equation modeling revealed that patients treated with fluoxetine exhibited a significant improvement in QOL as shown by the Functional Assessment of Cancer Therapy-General , compared with patients given placebo ( P = .01 ) . Specifically , the level of depressive symptoms expressed was lower in patients treated with fluoxetine ( P = .0005 ) , and the subgroup of patients showing higher levels of depressive symptoms on the two- question screening survey were the most likely to benefit from treatment . CONCLUSION In this mix of patients with advanced cancer who had symptoms of depression as determined by a two- question bedside survey , use of fluoxetine was well tolerated , overall QOL was improved , and depressive symptoms were reduced OBJECTIVE To compare narrative therapy ( NT ) plus escitalopram versus escitalopram plus usual care on quality of life and depressive symptomatology of depressed patients with oncologic disease . METHODS A total of 72 subjects ( mean age 54.6 years ) , predominantly female with non-metastatic breast , lung and colon cancer and depressive disorder ( DSM-IV-TR ) were r and omized to receive treatment with NT plus escitalopram ( n=39 ) or escitalopram ( 10 - 20 mg QD ) plus usual care ( n=33 ) . Main endpoints were improvement in dimensions of quality of life measured by the European Organization for Research and Treatment of Cancer Quality of Life Question naire C-30 and reduction of depressive symptoms using the Hospital Anxiety and Depression Scale at weeks 12 and 24 . RESULTS The combined therapy group showed significantly greater improvement in all the functioning dimensions ( p<0.01 ) , pain scale ( p=0.02 ) , global health ( p=0.02 ) , and global quality of life ( p=0.007 ) at weeks 12 and 24 . There were no statistically significant differences in depressive symptomatology between the groups . From week 12 to week 24 study retention was higher in the combined treatment group ( p=0.01 ) . CONCLUSIONS Brief NT in combination with escitalopram was superior to usual care and escitalopram in improving functioning dimensions of quality life To examine the prevalence of depressive symptoms and its relationship with quality -of-life domains in home-care cancer patients at an advanced stage of illness , 86 patients were given psychological tests for depression ( Hospital Anxiety Depression Scale ) ( HAD ) and quality of life ( EORTC-QLQ-C30 ) 1 week after admission to the home-care program . Using a proper cut-off score on the HAD-Depression subscale , depressive symptoms were reported by 45 % of the patients . The quality of life of depressed patients was more affected than non-depressed patients in the social , emotional , cognitive , and physical domains . Significant correlations were found between depression scores and impairment in most quality -of-life areas . These findings support the importance of depression and quality -of-life evaluation in patients with advanced cancer who are followed in a home-care setting . This evaluation is needed to provide patients , their families , and caregivers with appropriate psychosocial interventions The efficacy of problem-solving therapy ( PST ) to reduce psychological distress was assessed among a sample of 132 adult cancer patients . A second condition provided PST for both the patient and a significant other . At posttreatment , all participants receiving PST fared significantly better than waiting list control patients . Further , improvements in problem solving were found to correlate significantly with improvements in psychological distress and overall quality of life . No differences in symptom reduction were identified between the 2 treatment protocol s. At a 6-month follow-up , however , patients who received PST along with their significant other reported lower levels of psychological distress as compared with members of the PST-alone condition on approximately half of the outcome measures . These effects were further maintained 1-year posttreatment OBJECTIVE This study assessed longer-term outcomes of low-income patients with cancer ( predominantly female and Hispanic ) after treatment in a collaborative model of depression care or in enhanced usual care . METHODS The r and omized controlled trial , conducted in safety-net oncology clinics , recruited 472 patients with major depression symptoms . Patients r and omly assigned to a 12-month intervention ( a depression care manager and psychiatrist provided problem-solving therapy , antidepressants , and symptom monitoring and relapse prevention ) or enhanced usual care ( control group ) were interviewed at 18 and 24 months after enrollment . RESULTS At 24 months , 46 % of patients in the intervention group and 32 % in the control group had a ≥50 % decrease in depression score over baseline ( odds ratio=2.09 , 95 % confidence interval=1.13 - 3.86 ; p=.02 ) ; intervention patients had significantly better social ( p=.03 ) and functional ( p=.01 ) well-being . Treatment receipt among intervention patients declined ( 72 % , 21 % , and 18 % at 12 , 18 , and 24 months , respectively ) ; few control group patients reported treatment receipt ( 10 % , 6 % , and 13 % , respectively ) . Significant differences in receipt of counseling or antidepressants disappeared at 24 months . Depression recurrence was similar between groups ( intervention , 36 % ; control , 39 % ) . Among patients with depression recurrence , intervention patients were more likely to receive treatment after 12 months ( 34 % versus 10 % ; p=.03 ) . At 24 months , attrition ( 262 patients , 56 % ) did not vary by group ; 22 % were deceased , 20 % declined further participation , and 14 % could not be located . CONCLUSIONS Collaborative care reduced depression symptoms and enhanced quality of life ; however , results call for ongoing depression symptom monitoring and treatment for low-income cancer survivors BACKGROUND This study was conducted to determine the efficacy and tolerability of fluoxetine and desipramine in treating depressive symptoms in women with cancer . METHOD In this prospect i ve , 6-week , double-blind , placebo-controlled trial , we compared fluoxetine with desipramine in treating depressive symptoms in 40 women diagnosed with cancer . Scales used to measure efficacy and tolerability were the Hamilton Depression Rating Scale ( HAM-D ) , the Hamilton Anxiety Rating Scale ( HAM-A ) , the Clinical and Patient 's Global Impression ( CGI and PGI ) scales , the Functional Living Index for Cancer ( FLIC ) , the Memorial Pain Assessment Card ( MPAC ) , and the SF-36 Health Survey . RESULTS Fluoxetine and desipramine treatments improved depression and anxiety symptoms . There was a trend towards significance in improvement of FLIC scores ( as evidence d by greater numerical improvements with fluoxetine treatment ) . Fluoxetine treatment alone was associated with statistically significant improvements in MPAC Mood scale scores . Both treatments showed statistically significant improvements in the quality of life SF-36 scores in Role Emotional , Social Functioning , Mental Health , and Vitality . CONCLUSIONS Both fluoxetine and desipramine were effective and well-tolerated in improving depressive symptoms and quality of life in women with advanced cancer . Fluoxetine may offer greater benefit to these patients , as evidence d by greater improvements in fluoxetine-treated patients on several quality of life measures . Our results , while meaningful , should be confirmed in a larger patients sample . However , experience from studies of antidepressant use in patients with advanced cancer has shown that intercurrent disease and treatment variables make it difficult to conduct large studies Although many studies have documented patterns of emotional distress in persons undergoing radiation treatment for cancer , there have been few controlled evaluations of counseling or psychotherapy outcomes with these persons . In this research , the effects of cognitive-behavioral and socially supportive group therapy were evaluated . A total of 72 depressed cancer patients were r and omly assigned to one of three conditions -- cognitive-behavioral treatment , social support , or a no-treatment control condition . Before and after intervention and at 6-month followup , study participants were individually assessed by using measures of symptom distress . Relative to the comparison group , both the cognitive-behavioral and social support therapies result ed in less depression , hostility , and somatization . The social support intervention also result ed in fewer psychiatric symptoms and reduced maladaptive interpersonal sensitivity and anxiety . It was concluded that both group therapies can reduce symptoms of distress for depressed persons undergoing radiation treatment for cancer . Both forms of therapy result ed in improvements in psychosocial function ( compared with no treatment at all ) , but social support groups demonstrated more changes that were evident at 6-month followup . Further research is needed to evaluate the differential effectiveness of mental health services provided to cancer patients undergoing radiation OBJECTIVE This study compared the efficacy and safety of paroxetine and desipramine with those of placebo in the treatment of depressive disorders in adult women with breast cancer , stages I-IV . METHOD In a double-blind , placebo-controlled study , 35 female out patients with breast cancer and DSM-III-R major depression or adjustment disorder with depressed mood were r and omly assigned to treatment with paroxetine ( N=13 ) , desipramine ( N=11 ) , or placebo ( N=11 ) for 6 weeks . Primary efficacy was assessed by change from baseline in score on the 21-item Hamilton Rating Scale for Depression ( HAM-D ) , and the secondary outcome measure was change from baseline in the Clinical Global Impressions-Severity of Illness scale ( CGI-S ) score . RESULTS Mean changes in the total HAM-D and CGI-S scores from baseline to 6-week endpoint for the paroxetine and desipramine groups were not significantly different than those for the placebo-treated group . An unusually high rate of response ( defined as > or=50 % improvement in the HAM-D score ) in the placebo group was observed ( 55 % [ N=6 ] ) ; adverse events precipitated patient discontinuation in the active treatment groups ( 9 % [ N=1 ] for desipramine , 15 % [ N=2 ] for paroxetine ) similar to that in the placebo-treated patients ( 18 % [ N=2 ] ) . Improvement on symptom dimensions within the HAM-D and Hamilton Rating Scale for Anxiety ( depressive , anxiety , cognitive , neurovegetative , or somatic ) was also similar between groups . CONCLUSION The small number of women in this study most likely contributed to the lack of observed differences in efficacy observed during the 6 weeks of treatment . R and omized , placebo-controlled trials of adequate power seeking to determine efficacy of antidepressants in the United States for the treatment of women with breast cancer and comorbid depression remain of paramount importance BACKGROUND Anxiety and depression are the two most frequent comorbidities of tumour patients . At present , it is unclear to which degree a patient 's psychological condition can be altered during the treatment period and if psycho-oncological support positively affects a patient 's psychological condition . METHODS In a r and om sample analyses , 131 patients beginning inpatient treatment at a hospital specialising in surgical oncology were either classified as ' low-risk ' or ' high-risk ' , according to the HADS . Patients from both categories were then r and omly placed in either a low-threshold ' intervention ' group or an ' observation ' group . Anxiety and depression levels were measured again with the HADS scale prior to the patients discharge from the department of surgical oncology , and at a follow up 12 months after . RESULTS Our findings showed a significant reduction of anxiety and depression in the high-risk patients who had undergone psycho-oncological intervention at the end of inpatient care and even a year after discharge from the hospital . The effects of psychological intervention could be observed in terms of anxiety and depression in the group of high-risk patients during the hospital stay . In the other three groups , no statistically significant changes could be measured . CONCLUSION Cancer patients on a surgical ward benefit from psycho-oncological support especially at an early stage of therapy but also over a long time after discharge from the hospital . The aim of all interventions should be to decrease psychological distress and disorders and thereby improve the quality of life for cancer patients |
13,647 | 24,825,644 | AND RELEVANCE Both acamprosate and oral naltrexone were associated with reduction in return to drinking .
When directly compared with one another , no significant differences were found between acamprosate and naltrexone for controlling alcohol consumption . | IMPORTANCE Alcohol use disorders cause substantial morbidity and early mortality yet remain greatly undertreated .
Medications are considerably underused .
OBJECTIVE To conduct a systematic review and meta- analysis of the benefits and harms of medications ( US FDA -approved and others ) for adults with alcohol use disorders . | CONTEXT Hypothetically , topiramate can improve drinking outcomes among alcohol-dependent individuals by reducing alcohol 's reinforcing effects through facilitation of gamma-aminobutyric acid function and inhibition of glutaminergic pathways in the corticomesolimbic system . OBJECTIVE To determine if topiramate is a safe and efficacious treatment for alcohol dependence . DESIGN , SETTING , AND PARTICIPANTS Double-blind , r and omized , placebo-controlled , 14-week trial of 371 men and women aged 18 to 65 years diagnosed with alcohol dependence , conducted between January 27 , 2004 , and August 4 , 2006 , at 17 US sites . INTERVENTIONS Up to 300 mg/d of topiramate ( n = 183 ) or placebo ( n = 188 ) , along with a weekly compliance enhancement intervention . MAIN OUTCOME MEASURES Primary efficacy variable was self-reported percentage of heavy drinking days . Secondary outcomes included other self-reported drinking measures ( percentage of days abstinent and drinks per drinking day ) along with the laboratory measure of alcohol consumption ( plasma gamma-glutamyltransferase ) . RESULTS Treating all dropouts as relapse to baseline , topiramate was more efficacious than placebo at reducing the percentage of heavy drinking days from baseline to week 14 ( mean difference , 8.44 % ; 95 % confidence interval , 3.07%-13.80 % ; P = .002 ) . Prespecified mixed-model analysis also showed that topiramate compared with placebo decreased the percentage of heavy drinking days ( mean difference , 16.19 % ; 95 % confidence interval , 10.79%-21.60 % ; P < .001 ) and all other drinking outcomes ( P < .001 for all comparisons ) . Adverse events that were more common with topiramate vs placebo , respectively , included paresthesia ( 50.8 % vs 10.6 % ) , taste perversion ( 23.0 % vs 4.8 % ) , anorexia ( 19.7 % vs 6.9 % ) , and difficulty with concentration ( 14.8 % vs 3.2 % ) . CONCLUSION Topiramate is a promising treatment for alcohol dependence . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00210925 AIMS To assess the effectiveness of pharmacotherapy with acamprosate in alcohol-dependent patients treated in a naturalistic setting in primary care in France . METHODS The ARES ( Acamprosate et Repercussions Economiques et Sociales ; Acamprosate and Economic and Social Repercussions ) study was performed by 149 general practitioners interested in treating alcohol use disorders in France who included patients fulfilling DSM-IV criteria for alcohol dependence . The only exclusion criteria concerned contra-indications to acamprosate , co-medication with naltrexone and multiple substance abuse . Eligible patients were r and omized to one of two treatment arms , either st and ard care alone or st and ard care with acamprosate , using an open-label design and followed up quarterly for a period of 1 year . The primary outcome variable was the change from baseline on the Alcohol-Related Problems Question naire . Secondary efficacy variables were abstinence , Clinical Global Impression , quality of life measured with the SF-36 and incidence of adverse events . An intent-to-treat population was used for outcome analysis . RESULTS 422 patients were included , of whom 348 ( 82 % ) completed the protocol as planned . At the end of the study , patients r and omized to the acamprosate group had significantly better outcomes in terms of total ARPQ score , change from baseline ( -2.61 vs -3.44 ) and number of subjects with no alcohol-related problem . On average , patients treated with acamprosate had one less alcohol-related problem than did the controls . The number needed to treat in order to save one additional patient from alcohol-related problems compared to st and ard care was 7.14 . Statistically significant differences in favour of the acamprosate group were observed for all secondary efficacy outcome measures including quality of life . CONCLUSIONS Adjunctive therapy with acamprosate in primary care is associated with significantly better functional outcome . Pragmatic trials in alcohol dependence are both feasible and informative BACKGROUND Promising treatments for alcoholics include naltrexone ( NTX ) , cue exposure combined with urge-specific coping skills training ( CET ) , and communication skills training ( CST ) . This study investigated the effects of combining these elements as treatment adjuncts . METHODS A 2 x 2 design investigated the effects of CET combined with CST , as compared with an education and relaxation control treatment , during a 2-week partial hospital program ( n = 165 ) followed by 12 weeks of NTX ( 50 mg/day ) or placebo during aftercare ( n = 128 ) . Drinking outcomes were assessed at 3 , 6 , and 12 months after discharge from the partial hospital . Process measures included urge , self-efficacy ( confidence about staying abstinent in risky situations ) , and self-reported coping skills . Medically eligible alcohol-dependent patients were recruited . RESULTS Among those compliant with medication on at least 70 % of days , those who received NTX had significantly fewer heavy drinking days and fewer drinks on days that they drank than those receiving placebo during the medication phase but not during the subsequent 9 months . CET/CST-condition patients were significantly less likely to report a relapse day and reported fewer heavy drinking days at the 6- and 12-month follow-ups than patients in the control treatment . Interactions of medication with behavioral treatments were not significant . Process measures showed that NTX result ed in lower weekly urge ratings , and those in CET/CST used more of the prescribed coping skills after treatment , reported fewer cue-elicited urges , and reported more self-efficacy in a posttest role-play test . Drinking reductions at 3 , 6 , and 12 months correlated with more use of coping skills , lower urge , and higher self-efficacy . CONCLUSIONS The results suggest the probable value of keeping alcoholics on NTX for longer periods of time and the importance of increasing compliance with NTX . They also support the earlier promising effects of CET and CST as adjuncts to treatment programs for alcoholics by maintaining treatment gains over at least a year . The value of the urge-specific and general coping skills and of self-efficacy and urge constructs was demonstrated in their association with drinking outcomes OBJECTIVE This study tested the comparative effectiveness of modified behavioral self-control therapy ( MBSCT ) and naltrexone ( NTX ) , as well as the added benefit of combining the 2 , in problem drinking men who have sex with men ( MSM ) seeking to reduce but not quit drinking . METHOD Participants ( N = 200 ) were recruited and urn r and omized to 1 of 2 medication conditions , NTX or placebo ( PBO ) , and either MSBCT or no behavioral intervention , yielding 4 conditions : PBO , NTX , MSBCT , and NTX + MSBCT . In addition , all participants received a brief medication compliance intervention . Participants were treated for 12 weeks and assessed 1 week after treatment completion . Two primary outcomes -sum of st and ard drinks and number of heavy drinking days- and 1 secondary outcome -percentage of those drinking in a nonhazardous manner (NoH)-were selected a priori . RESULTS There was a significant main effect for MBSCT ( all ps < .01 ) but not NTX on all 3 outcomes . In addition , the combination of NTX and MBSCT was not more effective than either MSCBT or PBO . There was a significant interaction effect on NoH , such that NTX significantly increased the likelihood ( odds ratio = 3.3 ) of achieving a nonhazardous drinking outcome relative to PBO . In addition , NTX was significantly more effective than PBO on a descriptive outcome : negative consequences of drinking . CONCLUSIONS There was no advantage to adding NTX to MBSCT . In addition , MBSCT showed stronger evidence of efficacy than NTX . At the same time , NTX delivered in the context of a minimal medication compliance intervention was significantly more effective than PBO on an important clinical indicator . Results provide new information to guide the treatment of problem drinking , including in primary care setting BACKGROUND Topiramate , a sulphamate fructopyranose derivative , might antagonise alcohol 's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of gamma-amino-butyric acid activity and inhibition of glutamate function . We aim ed to see whether topiramate was more effective than placebo as a treatment for alcohol dependence . METHODS We did a double-blind r and omised controlled 12-week clinical trial comparing oral topiramate and placebo for treatment of 150 individuals with alcohol dependence . Of these 150 individuals , 75 were assigned to receive topiramate ( escalating dose of 25 - 300 mg per day ) and 75 had placebo as an adjunct to weekly st and ardised medication compliance management . Primary efficacy variables were : self-reported drinking ( drinks per day , drinks per drinking day , percentage of heavy drinking days , percentage of days abstinent ) and plasma gamma-glutamyl transferase , an objective index of alcohol consumption . The secondary efficacy variable was self-reported craving . FINDINGS At study end , participants on topiramate , compared with those on placebo , had 2.88 ( 95 % CI -4.50 to -1.27 ) fewer drinks per day ( p=0.0006 ) , 3.10 ( -4.88 to -1.31 ) fewer drinks per drinking day ( p=0.0009 ) , 27.6 % fewer heavy drinking days ( p=0.0003 ) , 26.2 % more days abstinent ( p=0.0003 ) , and a log plasma gamma-glutamyl transferase ratio of 0.07 ( -0.11 to -0.02 ) less ( p=0.0046 ) . Topiramate-induced differences in craving were also significantly greater than those of placebo , of similar magnitude to the self-reported drinking changes , and highly correlated with them . INTERPRETATION Topiramate ( up to 300 mg per day ) is more efficacious than placebo as an adjunct to st and ardised medication compliance management in treatment of alcohol dependence BACKGROUND Naltrexone and acamprosate have been shown to be effective in relapse prevention of alcoholism via different pharmacologic mechanisms . Since it remains uncertain whether both substances are equally efficient and whether a combination of both drugs potentiates the efficacy , we conducted the first published controlled study comparing and combining both compounds . METHODS After detoxification , 160 patients with alcoholism participated in a r and omized , double-blind , placebo-controlled protocol . Patients received naltrexone , acamprosate , naltrexone plus acamprosate , or placebo for 12 weeks . Patients were assessed weekly by interview , self-report , question naires , and laboratory screening . Time to first drink , time to relapse , and the cumulative abstinence time were the primary outcome measures . RESULTS Naltrexone , acamprosate , and the combined medication were significantly more effective than placebo . Comparing the course of nonrelapse rates between naltrexone and acamprosate , the naltrexone group showed a tendency for a better outcome regarding time to first drink and time to relapse . The combined medication was most effective with significantly lower relapse rates than placebo and acamprosate but not naltrexone . CONCLUSIONS The results of this study support the efficacy of pharmacotherapeutic strategies in the relapse prevention of alcoholism . Naltrexone and acamprosate , especially in combination , considerably enhance the potential of relapse prevention The objective of this study was to compare acamprosate with placebo in the treatment of alcohol-dependent patients during a 6-month post-detoxification treatment and a 3-month medication-free follow-up . Patients ( n = 330 ) were detoxified and r and omized to treatment with acamprosate ( 1998 mg/day ) or placebo within an out-patient programme including medical counselling , psychotherapy and self-help groups . The main outcome criterion was drinking behaviour as assessed by : abstinence/relapse ratio , cumulative abstinence duration ( CAD ) and the period of continued abstinence . Anxiety , depression and craving were also monitored . Intention to treat ( ITT ) statistical principles were followed . Twenty-five per cent of patients dropped out over the first 6 months . At the end of the treatment period , the abstinence rate was 57.9 % for acamprosate and 45.2 % for placebo ( P = 0.03 ) . The CAD was 110+/-77 days for acamprosate and 89+/-77 days for placebo ( P = 0.016 ) . Patients on acamprosate had a higher continuous abstinence rate and experienced less severe relapses . No differential effect was noted for anxiety , depression or craving . Treatment remained positive , but not significant , 3 months after termination of study medication . No significant difference in adverse events was noted between treatment groups . Acamprosate treatment over 180 days was consistently more effective than placebo to maintain abstinence and to diminish relapse severity The results of placebo‐controlled trials ( RCTs ) with acamprosate or naltrexone vary substantially . Those differences have been attributed to differing patient characteristics , recruitment strategies , treatment setting s and remuneration systems . We tested these assumptions by comparing a new double – blind , placebo‐controlled r and omized trial conducted in Germany ( called PREDICT Study ) with data from the US COMBINE Study . PREDICT was design ed according to the protocol of the COMBINE Study . A total of 426 alcohol‐dependent patients were compared to 459 COMBINE Study patients corresponding to the treatment cells in PREDICT . All patients received acamprosate , naltrexone or placebo for 3 months ( PREDICT ) or 4 months ( COMBINE ) . Biweekly manualized ‘ medical management ’ to enhance compliance was delivered in both studies . Time until the first occurrence of heavy drinking was the main outcome measure . PREDICT found neither acamprosate nor naltrexone to supply any additional benefit compared with placebo , which is at variance with a positive naltrexone effect being reported in the COMBINE Study . A secondary comparison between both studies showed better overall treatment outcomes in PREDICT , although these patients had been more severely affected than their COMBINE counterparts . The divergence in results may be attributable to basic differences in the treatment environments ( such as in‐patient pre‐treatment versus primary outpatient care ) . We suggest that identically design ed RCTs conducted in different parts of the world may help improve the external validity of RCTs . This approach could be called ‘ comparative efficacy research ’ BACKGROUND More than half of all individuals with bipolar disorder have a substance abuse problem at some point in their lifetime . Patients with comorbid substance abuse disorders often are excluded from clinical trials . Thus , treatments targeting this high-risk clinical population are lacking . OBJECTIVE To evaluate the efficacy of divalproex sodium ( hereafter referred to as valproate ) in decreasing alcohol use and stabilizing mood symptoms in acutely ill patients with bipolar disorder and alcoholism . DESIGN A 24-week , double-blind , placebo-controlled , r and omized parallel-group trial . SETTING A university hospital serving as a primary catchment-area hospital and tertiary-care facility . PARTICIPANTS Fifty-nine subjects with diagnoses of bipolar I disorder and alcohol dependence . Intervention All study subjects received treatment as usual , including lithium carbonate and psychosocial interventions , and were r and omized to receive valproate or placebo . MAIN OUTCOME MEASURES Primary alcohol use outcomes included changes in alcohol use as indicated by changes in proportion of heavy drinking days and number of drinks per heavy drinking day . Other alcohol use outcomes included proportion of any drinking days , number of drinks per drinking day , and relapse to sustained heavy drinking . Mood outcomes included changes in depressive and manic symptoms . We used the mixed model to analyze longitudinal data . The first model used time of assessment , bipolar subtype ( mixed , manic , or depressed ) , and treatment group ( placebo or valproate ) as covariates . The second nested model included the additional covariate of medication adherence . RESULTS The valproate group had a significantly lower proportion of heavy drinking days ( P = .02 ) and a trend toward fewer drinks per heavy drinking day ( P = .055 ) than the placebo group . When medication adherence was added as covariate , the valproate group had significantly fewer drinks per heavy drinking day ( P = .02 ) and fewer drinks per drinking day ( P = .02 ) . Higher valproate serum concentration significantly correlated with improved alcohol use outcomes . Manic and depressive symptoms improved equally in both groups . Level of gamma-glutamyl transpeptidase was significantly higher in the placebo group compared with the valproate group . CONCLUSIONS Valproate therapy decreases heavy drinking in patients with comorbid bipolar disorder and alcohol dependence . The results of this study indicate the potential clinical utility of the anticonvulsant mood stabilizer , valproate , in bipolar disorder with co-occurring alcohol dependence AIMS To evaluate the efficacy of acamprosate in maintaining abstinence in weaned alcohol-dependent patients . DESIGN A multicentre , double-blind , r and omized control trial . Patients were individually r and omly allocated to active or placebo conditions . Abstinence was assessed during a 6-month treatment period and after a 6-month follow-up period . SETTING A community-based , outpatient alcohol rehabilitation programme . PARTICIPANTS Two hundred and forty-six alcohol-dependent patients between the ages of 18 and 65 years were recruited immediately following acute , inpatient withdrawal treatment . MEASUREMENTS The primary outcome measure was self-reported abstinence from alcohol since the previous sessions at 3 , 6 , 9 and 12 months following the start of treatment , with treatment taking place for a period of 6 months . FINDINGS A significantly higher proportion of patients in the acamprosate group were abstinent after 3 months and 6 months of treatment . The percentage of patients with continuous abstinence at the end of the treatment period was almost double for the acamprosate group than for the placebo group ( 40.7 % vs. 20.8 % , respectively ) . Acamprosate significantly increased the retention of patients in the treatment programme . Six months after drug treatment ceased , the criterion of abstinence since the previous visit was reached by significantly more patients from the acamprosate group ( 43.4 % ) than from the placebo group ( 29.8 % ) , but this difference was not statistically significant at the 3-month point after cessation of study medication . CONCLUSIONS Acamprosate may be a useful pharmacological compound for the long-term treatment of alcohol-dependence when applied in a community-based rehabilitation programme CONTEXT Alcohol dependence treatment may include medications , behavioral therapies , or both . It is unknown how combining these treatments may impact their effectiveness , especially in the context of primary care and other nonspecialty setting s. OBJECTIVES To evaluate the efficacy of medication , behavioral therapies , and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome . DESIGN , SETTING , AND PARTICIPANTS R and omized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers ( median age , 44 years ) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders , Fourth Edition , diagnoses of primary alcohol dependence . INTERVENTIONS Eight groups of patients received medical management with 16 weeks of naltrexone ( 100 mg/d ) or acamprosate ( 3 g/d ) , both , and /or both placebos , with or without a combined behavioral intervention ( CBI ) . A ninth group received CBI only ( no pills ) . Patients were also evaluated for up to 1 year after treatment . MAIN OUTCOME MEASURES Percent days abstinent from alcohol and time to first heavy drinking day . RESULTS All groups showed substantial reduction in drinking . During treatment , patients receiving naltrexone plus medical management ( n = 302 ) , CBI plus medical management and placebos ( n = 305 ) , or both naltrexone and CBI plus medical management ( n = 309 ) had higher percent days abstinent ( 80.6 , 79.2 , and 77.1 , respectively ) than the 75.1 in those receiving placebos and medical management only ( n = 305 ) , a significant naltrexone x behavioral intervention interaction ( P = .009 ) . Naltrexone also reduced risk of a heavy drinking day ( hazard ratio , 0.72 ; 97.5 % CI , 0.53 - 0.98 ; P = .02 ) over time , most evident in those receiving medical management but not CBI . Acamprosate showed no significant effect on drinking vs placebo , either by itself or with any combination of naltrexone , CBI , or both . During treatment , those receiving CBI without pills or medical management ( n = 157 ) had lower percent days abstinent ( 66.6 ) than those receiving placebo plus medical management alone ( n = 153 ) or placebo plus medical management and CBI ( n = 156 ) ( 73.8 and 79.8 , respectively ; P<.001 ) . One year after treatment , these between-group effects were similar but no longer significant . CONCLUSIONS Patients receiving medical management with naltrexone , CBI , or both fared better on drinking outcomes , whereas acamprosate showed no evidence of efficacy , with or without CBI . No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management . Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment . Naltrexone with medical management could be delivered in health care setting s , thus serving alcohol-dependent patients who might otherwise not receive treatment . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00006206 BACKGROUND Studies of the efficacy of naltrexone for alcohol dependence have yielded variable findings , which may be due , in part , to variation in compliance with oral naltrexone . Efforts to improve naltrexone compliance have included the development of injectable , long-acting depot formulations . METHODS We conducted a multicenter trial in 315 subjects who were r and omly assigned to receive an intramuscular injection of a depot formulation containing naltrexone ( n = 158 ) or a placebo formulation ( n = 157 ) monthly for 3 months . All patients received five sessions of manual-guided motivational enhancement therapy during the 12 weeks of the study . The outcomes of interest were based on self-reported alcohol use and gamma-glutamyl transpeptidase level . Missing data or data from subjects who discontinued the study were conservatively treated as heavy-drinking days . RESULTS Groups were comparable on pretreatment demographic and clinical measures . The medication was well tolerated ; 73.7 % of subjects received all injections . The time to the first heavy-drinking day , the percentage of subjects with no heavy drinking throughout the study , and gamma-glutamyl transpeptidase levels favored the naltrexone depot , although the effects did not reach statistical significance . There was a significant advantage for naltrexone depot treatment on the time to the first drinking day . Naltrexone depot subjects also had significantly fewer drinking days during treatment and a significantly greater abstinence rate than the placebo group ( 18 % vs. 10 % ) . CONCLUSIONS This is the first multicenter study of a depot formulation of naltrexone for the treatment of alcohol dependence . Using a conservative intent-to-treat analysis , the study showed an advantage for the active medication . Further research with this formulation is warranted OBJECTIVE To evaluate the full range of alcohol treatment effectiveness , it is important to assess secondary nondrinking outcome dimensions in addition to primary alcohol consumption outcomes . METHOD We used a large sample ( n=1,226 ) of alcohol-dependent participants entering the National Institute on Alcohol Abuse and Alcoholism-sponsored COMBINE ( Combining Medications and Behavioral Interventions ) Study , a multisite clinical trial of pharmacological ( naltrexone [ ReVia ] and acamprosate [ Campral ] ) and behavioral interventions , to examine the effects of specific treatment combinations on nondrinking functional outcomes . We assessed the outcomes at baseline and at the end of 16 weeks of alcohol treatment and again at the 26-week and /or 52-week postr and omization follow-ups . RESULTS ( 1 ) Drinking and secondary outcomes were significantly related , especially at the follow-up periods . A higher percentage of heavy drinking days , more drinks per drinking day , and lower percentage of days abstinent were associated with lower quality -of-life measures . ( 2 ) All nondrinking outcomes showed improvement at the end of 16 weeks of treatment and most maintained improvement over the 26-week and 52-week follow-ups . Only two measures returned to pretreatment levels at 52 weeks : percentage of days paid for work and physical health . Improvements of nondrinking outcomes remained even after adjusting for posttreatment heavy drinking status . ( 3 ) Although nondrinking outcomes showed overall improvement , specific pharmacological and behavioral treatment combinations were not differentially effective on specific secondary outcomes . CONCLUSIONS In the current study , changes that result ed from treatment were multidimensional , and improvements in nondrinking outcomes reflected the overall significant improvement in drinking but they were not differentiated between treatment combination groups . Findings from this study support the importance of including secondary nondrinking outcomes in clinical alcohol-treatment trials IMPORTANCE People with substance dependence have health consequences , high health care utilization , and frequent comorbidity but often receive poor- quality care . Chronic care management ( CCM ) has been proposed as an approach to improve care and outcomes . OBJECTIVE To determine whether CCM for alcohol and other drug dependence improves substance use outcomes compared with usual primary care . DESIGN , SETTING , AND PARTICIPANTS The AHEAD study , a r and omized trial conducted among 563 people with alcohol and other drug dependence at a Boston , Massachusetts , hospital-based primary care practice . Participants were recruited from September 2006 to September 2008 from a freest and ing residential detoxification unit and referrals from an urban teaching hospital and advertisements ; 95 % completed 12-month follow-up . INTERVENTIONS Participants were r and omized to receive CCM ( n=282 ) or no CCM ( n=281 ) . Chronic care management included longitudinal care coordinated with a primary care clinician ; motivational enhancement therapy ; relapse prevention counseling ; and on-site medical , addiction , and psychiatric treatment , social work assistance , and referrals ( including mutual help ) . The no CCM ( control ) group received a primary care appointment and a list of treatment re sources including a telephone number to arrange counseling . MAIN OUTCOMES AND MEASURES The primary outcome was self-reported abstinence from opioids , stimulants , or heavy drinking . Biomarkers were secondary outcomes . RESULTS There was no significant difference in abstinence from opioids , stimulants , or heavy drinking between the CCM ( 44 % ) and control ( 42 % ) groups ( adjusted odds ratio , 0.84 ; 95 % CI , 0.65 - 1.10 ; P=.21 ) . No significant differences were found for secondary outcomes of addiction severity , health-related quality of life , or drug problems . No subgroup effects were found except among those with alcohol dependence , in whom CCM was associated with fewer alcohol problems ( mean score , 10 vs 13 ; incidence rate ratio , 0.85 ; 95 % CI , 0.72 - 1.00 ; P=.048 ) . CONCLUSIONS AND RELEVANCE Among persons with alcohol and other drug dependence , CCM compared with a primary care appointment but no CCM did not increase self-reported abstinence over 12 months . Whether more intensive or longer- duration CCM is effective requires further investigation . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00278447 BACKGROUND Access to specialty alcoholism treatment in rural environments is limited and new treatment approaches are needed . The objective was to evaluate the efficacy of naltrexone alone and in combination with sertraline among Alaska Natives and other Alaskans living in rural setting s. An exploratory aim examined whether the Asn40Asp polymorphism of the mu-opioid receptor gene ( OPRM1 ) predicted response to naltrexone , as had been reported in Caucasians . METHODS R and omized , controlled trial enrolling 101 Alaskans with alcohol dependence , including 68 American Indians/Alaska Natives . Participants received 16 weeks of either ( 1 ) placebo ( placebo naltrexone + placebo sertraline ) , ( 2 ) naltrexone monotherapy ( 50 mg naltrexone + sertraline placebo ) and ( 3 ) naltrexone + sertraline ( 100 mg ) plus nine sessions of medical management and supportive advice . Primary outcomes included Time to First Heavy Drinking Day and Total Abstinence . RESULTS Naltrexone monotherapy demonstrated significantly higher total abstinence ( 35 % ) compared with placebo ( 12 % , p = 0027 ) and longer , but not statistically different , Time to First Heavy Drinking Day ( p = 0.093 ) . On secondary measures , naltrexone compared with placebo demonstrated significant improvements in percent days abstinent ( p = 0.024 ) and drinking-related consequences ( p = 0.02 ) . Combined sertraline and naltrexone did not differ from naltrexone alone . The pattern of findings was generally similar for the American Indian/Alaska Native sub sample . Naltrexone treatment response was significant within the group of 75 individuals who were homozygous for OPRM1 Asn40 allele . There was a small number of Asp40 carriers , precluding statistical testing of the effect of this allele on response . CONCLUSIONS Naltrexone can be used effectively to treat alcoholism in remote and rural communities , with evidence of benefit for American Indians and Alaska Natives . New models of care incorporating pharmacotherapy could reduce important health disparities related to alcoholism ABSTRACT BACKGROUND Alcohol use disorder is one of the leading causes of disability worldwide . Despite the availability of efficacious treatments , few individuals with an alcohol use disorder are actively engaged in treatment . Available evidence suggests that primary care may play a crucial role in the identification of patients with an alcohol use disorder , delivery of interventions , and the success of treatment . OBJECTIVE The principal aims of this study were to test the effectiveness of a primary care-based Alcohol Care Management ( ACM ) program for alcohol use disorder and treatment engagement in veterans . DESIGN The design of the study was a 26-week single-blind r and omized clinical trial . The study was conducted in the primary care practice s at three VA medical centers . Participants were r and omly assigned to treatment in ACM or st and ard treatment in a specialty outpatient addiction treatment program . PARTICIPANTS One hundred and sixty-three alcohol-dependent veterans were r and omized . INTERVENTIONACM focused on the use of pharmacotherapy and psychosocial support . ACM was delivered in-person or by telephone within the primary care clinic . MAIN MEASUREMENTS Engagement in treatment and heavy alcohol consumption . KEY RESULTS The ACM condition had a significantly higher proportion of participants engaged in treatment over the 26 weeks [ OR = 5.36 , 95 % CI = ( 2.99 , 9.59 ) ] . The percentage of heavy drinking days were significantly lower in the ACM condition [ OR = 2.16 , 95 % CI = ( 1.27 , 3.66 ) ] , while overall abstinence did not differ between groups . CONCLUSIONS Results demonstrate that treatment for an alcohol use disorder can be delivered effectively within primary care , leading to greater rates of engagement in treatment and greater reductions in heavy drinking Most published studies of the efficacy of naltrexone for alcohol treatment have focused on daily medication for relapse prevention among abstinent alcoholics . The present study compared the effects of naltrexone with those of placebo in a sample of early problem drinkers who received study medication either daily or targeted to situations identified by the patients as being high risk for heavy drinking . Patients ( n = 153 ; 58 % male ) were r and omly assigned to receive naltrexone ( 50 mg ) or placebo on a daily or targeted basis , yielding comparable numbers of patients in each of four treatment groups . Patients were trained to use structured nightly diaries in which they recorded their alcohol consumption and medication intake . Analysis was conducted with hierarchical linear modeling . Irrespective of whether they received naltrexone or placebo , patients in the targeted condition showed a reduced likelihood of any drinking . There was a reduced likelihood of heavy drinking , both for patients who received naltrexone and for patients who were in the targeted groups ( either naltrexone or placebo ) , although these effects diminished as the number of tablets available to the targeted groups was reduced over the 8-week treatment period . Although the effect was a modest one , daily naltrexone reduced the risk of heavy drinking in this patient group . Furthermore , use of a targeted approach to medication treatment appears to be a useful strategy for reducing both drinking and heavy drinking . Efforts to replicate these findings are warranted , since they suggest that schedules of medication administration other than daily should be evaluated for treatment of problem drinking BACKGROUND Despite important gender differences in drinking patterns , physiological effects of alcohol , and co-occurring psychiatric conditions , relatively little is known about the efficacy of naltrexone for the treatment of alcohol dependence in women . This study investigated the safety and efficacy of naltrexone in combination with Cognitive Behavioral Coping Skills Therapy ( CBCST ) in a sample of alcohol-dependent women , some with comorbid eating pathology . METHODS One hundred three women meeting DSM-IV criteria for alcohol dependence ( 29 with comorbid eating disturbances ) were r and omized to receive either naltrexone 50 mg or placebo for 12 weeks in addition to weekly group CBCST . Subjects were enrolled between October 1995 and December 2000 at an outpatient research clinic . RESULTS No significant differences were observed on the primary outcomes of time to first drinking day , time to first day of heavy drinking , or the percentage of participants who continued to meet the criteria for alcohol dependence . Secondary analyses revealed that naltrexone significantly delayed the time to the second ( chi2=5.37 , p=0.02 ) and third ( chi2=4.35 , p=0.04 ) drinking days among subjects who did not maintain abstinence from alcohol . Among those with eating disturbances , symptoms of eating pathology improved during treatment , but the effects did not differ according to medication condition . CONCLUSION When used in conjunction with CBCST , naltrexone did not significantly improve drinking outcomes in the overall sample of alcohol-dependent women . However , naltrexone may be of benefit to women who are unable to maintain total abstinence from alcohol . For women with concurrent eating pathology , participation in treatment for alcoholism may be associated with improvements in eating pathology OBJECTIVES To determine whether naltrexone is beneficial in the treatment of alcohol dependence in the absence of obligatory psychosocial intervention . DESIGN Multicentre , r and omised , double-blind , placebo-controlled trial . SETTING Hospital-based drug and alcohol clinics , 18 March 1998 - 22 October 1999 . PATIENTS 107 patients ( mean age , 45 years ) fulfilling Diagnostic and statistical manual of mental disorders ( 4th edition ) criteria for alcohol dependence . INTERVENTIONS Patients with alcohol dependence were r and omly allocated to naltrexone ( 50 mg/day ) or placebo for 12 weeks . They were medically assessed , review ed and advised by one physician , and encouraged to strive for abstinence and attend counselling and /or Alcoholics Anonymous , but this was not obligatory . MAIN OUTCOME MEASURES Relapse rate ; time to first relapse ; side effects . RESULTS On an intention-to-treat basis , the Kaplan-Meier survival curve showed a clear advantage in relapse rates for naltrexone over placebo ( log-rank test , chi(2)(1 ) = 4.15 ; P = 0.042 ) . This treatment effect was most marked in the first 6 weeks of the trial . The median time to relapse was 90 days for naltrexone , compared with 42 days for placebo . In absolute numbers , 19 of 56 patients ( 33.9 % ) taking naltrexone relapsed , compared with 27 of 51 patients ( 52.9 % ) taking placebo ( P = 0.047 ) . Naltrexone was well tolerated . CONCLUSIONS Unlike previous studies , we have shown that naltrexone with adjunctive medical advice is effective in the treatment of alcohol dependence irrespective of whether it is accompanied by psychosocial interventions A 6-month r and omized controlled study of acamprosate versus placebo in preventing relapse following withdrawal from alcohol was undertaken in 20 centres throughout the UK . Patients diagnosed as alcohol-dependent and detoxified within the preceding 5 weeks were r and omly assigned to treatment with either acamprosate ( A ) 666 mg three times/day or identical placebo ( P ) . A total of 664 patients were screened ; 581 were entered into the treatment phase . One-third were episodic drinkers , 84 % were male , 44 % were unmarried and 48 % were unemployed . Medication was first taken on average 24 days after the start of detoxification ; 32 % of patients had already relapsed by this time . The 6-month study period was completed by 35 % of patients ; adverse events led to withdrawal of a further 14 % ( A ) and 9 % ( P ) respectively . Compliance was poor in that , by the end of the second week , only 57 % of patients were judged to be taking at least 90 % of their tablets . The mean total of abstinent days achieved was 77 ( A ) and 81 ( P ) . Complete abstinence for 6 months was achieved by 12 % ( A ) and 11 % ( P ) ; drinking remained within controlled limits in a further 3 % ( A ) and 6 % ( P ) . An effect of acamprosate on consumption was not seen when subgroups , including those defined by the Lesch typology , were analysed separately . However , the mean percentage reduction in craving for alcohol measured on a visual analogue scale was greater in the acamprosate , than placebo , patients at week 2 and week 4 ( P<0.001 ) and the mean decrease in the Hamilton Anxiety score at the 4th week was greater in the acamprosate than placebo patients ( P = 0.017 ) . In comparison with other published trials of acamprosate , patients started study medication after a longer time following detoxification , had more often recommenced drinking before medication was started and had a higher drop-out rate , and this might have contributed to the lack of a treatment effect in this study CONTEXT Alcohol dependence is a common disorder associated with significant morbidity and mortality . Naltrexone , an opioid antagonist , has been shown to be effective for treatment of alcohol dependence . However , adherence to daily oral pharmacotherapy can be problematic , and clinical acceptance and utility of oral naltrexone have been limited . OBJECTIVE To determine efficacy and tolerability of a long-acting intramuscular formulation of naltrexone for treatment of alcohol-dependent patients . DESIGN , SETTING , AND PARTICIPANTS A 6-month , r and omized , double-blind , placebo-controlled trial conducted between February 2002 and September 2003 at 24 US public hospitals , private and Veterans Administration clinics , and tertiary care medical centers . Of the 899 individuals screened , 627 who were diagnosed as being actively drinking alcohol-dependent adults were r and omized to receive treatment and 624 received at least 1 injection . INTERVENTION An intramuscular injection of 380 mg of long-acting naltrexone ( n = 205 ) or 190 mg of long-acting naltrexone ( n = 210 ) or a matching volume of placebo ( n = 209 ) each administered monthly and combined with 12 sessions of low-intensity psychosocial intervention . MAIN OUTCOME MEASURE The event rate of heavy drinking days in the intent-to-treat population . RESULTS Compared with placebo , 380 mg of long-acting naltrexone result ed in a 25 % decrease in the event rate of heavy drinking days ( P = .02 ) [ corrected ] and 190 mg of naltrexone result ed in a 17 % decrease ( P = .07 ) . Sex and pretreatment abstinence each showed significant interaction with the medication group on treatment outcome , with men and those with lead-in abstinence both exhibiting greater treatment effects . Discontinuation due to adverse events occurred in 14.1 % in the 380-mg and 6.7 % in the 190-mg group and 6.7 % in the placebo group . Overall , rate and time to treatment discontinuation were similar among treatment groups . CONCLUSIONS Long-acting naltrexone was well tolerated and result ed in reductions in heavy drinking among treatment-seeking alcohol-dependent patients during 6 months of therapy . These data indicate that long-acting naltrexone can be of benefit in the treatment of alcohol dependence The opioid antagonist , naltrexone , is reported , in single centre studies , to improve the clinical outcome of individuals with alcohol dependence participating in outpatient psychosocial programmes . This is the first multicentre controlled study to evaluate the efficacy and safety of naltrexone as adjunctive treatment for alcohol dependence or abuse . Patients who met criteria for alcohol dependence ( n = 169 ) or alcohol abuse ( n = 6 ) were r and omly assigned to receive double-blind oral naltrexone 50 mg daily ( n = 90 ) or placebo ( n = 85 ) for 12 weeks as an adjunct to psychosocial treatment . The primary efficacy variable was time to first episode of heavy drinking ; secondary efficacy assessment s included time to first drink , alcohol consumption , craving , and changes in the serum biological markers gamma-glutamyl transferase ( GGT ) , and aspartate and alanine aminotransferases . Compliance was assessed by tablet counts and , in the naltrexone-treated group , by measurement of urinary concentrations of 6-ss-naltrexol . Forty-nine ( 58 % ) patients r and omized to placebo and 53 ( 59 % ) r and omized to naltrexone did not complete the study . In intention-to-treat analyses , there was no difference between groups on measures of drinking . The median reduction from baseline of serum GGT ( P : < 0.05 ) and the reductions in alcohol craving ( Obsessive and Compulsive Drinking Scale : OCDS ) were greater in the naltrexone group ( P : < 0.05 ) , from approximately half-way through the study . Of 70 patients ( 35 placebo ; 35 naltrexone ) who met an a priori definition of compliance ( 80 % tablet consumption , attendance at all follow-up appointments ) , those allocated to naltrexone reported consuming half the amount of alcohol ( P : < 0.05 ) , had greater median reduction in serum GGT activity ( P : < 0.05 ) , and greater reduction in alcohol craving ( OCDS total score : P : < 0.05 ; Obsessive subscale score : P : < 0.05 ) , compared to patients in the placebo group . Use of naltrexone raised no safety concerns . Naltrexone is effective in treating alcohol dependence/abuse in conjunction with psychosocial therapy , in patients who comply with treatment The authors examined the efficacy of naltrexone as an adjunctive treatment for alcohol dependence in older adults . Forty-four veterans over 50 years of age were enrolled in a 12-week , double-blind , placebo-controlled efficacy study of naltrexone ( the equivalent of 50 mg per day ) . There were no differences in the frequency of any self-reported adverse effects or in liver enzyme values between the placebo- and naltrexone-treated groups . There were no differences between the treatment groups in the number of subjects remaining abstinent or in the number of subjects who relapsed . However , all placebo-treated subjects relapsed after sampling alcohol , whereas only three of six naltrexone-treated subjects met relapse criteria after alcohol exposure ( P = 0.024 ) . The authors conclude that naltrexone was well tolerated and efficacious in preventing relapse in subjects who drank BACKGROUND Acamprosate has been found to enhance rates of complete abstinence and to increase percent days abstinent ( PDA ) from alcohol relative to placebo treatment . As most U.S. clinical trials of acamprosate have been conducted in alcohol and other drug specialty clinics , there is a need to examine the efficacy of acamprosate in generalist setting s. This study tested the efficacy of acamprosate versus placebo on the primary study outcome of PDA in the treatment of alcohol-dependent patients in a family medicine setting . Secondary study outcomes included percent heavy drinking days ( % HDD ) and gamma glutamyltransferase level ( normal or high ) . METHODS A r and omized , double-blind , placebo-controlled , parallel group design of acamprosate was conducted in 2 family medicine setting s ( North Carolina and Wisconsin ) . One hundred volunteers were recruited primarily by advertisement , and participants were assigned to 666 mg ( 2 pills ) oral acamprosate 3 times daily ( 1,998 mg/d ) or matching placebo over a 12-week period . All participants concomitantly received 5 sessions of a brief behavioral intervention from a family/ primary care physician . RESULTS No significant treatment effect of acamprosate was found on PDA or the secondary outcomes . Significant treatment goal by time interaction effects was found on PDA and % HDD . Participants who had an initial goal of abstinence versus a reduction in alcohol use improved on average over time in PDA and had less % HDD from baseline to the end of treatment . CONCLUSIONS This clinical trial did not find evidence of efficacy for acamprosate compared to placebo among alcohol-dependent individuals recruited primarily by advertisement as studied in a primary care setting . Drinking outcomes significantly improved regardless of medication condition . A goal of abstinence was significantly associated with improved drinking outcomes , suggesting that alcohol-dependent patients with such a goal may do particularly well with counseling in a family medicine setting BACKGROUND Although naltrexone , an opiate-receptor antagonist , has been approved by the Food and Drug Administration for the treatment of alcohol dependence , its efficacy is uncertain . METHODS We conducted a multicenter , double-blind , placebo-controlled evaluation of naltrexone as an adjunct to st and ardized psychosocial treatment . We r and omly assigned 627 veterans ( almost all men ) with chronic , severe alcohol dependence to 12 months of naltrexone ( 50 mg once daily ) , 3 months of naltrexone followed by 9 months of placebo , or 12 months of placebo . All patients were offered individual counseling and programs to improve their compliance with study medication and were encouraged to attend Alcoholics Anonymous meetings . RESULTS There were 209 patients in each group ; all had been sober for at least five days before r and omization . At 13 weeks , we found no significant difference in the number of days to relapse between patients in the two naltrexone groups ( mean , 72.3 days ) and the placebo group ( mean , 62.4 days ; 95 percent confidence interval for the difference between groups , -3.0 to 22.8 ) . At 52 weeks , there were no significant differences among the three groups in the percentage of days on which drinking occurred and the number of drinks per drinking day . CONCLUSIONS Our findings do not support the use of naltrexone for the treatment of men with chronic , severe alcohol dependence BACKGROUND A 12-week , multicenter , double-blind , r and omized , parallel-group clinical trial to compare naltrexone and placebo was carried out to determine the efficacy , safety , and tolerability of naltrexone together with a psychosocial intervention in the treatment of alcoholism . METHODS A total of 202 alcohol-dependent patients were assigned to 12 weeks ' treatment with either naltrexone or placebo . The relapse rate was evaluated by means of intention-to-treat analyses . Alcohol consumption , craving , adverse events , and changes in the biochemical markers of heavy drinking and possible toxicity were evaluated in the 192 patients who were considered to be assessable . RESULTS The survival function for patients who were treated with naltrexone was significantly better than that of the patients who were treated with placebo ( Kaplan-Meier log rank = 4 , df = 1 , p < 0.05 ) . In addition , 7.9 % of patients who were treated with naltrexone relapsed as compared with 18.8 % of those who received placebo [ chi = 5.89 , df = 2 , p = 0.050 ] . In comparing naltrexone with placebo-treated patients , the most common adverse events were abdominal pain [ 8.6 % vs. 1 % ; ( chi = 6.1 , df = 1 , p < 0.05 ) ] and headache [ 7.5 % vs. 1 % ( chi = 5.1 , df = 1 , p < 0.05 ) ] . CONCLUSIONS Naltrexone was well-tolerated , as the rate of adverse events was low , and safe , as it did not interfere with the normalization of biochemical markers of heavy drinking or alter liver function markers . Naltrexone seemed to reduce relapse rate to heavy drinking , but we found no differences in other alcohol consumption variables between naltrexone- and placebo-treated groups . Although the naltrexone group showed a tendency to consume fewer drinks per drinking day and had a longer time to first drink , differences were not statistically significant BACKGROUND Naltrexone is approved for the treatment of alcohol dependence when used in conjunction with a psychosocial intervention . This study was undertaken to examine the impact of 3 types of psychosocial treatment combined with either naltrexone or placebo treatment on alcohol dependency over 24 weeks of treatment : ( 1 ) Cognitive-Behavioral Therapy ( CBT ) + medication clinic , ( 2 ) BRENDA ( an intervention promoting pharmacotherapy ) + medication clinic , and ( 3 ) a medication clinic model with limited therapeutic content . METHODS Two hundred and forty alcohol-dependent subjects were enrolled in a 24-week double-blind placebo-controlled study of naltrexone ( 100 mg/d ) . Subjects were also r and omly assigned to 1 of 3 psychosocial interventions . All patients were assessed for alcohol use , medication adherence , and adverse events at regularly scheduled research visits . RESULTS There was a modest main treatment effect for the psychosocial condition favoring those subjects r and omized to CBT . Intent-to-treat analyses suggested that there was no overall efficacy of naltrexone and no medication by psychosocial intervention interaction . There was a relatively low level of medication adherence ( 50 % adhered ) across conditions , and this was associated with poor outcome . CONCLUSIONS Results from this 24-week treatment study demonstrate the importance of the psychosocial component in the treatment of alcohol dependence . Moreover , results demonstrate a substantial association between medication adherence and treatment outcomes . The findings suggest that further research is needed to determine the appropriate use of pharmacotherapy in maximizing treatment response BACKGROUND Clinical studies with opioid antagonists for treatment of problem drinking have mainly been conducted in specialized alcohol treatment centers , included structured psychosocial treatment , and have focused on maintaining abstinence after a period of abstinence from alcohol . METHODS This multisite , r and omized double-blind study investigated targeted nalmefene in reducing heavy drinking . Specialized alcohol treatment centers and private general practice s enrolled 403 subjects ( 328 men , 75 women ) . Subjects were instructed to take nalmefene 10 to 40 mg ( n=242 ) or placebo ( n=161 ) when they believed drinking to be imminent . After 28 weeks , 57 subjects from the nalmefene group continued into a 24-week r and omized withdrawal extension . Concomitant psychosocial intervention was minimal and no treatment goals were imposed . Alcohol consumption was recorded using the time-line follow-back method . Biochemical indicators of alcohol use were also measured . RESULTS The mean monthly number of heavy drinking days ( HDDs ) during the 12-week period before inclusion was 15.5 ( SD 6.9 ) in the nalmefene group and 16.2 ( SD 6.9 ) in the placebo group . During treatment , the mean numbers of HDDs were 8.6 to 9.3 in the nalmefene group and 10.6 to 12.0 in the placebo group ( p=0.0065 ) . The levels of serum alanine aminotransferase and gamma-glutamyl transferase decreased in the nalmefene group compared with the placebo group ( p=0.0088 and 0.0023 ) . During the r and omized withdrawal period , subjects r and omized to placebo apparently returned to heavier drinking . Subjects receiving nalmefene reported more nausea , insomnia , fatigue , dizziness , and malaise than subjects on placebo . CONCLUSIONS Nalmefene appears to be effective and safe in reducing heavy drinking , even when accompanied by minimal psychosocial support BACKGROUND About 50 % of alcoholic patients relapse within 3 months of treatment . Previous studies have suggested that acamprosate may help to prevent such relapse . The aim of our study was to assess the efficacy and safety of long-term acamprosate treatment in alcohol dependence . METHODS In this multicentre , double-blind , placebo-controlled study , we recruited 455 patients , aged 18 - 65 years , with chronic or episodic alcohol dependence . Patients were r and omly allocated treatment with acamprosate ( 1998 mg daily for bodyweight > 60 kg ; 1332 mg daily for < or = kg ) or placebo for 360 days . Patients were assessed on the day treatment started and on days 30 , 90 , 180 , 270 , and 360 by interview , self-report , question naire , and laboratory screening . Patients were classified as abstinent , relapsing , or non-attending . Time to first treatment failure ( relapse or non-attendance ) was the primary outcome measure . FINDINGS Seven patients were excluded from the intention-to-treat analysis because they did not attend on the first treatment day and therefore received no medication . The acamprosate ( n = 224 ) and placebo ( n = 224 ) groups were well matched in terms of baseline demographic and alcohol-related variables . 94 acamprosate-treated and 85 placebo-treated patients completed the treatment phase : of those withdrawn , 104 ( 52 in each group ) relapsed , 69 ( 33 vs 36 , respectively ) were lost to follow-up , 63 ( 31 vs 32 ) refused to continue treatment , 16 ( 15 vs 11 ) had concurrent illness , three ( two vs one ) died , ten ( six vs four ) had adverse side-effects , one ( acamprosate treated ) received the wrong medication , and three ( placebo treated ) were non-compliant . The proportion without treatment failure was higher in the acamprosate than in the placebo group throughout the treatment period ( p < 0.001 , Mantel-Cox ) . At the end of treatment , 41 ( 18.3 % ) acamprosate-treated and 16 ( 7.1 % ) placebo-treated patients had been continuously abstinent ( p = 0.007 ) . Mean cumulative abstinence duration was significantly greater in the acamprosate group than in the placebo group ( 138.8 [ SD 137.5 ] vs 103.8 [ 119.0 ] days ; p = 0.012 ) . 148 patients ( 79 acamprosate , 69 placebo ) completed 27 months follow-up : 27 ( 11.9 % ) acamprosate-treated and 11 ( 4.9 % ) placebo-treated patients remained continuously abstinent , and the mean cumulative abstinence duration was 230.8 days ( 259.1 ) and 183.0 days ( 235.2 ) , respectively . Apart from occasional diarrhoea , there was no difference in side-effects between groups . INTERPRETATION Acamprosate is an effective and well-tolerated pharmacological adjunct to psychosocial and behavioural treatment programmes for treatment of alcohol-dependent patients In a placebo-controlled , double-blind German multicenter study ( seven sites ) the efficacy of naltrexone as an adjunctive treatment in alcoholism to maintain abstinence was assessed for 12 weeks . A total of 171 detoxified patients ( 97.7 % met the DSM-III-R criteria for alcohol dependence ) were included . Patients had been abstinent for a mean of 19.5 ± 9.4 days at study entry . Eighty-four and 87 patients were r and omized to receive naltrexone ( 50 mg/day ) and placebo , respectively . Each site was instructed to provide its usual psychosocial alcohol treatment program . The primary effectiveness measure was the time to first heavy drinking as derived from self-reports of drinking ( timeline-follow-back method ) . Secondary effectiveness measures included time to first drink , amount of alcohol consumption , intensity of craving , severity of alcoholism problems , and liver enzymes . Thirty-three ( 38 % ) placebo patients and 28 ( 33 % ) naltrexone patients discontinued the study . At endpoint , 62 % of the patients in each group did not have an episode of heavy drinking . Also , there were no significant differences between the study groups concerning secondary effectiveness measures as well as compliance and adverse clinical events — with the exception of the γ-GT , which was significantly greater reduced in the naltrexone group throughout the study . Based upon an intention-to-treat population , this study confirms the safety but not the efficacy of naltrexone in prevention of alcohol relapse . Nevertheless , the question arises whether self-reports of drinking are more reliable than γ-GT as a measure of recent alcohol consumption BACKGROUND Topiramate increases GABAergic activity and antagonizes the AMPA/kainate subtype of glutamate receptors . Through these mechanisms of action , topiramate may reduce alcohol and cocaine reward and may reduce alcohol and cocaine craving . Topiramate has been shown to reduce drinking in persons with alcohol dependence , and reduce relapse in stimulant-dependent patients . The current trial was intended to test the ability of topiramate to promote cocaine and alcohol abstinence among patients addicted to both drugs . METHODS The study was a double-blind , placebo-controlled , 13-week trial involving 170 cocaine and alcohol dependent subjects . After achieving a period of cocaine and alcohol abstinence , subjects were r and omized to topiramate , 300 mg daily , or identical placebo capsules . In addition , subjects received weekly individual psychotherapy . Primary outcome measures included self-reported alcohol and cocaine use , and thrice weekly urine drug screens . Secondary outcome measures included cocaine and alcohol craving , Addiction Severity Index results , cocaine withdrawal symptoms , and clinical global improvement ratings . RESULTS Topiramate was not better than placebo in reducing cocaine use on the a priori primary outcome measure , or in reducing alcohol use . Topiramate was not better than placebo in reducing cocaine craving . Topiramate-treated subjects , compared to placebo-treated subjects , were more likely to be retained in treatment and more likely to be abstinent from cocaine during the last three weeks of the trial . Subjects who entered treatment with more severe cocaine withdrawal symptoms responded better to topiramate . DISCUSSION Topiramate plus cognitive behavioral therapy may reduce cocaine use for some patients with comorbid cocaine and alcohol dependence BACKGROUND The effectiveness of acamprosate ( calcium bisacetylhomotaurinate ) as a treatment to maintain abstinence in alcohol-dependent patients was assessed for 1 year . METHODS After short-term detoxification , 272 patients participated in a r and omized , double-blind , placebo-controlled study . Patients received routine counseling and either the study medication or placebo for 48 weeks ; they were followed up for another 48 weeks without medication . Statistical analysis was performed according to the intention-to-treat principle . RESULTS Patients who were receiving acamprosate showed a significantly higher continuous abstinence rate within the first 60 days of treatment compared with patients who were assigned to placebo treatment ( 67 % vs 50 % ) until completion of the treatment period ( 43 % vs 21 % , log rank P = .005 ) , and they had a significantly longer mean abstinence duration of 224 vs 163 days , or 62 % vs 45 % days abstinent ( P < .001 ) ; however , there was no difference in psychiatric symptoms . Of the patients who were receiving acamprosate , 41 % had dropped out , whereas 60 % of the placebo-treated patients dropped out of the study . Few side effects ( mainly diarrhea and headache ) were recorded . At the end of a further 48 weeks without receiving study medication , 39 % and 17 % of the acamprosate- and placebo-treated patients , respectively , had remained abstinent ( P = .003 ) . CONCLUSION Acamprosate proved to be a safe and effective aid in treating alcohol-dependent patients and in maintaining the abstinence of patients during 2 years A prospect i ve placebo-controlled , r and omized double-blind study of Acamprosate at two dose levels in alcohol-dependent patients followed up for 12 months was performed . After detoxification , each of the 538 patients included was r and omly assigned to one of three groups : 177 patients received placebo , 188 received Acamprosate at 1.3 g/day ( low dose group ) and 173 received 2.0 g/day ( high dose group ) for 12 months . This was followed by a single blind 6 month period on placebo . The patients ' mean age was 43.2 + /- 8.6 years . Their mean daily alcohol intake was high ( nearly 200 g/day ) and of long duration ( 9.5 + /- 7.1 years ) . Abstinence figures followed the order high dose > low dose > placebo . The difference was significant at 6 months ( P < or = 0.02 ) but not at 12 months ( P = 0.096 ) . The number of days of continuous abstinence after detoxification was 153 + /- 197 for the high-dose group versus 102 + /- 165 for the placebo group ( P = 0.005 ) , with the lose-dose group reporting 135 + /- 189 days . Clinic attendance was significantly better in the Acamprosate groups than in the placebo group at 6 months ( P = 0.002 ) and 12 months ( P = 0.005 ) . During the 6-month post-treatment period , no increased relapse rate or residual drug effect was observed . The side effect profile for Acamprosate was good compared with controls with only diarrhoea being reported more frequently ( P < 0.01 ) . This study confirms the pharmacological efficacy of Acamprosate and its good acceptability . As an adjunct to psychotherapy , this study supports the inclusion of Acamprosate in a strategy for treating alcoholism OBJECTIVE Empirical evidence has only weakly supported antidepressant treatment for patients with co-occurring depression and alcohol dependence . While some studies have demonstrated that antidepressants reduce depressive symptoms in individuals with depression and alcohol dependence , most studies have not found antidepressant treatment helpful in reducing excessive drinking in these patients . The authors provide results from a double-blind , placebo-controlled trial that evaluated the efficacy of combining approved medications for depression ( sertraline ) and alcohol dependence ( naltrexone ) in treating patients with both disorders . METHOD A total of 170 depressed alcohol-dependent patients were r and omly assigned to receive 14 weeks of treatment with sertraline ( 200 mg/day [ N=40 ] ) , naltrexone ( 100 mg/day [ N=49 ] ) , the combination of sertraline plus naltrexone ( N=42 ) , or double placebo ( N=39 ) while receiving weekly cognitive-behavioral therapy . RESULTS The sertraline plus naltrexone combination produced a higher alcohol abstinence rate ( 53.7 % ) and demonstrated a longer delay before relapse to heavy drinking ( median delay=98 days ) than the naltrexone ( abstinence rate : 21.3 % ; delay=29 days ) , sertraline ( abstinence rate : 27.5 % ; delay=23 days ) , and placebo ( abstinence rate : 23.1 % ; delay=26 days ) groups . The number of patients in the medication combination group not depressed by the end of treatment ( 83.3 % ) approached significance when compared with patients in the other treatment groups . The serious adverse event rate was 25.9 % , with fewer reported with the medication combination ( 11.9 % ) than the other treatments . CONCLUSIONS More depressed alcohol-dependent patients receiving the sertraline plus naltrexone combination achieved abstinence from alcohol , had delayed relapse to heavy drinking , reported fewer serious adverse events , and tended to not be depressed by the end of treatment We conducted a controlled , blinded , multicenter study of disulfiram treatment of alcoholism in 605 men r and omly assigned to 250 mg of disulfiram ( 202 men ) ; 1 mg of disulfiram ( 204 men ) , a control for the threat of the disulfiram-ethanol reaction ; or no disulfiram ( 199 men ) , a control for the counseling that all received . Bimonthly treatment assessment s were done for one year . Relative/friend interviews and blood and urine ethanol analyses were used to corroborate patients ' reports . There were no significant differences among the groups in total abstinence , time to first drink , employment , or social stability . Among the patients who drank and had a complete set of assessment interviews , those in the 250-mg disulfiram group reported significantly fewer drinking days ( 49.0 + /- 8.4 ) than those in the 1-mg ( 75.4 + /- 11.9 ) or the no-disulfiram ( 86.5 + /- 13.6 ) groups . There was a significant relationship between adherence to drug regimen and complete abstinence in all groups . We conclude that disulfiram may help reduce drinking frequency after relapse , but does not enhance counseling in aiding alcoholic patients to sustain continuous abstinence or delay the resumption of drinking BACKGROUND In several studies , patients with alcohol dependence treated with the opioid antagonist naltrexone have shown fewer relapses to heavy drinking than those receiving placebo . An interaction between the naltrexone effect and the type of psychological therapy has been observed . METHODS A 6-month , double-blind , placebo-controlled , parallel-group study was performed at 10 different investigation sites . After a placebo run-in period of 1 week , 118 patients were r and omized into 4 treatment groups-50 mg of naltrexone daily or placebo in combination with either cognitive behavioral therapy ( CBT ) or supportive therapy . The CBT was performed over nine sessions according to the manual of Project MATCH ( Matching Alcoholism Treatments to Client Heterogeneity ) . The supportive therapy was defined as " the treatment as usual . " Alcohol consumption , craving , carbohydrate-deficient transferrin , medication compliance by tablet count , and adverse clinical events were assessed at all visits . Other liver enzymes and psychiatric symptoms were also determined . RESULTS Ninety-one ( 77 % ) patients completed the study , and 92 ( 78 % ) were 80 % compliant with the medication regimen . A lower percentage of heavy-drinking days was shown in the naltrexone group ( p = 0.045 ) compared with the placebo group , as was a lower craving score ( p = 0.029 ) . These results are supported by the lower levels of liver enzyme activities ( p < 0.010 for aspartate aminotransferase , alanine aminotransferase , and gamma-glutamyltransferase ) , but not by the carbohydrate-deficient transferrin levels , in the naltrexone group . The mean time period before the first day of heavy drinking was longer for the group treated with CBT ( p = 0.010 ) , especially in combination with naltrexone ( p = 0.007 ) . Naltrexone was well tolerated , and no patients discontinued the study due to side effects . CONCLUSIONS This study supports the effect of naltrexone in outpatient treatment of alcohol dependence and suggests that a beneficial interaction effect with CBT can be expected To test acamprosate 's role as an aid in preventing relapse after detoxification , 296 alcohol-dependent patients entered a prospect i ve , multicentre , r and omized , double-blind , parallel comparison of acamprosate treatment consisting of two 333 mg tablets given three times daily for 180 days with matching placebo treatment . Unlike previous studies , acamprosate was prescribed from the start of alcohol withdrawal , rather than after the detoxification process . During the treatment period , 110 patients dropped out . The two treatment groups were balanced with regard to baseline values and reasons for discontinuation . There was no difference between the groups in the severity of withdrawal symptoms as measured by the CIWA-Ar ( Clinical Institute Withdrawal Assessment for Alcohol scale ) . Acamprosate given during withdrawal did not cause unwanted effects . The cumulative abstinence duration ( CAD , main end-point ) was 19 days longer in the acamprosate treatment group than the placebo treatment group ( analysis of variance on ranks , P = 0.0006 ) and the stable recovery duration , defined as the number of abstinent days between the last relapse into any drinking and the end of the trial , was 16 days longer in the acamprosate treatment group ( P = 0.021 ) . Continuous abstinence , estimated by survival analysis on time to first relapse , was achieved by 35 % of acamprosate-treated patients and 26 % of placebo-treated patients ( log rank P = 0.068 ) . The geometric mean of the ratio final/baseline values for serum carbohydrate-deficient transferrin was 0.802 ( placebo ) and 0.733 ( acamprosate ) ( P = 0.059 ) . The geometric mean of the ratio final/baseline values for serum gamma-glutamyltransferase was 0.496 ( placebo ) and 0.415 ( acamprosate ) ( P = 0.024 ) which corroborated the greater abstinence reported by the acamprosate group AIMS The aim of this r and omized , controlled , multisite trial was to evaluate the efficacy of combined treatment with integrative behaviour therapy ( IBT ) and acamprosate on drinking behaviour in detoxified alcohol-dependent patients . METHODS A total of 371 patients were r and omized to one of the three treatment conditions : IBT plus acamprosate , IBT plus placebo , or supportive counselling ( ' treatment as usual ' , TAU ) plus acamprosate . The main outcome was success rate , i.e. , rate of abstinence plus improvement according to the criteria of Feuerlein and Küfner ( 1989 ) , at the end of the six-month treatment phase and at the subsequent six-month follow-up . Drinking status was vali date d by blood parameters ( CDT , GGT , and MCV ) . Data were analyzed by an intent-to-treat model and missing data were classified as relapse . RESULTS The success rates at the end of treatment under both TAU plus acamprosate ( 37.7 % ) and IBT plus placebo ( 48 % ) almost reached the levels derived from the literature . However , adding acamprosate to IBT did not result in the expected increase in success rate ( IBT plus acamprosate : 47.6 % ) , and success rates did not differ significantly between groups . Similarly , there was no significant difference between treatment success rates at follow-up . CONCLUSION The results suggest that the combination of acamprosate and IBT is not more effective than treatment with either IBT or acamprosate alone . However , the two acamprosate conditions differed in success rate by about 10 % , which might constitute a clinical ly relevant though statistically non-significant effect This study presents the results of a multicenter investigation of the efficacy of acamprosate in the treatment of patients with chronic or episodic alcohol dependence . One hundred eighteen patients were r and omly assigned to either placebo or acamprosate , and both groups were stratified for concomitant voluntary use of disulfiram . Treatment lasted for 360 days , with an additional 360-day follow-up period . The primary efficacy parameters evaluated were : relapse rate and cumulative abstinence duration ( CAD ) . Results were analyzed according to Intention-To-Treat principles using chi2 , t , and multiple regression analyses where appropriate . After 30 days on study medication , 40 of 55 ( 73 % ) acamprosate-treated patients were abstinent , compared with 26 of 55 ( 43 % ) placebo-treated patients ( p = 0.019 ) . The treatment advantage remained throughout the study medication period and was statistically significant until day 270 ( p = 0.028 ) . Twenty-seven percent of patients on acamprosate and 53 % of patients on placebo had a first drink within the first 30 days of the study . The mean CAD was 137 days ( 40 % abstinent days ) for the patients treated with acamprosate and 75 days ( 21 % abstinent days ) for the placebo group ( p = 0.013 ) . No adverse interaction between acamprosate and disulfiram occurred , and the subgroup who received both medications had a better outcome on CAD than the those on only one or no medication . Acamprosate was well tolerated . Diarrhea was the only significant treatment-induced effect . It was concluded that acamprosate was a useful and safe pharmacotherapy in the long-term treatment of alcoholism . Concomitant administration of disulfiram improved the effectiveness of acamprosate Abstract : The opiate antagonist nalmefene has been shown in 2 single-site studies to reduce alcohol consumption and relapse drinking in alcohol-dependent individuals . This safety and preliminary multisite efficacy study evaluated 3 doses of nalmefene ( 5 , 20 , or 40 mg ) in a double-blind comparison to placebo over a 12-week treatment period in 270 recently abstinent outpatient alcohol-dependent individuals . Participants concomitantly received 4 sessions of a motivational enhancement therapy ( with a medication compliance component ) delivered from trained counselors . Although more subjects in the active medication groups terminated the study early secondary to adverse events , the rates did not differ significantly from that of placebo . The 20-mg/d group experienced more insomnia , dizziness , and confusion , while the 5-mg group also had more dizziness and the 40-mg group had more nausea than the placebo group . Most of these symptoms were mild and improved over time . Although all subjects had a reduction in heavy drinking days , craving , γ-glutamyl transferase , and carbohydrate-deficient transferrin concentrations over the course of the study , there was no difference between the active medication and placebo groups on these measures . The time to first heavy drinking day was also not significantly different between the placebo and the active treatment groups . This relatively small multisite trial showed that nalmefene was reasonably well tolerated in recently abstinent alcoholics . However , possibly because of variation among the sites or the comparatively small sample size , there was no evidence of superior efficacy outcomes with nalmefene treatment 90 patients with alcoholism stage II suffering from secondary affective disorders ( anxiety , depression ) were divided into 4 groups : treated with GABA-B-receptor lig and baclofen ( group 1 ) , with sibazon ( group 2 ) , amitriptylin ( group 3 ) , placebo ( group 4 ) . As shown by clinical , experimental psychological and electrophysiological examinations , baclofen is not inferior in efficacy to sibazon and amitriptylin , but is free of side effects and complications typical for the above drugs ( central deprivation , addiction , etc . ) . MAO activity was unaffected in all the patients , so were dopamine , serotonin and GABA blood concentrations after the treatment . This does not allow to relate the peripheral metabolism of GABA and monoamines to emergence of secondary affective disorders in alcoholism . The authors think promising to seek for drugs effective against affective disorders among lig and s of GABA-B receptors A population of 127 alcoholics of both sexes , hospitalized and weaned ( DSM III diagnose : Alcohol Abuse and Alcohol Dependence ) received Acamprosate ( n = 63 ) or placebo ( n = 64 ) in a double blind r and omized therapeutic trail . The patients were followed during three months and anamnestic as well as biological data were recorded . It appeared no significant differences between the two groups of patients . This negative result could perhaps be explained by the heaviness of the pathology of this hospitalized alcoholic population BACKGROUND Naltrexone may improve success in primary care treatment of alcohol dependence ( AD ) . This study tests naltrexone and primary care management ( PCM ) vs naltrexone and cognitive behavior therapy ( CBT ) and tests naltrexone maintenance among patients who respond to an initial course of naltrexone combined with PCM vs CBT . METHODS A nested sequence of 3 r and omized trials was conducted . In study 1 , 197 subjects with AD participated in a 10-week comparison of PCM and naltrexone ( 50 mg/d ) vs CBT and naltrexone ( 50 mg/d ) . In study 2 , 53 PCM responders from study 1 continued in a 24-week placebo-controlled study of maintenance naltrexone . In study 3 , 60 CBT responders from study 1 continued in a 24-week placebo-controlled study of maintenance naltrexone and CBT . RESULTS Study 1 : No difference in the response to treatment ; 84.1 % ( 74/88 ) of the PCM patients and 86.5 % ( 77/89 ) of the CBT patients avoided persistent heavy drinking . Percentage of days abstinent ( PDA ) declined over time for PCM vs CBT ( P = .03 ) . Study 2 : Higher response maintenance for PCM and naltrexone ( 21/26 , 80.8 % ) vs PCM and placebo ( 14/27 , 51.9 % ; P = .03 ) and PDA declined more for the placebo group ( P = .02 ) . Study 3 : The differences between naltrexone vs placebo on maintenance of response ( 25/30 , 83.3 % vs 21/30 , 70.0 % ) or PDA did not reach statistical significance . CONCLUSIONS Naltrexone yielded comparable results during the initial 10 weeks of treatment when combined with PCM or CBT . Maintenance of improvement was enhanced by continued naltrexone treatment in the PCM but not in the CBT arm BACKGROUND Nalmefene is a newer opioid antagonist that is structurally similar to naltrexone but with a number of potential pharmacological advantages for the treatment of alcohol dependence , including no dose-dependent association with toxic effects to the liver , greater oral bioavailability , longer duration of antagonist action , and more competitive binding with opioid receptor subtypes that are thought to reinforce drinking . METHODS A double-blind , placebo-controlled trial was conducted to evaluate the safety and efficacy of 2 doses of oral nalmefene for alcohol dependence . The 105 outpatient volunteers were abstinent for a mean of 2 weeks prior to r and om assignment to the placebo or 20- or 80-mg/d dose nalmefene groups for 12 weeks . Cognitive behavioral therapy was provided weekly during treatment . Self-reported drinking or abstinence was confirmed by determinations of breath alcohol concentration and by collateral informant reports . RESULTS Outcomes did not differ between the 20- and 80-mg dose nalmefene groups . Significantly fewer patients treated with nalmefene than patients given placebo relapsed to heavy drinking through 12 weeks of treatment ( P<.02 ) , with a significant treatment effect at the first weekly study visit ( P<.02 ) . The odds ratio of relapsing to heavy drinking was 2.4 times greater with placebo compared with nalmefene ( 95 % confidence interval , 1.05 - 5.59 ) . Patients treated with nalmefene also had fewer subsequent relapses ( P<.03 ) than patients given placebo . CONCLUSIONS Treatment with nalmefene was effective in preventing relapse to heavy drinking relative to placebo in alcohol-dependent out patients and was accompanied by acceptable side effects OBJECTIVE In several large , well- design ed , r and omized , double-blind studies , the opiate antagonist naltrexone demonstrated efficacy in the treatment of alcohol dependence . Specifically , when combined with certain psychosocial therapies , naltrexone reduces the number of drinking days , heavy drinking , and time to relapse to alcohol use in alcohol-dependent individuals . Whether this efficacy can be generalized to individuals who have alcohol use disorders and present for treatment at front-line community treatment programs has not been well established . METHODS A total of 145 patients who presented for treatment at a rural community substance abuse treatment center were r and omized to receive naltrexone 50 mg daily plus usual program treatment ( n = 54 ) , placebo plus usual treatment ( n = 43 ) , or usual treatment alone ( n = 48 ) for 12 week . A total of 133 participants had at least one follow-up visit . Primary outcome measures included percent days drinking , average drinks per drinking day , average drinks per day , heavy drinking days ( four or more for women and six or more for men ) , and time to first heavy drinking day . Secondary measures included changes in serum biological markers ( alkaline phosphatase , alanine transaminase , aspartate transaminase , and gamma-glutamyltransferase ) , craving , and psychosocial functioning . RESULTS In the intention-to-treat analysis , there were no between-group differences for any of the primary drinking outcomes at 12 weeks . In post hoc exploratory analyses , the entire sample of participants was divided into two new groups : ( 1 ) people who drank during the 2 weeks before the start of medication ( entry drinkers ) and ( 2 ) people who did not drink during this interval ( entry abstainers ) . Entry abstainers were at an advantage at study entry in that they were significantly more likely to have an inpatient hospitalization immediately before entry into outpatient treatment . Mixed-model analysis of variance revealed a main effect for entry group at the 12-week treatment endpoint on the primary outcome measures of percent days drinking , average drinks per drinking day , average drinks per day , heavy drinking days , and time to first heavy drinking day . Participants in any of the r and omized groups who were entry abstainers had significantly better improvement on all of the primary outcome measures . The abstainer groups that were r and omized to placebo and usual treatment had significantly better outcomes than the entry drinkers in those perspective groups . However , for the naltrexone-treated group , entry drinkers and entry abstainers had similar improvement in drinking-related outcomes . CONCLUSIONS These data suggest that naltrexone may offer particular benefit to patients who continue to drink during the early stages of the trial as compared with those who have achieved abstinence before treatment entry BACKGROUND In a search for an effective ' anti-alcohol pill ' , three modern anti-craving agents have been studied in alcoholics of Army/ DSC , Air Force , Navy and Coast Guard . METHODS 129 patients of alcohol dependence syndrome were r and omly assigned to three groups where topiramate , acamprosate and naltrexone were used as anti-craving agents in a year long prospect i ve study . Of these 92 patients completed the study . RESULT AND CONCLUSION Topiramate ( 76.3 % ) appears to be significantly more effective ( p<0.01 ) in sustaining abstinence , though naltrexone ( 57.7 % ) and acamprosate ( 60.70 % ) offer moderate relapse-prevention efficacy . Side effects of all the three agents have been mild , transient and self-limiting . We recommend a trial of topiramate , before invaliding out of any alcoholic soldier In a one-year double-blind-treatment study with acamprosat ( six months with and six months without substance ) the efficiency of this new medicament could be proved . The number of relapses in the treatment group was significantly lower during the first 30 days with a trend to further 150 days . The substance caused very few side effects Ninety-seven alcohol-dependent patients were treated for 12 weeks in a double-blind , placebo-controlled study evaluating naltrexone and two manual guided psychotherapies in the treatment of alcohol dependence . Patients were r and omized to receive either naltrexone or placebo and either coping skills/relapse prevention therapy or a supportive therapy design ed to support the patient 's own efforts at abstinence without teaching specific coping skills . Naltrexone proved superior to placebo in measures of drinking and alcohol-related problems , including abstention rates , number of drinking days , relapse , and severity of alcohol-related problems . Medication interacted with the type of psychotherapy received . The cumulative rate of abstinence was highest for patients treated with naltrexone and supportive therapy . For those patients who initiated drinking , however , patients who received naltrexone and coping skills therapy were the least likely to relapse OBJECTIVE This study was undertaken to evaluate the efficacy and safety of acamprosate in the treatment of alcohol dependence . METHOD The investigation was a double-blind , placebo-controlled , 24-week study carried out at the University of São Paulo , Brazil . The sample comprised 75 patients , 18 - 60 years of age , with an International Classification of Diseases ( ICD-10 ) diagnosis of alcohol dependence . After a 1-week detoxification period the patients were r and omly divided into two groups : the first received acamprosate ( 1.998 mg/day ) and the second received placebo . After the first 12 weeks , the patients continued follow-up for a similar length of time without medication . The main outcome measures were relapse rates , side effects and time to first relapse . RESULTS On an intention-to-treat basis , the Kaplan-Meier survival curve showed an advantage in relapse rates for acamprosate over placebo ( log-rank test , p = .02 ) , and acamprosate was well tolerated . CONCLUSIONS Acamprosate seems to be an effective treatment for alcohol dependence in a Brazilian population BACKGROUND There is a large treatment gap in alcohol dependence , and current treatments are only moderately effective in preventing relapse . New treatment modalities , allowing for reduction of alcohol consumption as a treatment goal are needed . This study evaluated the efficacy of as-needed use of the opioid system modulator nalmefene in reducing alcohol consumption in patients with alcohol dependence . METHODS Six hundred and four patients ( placebo = 298 ; nalmefene = 306),≥18 years of age , with a diagnosis of alcohol dependence,≥6 heavy drinking days , and average alcohol consumption≥World Health Organization medium drinking risk level in the 4 weeks preceding screening , were r and omized ( 1:1 ) to 24 weeks of as-needed placebo or nalmefene 18 mg . RESULTS Patients taking placebo ( n = 289 ) and patients taking nalmefene ( n = 290 ) were included in the efficacy analyses . At Month 6 , there was a significant effect of nalmefene compared with placebo in reducing the number of heavy drinking days ( -2.3 days [ 95 % confidence interval:-3.8 to-.8 ] ; p = .0021 ) and total alcohol consumption ( -11.0 g/day [ 95 % confidence interval:-16.8 to-5.1 ] ; p = .0003 ) . Improvements in Clinical Global Impression and liver enzymes were larger in the nalmefene group compared with placebo at Week 24 . Adverse events ( most mild or moderate ) and dropouts due to adverse events were more common with nalmefene than placebo . The number of patients with serious adverse events was similar in the two groups . CONCLUSIONS Nalmefene provides clinical benefit , constitutes a potential new pharmacological treatment paradigm in terms of the treatment goal and dosing regimen , and provides a method to address the unmet medical need in patients with alcohol dependence that need to reduce their alcohol consumption One hundred twenty-eight alcoholic men were assigned r and omly to receive either a regular dose of disulfiram ( 250 mg ) , a pharmacologically inactive dose ( 1 mg ) , or no disulfiram . There were no statistically significant differences among the three treatment groups in total abstinence , percentage of drinking days , days worked , family stability ( living with same relative ) , or percent of scheduled appointments kept . However , 21 % of those who received the regular dose of disulfiram and 25 % who received the pharmacologically inactive dose remained abstinent , whereas only 12 % of those who received no disulfiram did so . These results indicate that disulfiram may be of limited value in the treatment of alcoholism , fear of the disulfiram-ethanol reaction is important in preventing drinking , and patients willing to take disulfiram are more likely to be abstinent if given the drug . We also found that complete abstinence correlated significantly with compliance and obtaining employment BACKGROUND Two previous double-blind , placebo-controlled studies demonstrated that naltrexone ( 50 mg/d ) reduces alcohol drinking in alcohol-dependent subjects . In both studies , treatment compliance was excellent . However , a robust treatment effect size for naltrexone relative to placebo has been shown for compliant subjects but not for subjects who missed research visits . The goal of this study was to determine the effectiveness of naltrexone in subjects who received psychosocial treatment in a more naturalistic setting with respect to the role of treatment attendance and medication compliance . METHODS Ninety-seven alcohol-dependent subjects were r and omly assigned to receive either naltrexone ( n = 48 ) or matching placebo ( n = 49 ) for 12 weeks . All subjects received individual counseling ( twice per week for the first month followed by once per week ) . RESULTS Overall , naltrexone showed only modest effects in reducing alcohol drinking for the 12 weeks of treatment . However , naltrexone treatment efficacy improved across a variety of outcome measures for subjects who completed treatment and were highly compliant with taking medication . CONCLUSIONS Naltrexone is clinical ly effective relative to placebo in individuals who comply with the treatment protocol and take medication . The modest treatment effects in the entire sample suggest that the clinical efficacy of naltrexone could be improved by enhancing treatment compliance AIM We examined the efficacy of naltrexone ( an opioid antagonist ) for alcohol dependence in a sample of alcohol-dependent men . DESIGN A 12-week r and omized placebo-controlled clinical trial . SETTING The outpatient clinic of a combined war veteran and general teaching hospital in Melbourne , Australia . PARTICIPANTS Male alcohol-dependent subjects recruited from the community and from veteran groups . INTERVENTION Alcohol-dependent subjects were treated with 50 mg of naltrexone or placebo daily for 12 weeks . Both treatment groups attended a weekly education support group . Subjects were assessed weekly . MEASUREMENTS Primary study outcomes were the maintenance of abstinence and relapse to drinking . FINDINGS Fifty-five subjects were r and omized to naltrexone and 56 to placebo . Forty subjects did not complete 12 weeks of therapy ( 17 naltrexone , 23 placebo ) . In the intention-to-treat sample ( N = 111 ) fewer naltrexone treated subjects relapsed ( p = 0.001 ) . Among patients who completed the 12-week trial , naltrexone reduced the consumption of alcohol . Naltrexone was well tolerated and there were few adverse experiences . CONCLUSIONS These findings demonstrate that naltrexone is effective in preventing relapse to drinking in the setting of limited psychosocial treatment . Further studies should examine the duration of treatment needed to maintain the effect long term BACKGROUND Extended-release naltrexone ( XR-NTX ) is a once-a-month injectable formulation for the treatment of alcohol dependence previously shown to reduce drinking and heavy drinking relative to placebo ( Garbutt et al. , 2005 ) . A 24-week , r and omized , double-blind , placebo-controlled study established the efficacy and safety of XR-NTX in this patient population . In this report , the effect of XR-NTX on quality of life ( QOL ) was examined . METHODS Alcohol-dependent patients were r and omly assigned to receive XR-NTX 380 mg ( N = 205 ) , XR-NTX 190 mg ( N = 210 ) , or placebo ( N = 209 ) , combined with a st and ardized psychosocial intervention . QOL was assessed using the Medical Outcomes Study 36-item short-form health survey , administered at baseline and at 4-week intervals during 24 weeks of treatment . RESULTS Compared with U.S. population norms , patients showed initial impairment in the health-related QOL domains of mental health , social functioning , and problems with work or other daily activities due to emotional problems . Adherence to all 6 injections was 65 % for XR-NTX 190 mg , 63 % for XR-NTX 380 mg , and 64 % for placebo . Generalized estimating equations analyses using an intention-to-treat sample revealed that XR-NTX 380 mg was associated with significantly greater improvements from baseline in mental health ( p = 0.0496 ) , social functioning ( p = 0.010 ) , general health ( p = 0.048 ) , and physical functioning ( p = 0.028 ) , compared with placebo . Linear regression analyses revealed that reductions from baseline in drinking ( percentage of drinking days and percentage of heavy drinking days in the last 30 days ) were significantly ( p < 0.05 ) correlated with improvements in quality of life . CONCLUSION Extended-release naltrexone 380 mg in combination with psychosocial intervention was associated with improvements in QOL , specifically in the domains of mental health , social functioning , general health , and physical functioning Anticonvulsant agents show promise in the treatment of the acute symptoms of alcohol withdrawal and may also treat some symptoms associated with the protracted abstinence syndrome . Impulsivity , hostility and irritability are common characteristics of alcohol-dependent individuals , and there is some evidence that anticonvulsant agents decrease these traits in individuals with a number of different psychiatric disorders . This pilot study is a 12-week , double-blind , placebo-controlled trial of an anticonvulsant agent , divalproex ( DVPX ) , in alcohol-dependent individuals . Alcohol use ( Timeline Follow Back ) , impulsivity ( Barratt Impulsivity Scale ) , irritability and aggression ( Buss-Durkee Hostility Index ; and Anger , Irritability , Aggression Scale ) were measured at baseline and throughout the 12-week treatment period . Drinking decreased significantly in both the placebo and the DVPX-treated groups . In the DVPX group , a significantly smaller percentage of individuals relapsed to heavy drinking , but there were no significant differences in other alcohol-related outcomes . There were significantly greater decreases in irritability in the DVPX-treated group and a trend towards greater decreases on measures of lability and verbal assault . There were no significant between-group differences on measures of impulsivity . While DVPX did not have a robust effect on alcohol-related outcomes , it did have modest impact on a measure of irritability . This is consistent with the findings of other investigators exploring the use of DVPX in schizophrenia , personality disorder and a number of other psychiatric disorders Abstract : Although naltrexone has been shown to be effective in the treatment of alcohol dependence , less is known about its efficacy when combined with different behavioral therapies . Previous work has suggested that naltrexone works best when combined with weekly cognitive behavioral therapy ( CBT ) . This study examined the efficacy of naltrexone when combined with CBT or a motivational enhancement therapy involving less patient contact . Outpatient alcoholics ( N = 160 ) were r and omly assigned to either naltrexone ( 50 mg/d ) or placebo and either CBT ( 12 sessions ) or motivational enhancement therapy ( 4 sessions ) , in a 4-cell design , and treated over a 12-week period . Subjects were evaluated periodically for alcohol consumption , craving , and biologic markers of drinking ( carbohydrate-deficient transferrin and γ-glutamyltransferase ) . There was high retention and adherence to therapy and medication in the trial with no significant difference across the treatment groups . Naltrexone , independent of therapy assignment , increased the time to first relapse . However , the CBT-naltrexone group did better than the other groups on a variety of outcome measures . Fewer CBT-naltrexone-treated subjects relapsed , and those that did had both fewer , and more time between , subsequent relapses . This r and omized controlled trial is consistent with previous reports about the utility of combining naltrexone with CBT . Despite being more efficient to administer , the combination of motivational enhancement therapy and naltrexone is less effective than CBT and naltrexone . Because CBT and naltrexone share common mechanisms of action , such as craving reduction and relapse prevention , these therapies are likely to be well suited to use in combination BACKGROUND Disulfiram and naltrexone are approved by the Food and Drug Administration ( FDA ) for the treatment of alcoholism , but these agents have not been rigorously evaluated in dually diagnosed individuals . METHOD Two-hundred and fifty-four patients with an Axis I psychiatric disorder and comorbid alcohol dependence were treated for 12 weeks in an outpatient medication study conducted at three Veterans Administration outpatient clinics . R and omization included assignment to one of four groups : 1 ) naltrexone alone ; 2 ) placebo alone ; 3 ) ( open-label ) disulfiram and ( blinded ) naltrexone ; or 4 ) ( open-label ) disulfiram and ( blinded ) placebo . Medication compliance was evaluated using the Microelectric Events Monitoring System . Primary outcomes were measures of alcohol use . Secondary outcomes included psychiatric symptoms , alcohol craving , g-GGT levels and adverse events . RESULTS There was a high rate of abstinence across groups . Subjects treated with an active medication had significantly more consecutive weeks of abstinence and less craving than those treated with placebo , but there were no significant group differences in other measures of alcohol consumption . There was no advantage of the combination of both medications . CONCLUSIONS These data suggest a modest advantage for the use of disulfiram and naltrexone for this group of dually diagnosed alcohol-dependent individuals but did not suggest an advantage in the combination Background : The COMBINE ( combined pharmacotherapies and behavioral intervention ) clinical trial recently evaluated the efficacy of pharmacotherapies , behavioral therapies , and their combinations for the treatment of alcohol dependence . Previously , the cost and cost-effectiveness of COMBINE have been studied . Policy makers , patients , and nonalcohol-dependent individuals may be concerned not only with alcohol treatment costs but also with the effect of alcohol interventions on broader social costs and outcomes . Objectives : To estimate the sum of treatment costs plus the costs of health care utilization , arrests , and motor vehicle accidents for the 9 treatments in COMBINE 3 years postr and omization . Research Design : A cost study based on a r and omized controlled clinical trial . Subjects : The study involved 786 participants 3 years postr and omization . Results : Multivariate results show no significant differences in mean costs between any of the treatment arms as compared with medical management ( MM ) + placebo for the 3-year postr and omization sample . The median costs of MM + acamprosate , MM + naltrexone , MM + acamprosate + naltrexone , and MM + acamprosate + combined behavioral intervention were significantly lower than the median cost for MM + placebo . Conclusions : The results show that social cost savings are generated relative to MM + placebo by 3 years postr and omization , and the magnitude of these cost savings is greater than the costs of the COMBINE treatment received 3 years prior . Our study suggests that several alcohol treatments may indeed lead to reduced median social costs associated with health care , arrests , and motor vehicle accidents |
13,648 | 25,858,345 | Rivastigmine ( 6 to 12 mg daily orally or 9.5 mg daily transdermally ) appears to be beneficial for people with mild to moderate Alzheimer 's disease .
In comparisons with placebo , better outcomes were observed for rate of decline of cognitive function and activities of daily living , although the effects were small and of uncertain clinical importance .
There was also a benefit from rivastigmine on the outcome of clinician 's global assessment .
There were no differences between the rivastigmine group and placebo group in behavioural change or impact on carers .
At these doses the transdermal patch may have fewer side effects than the capsules but has comparable efficacy . | BACKGROUND Alzheimer 's disease is the commonest cause of dementia affecting older people .
One of the therapeutic strategies aim ed at ameliorating the clinical manifestations of Alzheimer 's disease is to enhance cholinergic neurotransmission in the brain by the use of cholinesterase inhibitors to delay the breakdown of acetylcholine released into synaptic clefts .
Tacrine , the first of the cholinesterase inhibitors to undergo extensive trials for this purpose , was associated with significant adverse effects including hepatotoxicity .
Other cholinesterase inhibitors , including rivastigmine , with superior properties in terms of specificity of action and lower risk of adverse effects have since been introduced .
Rivastigmine has received approval for use in 60 countries including all member states of the European Union and the USA .
OBJECTIVES To determine the clinical efficacy and safety of rivastigmine for patients with dementia of Alzheimer 's type . | BACKGROUND Treatment with cholinesterase inhibitors improves cognition in patients with Alzheimer disease ( AD ) . In studies design ed with a washout period at the end of the study , after treatment with a cholinesterase inhibitor is discontinued , the cognitive benefits of therapy are no longer apparent following washout . The rivastigmine trials discussed in this article were not design ed with a posttreatment washout period at the end of the study . Therefore , to evaluate the effect of discontinuing treatment , we analyzed the retrieved dropout ( RDO ) population . OBJECTIVE To evaluate the change in cognition ( at week 26 vs baseline ) observed in patients from 3 large clinical trials of AD who prematurely discontinued treatment with placebo or rivastigmine . DESIGN AND METHODS Eligible patients with AD ( Mini-Mental State Examination [ MMSE ] score , 10 - 26 , inclusive ) were enrolled in 1 of three 26-week , double-blind , placebo-controlled studies ( Novartis US Pivotal [ dose-range ] Trial , US fixed-dose study , and a Global Pivotal [ dose-range ] Trial ) that compared rivastigmine therapy with placebo . Patients who discontinued study participation ( for any reason ) ( considered to be the RDO population ) were encouraged to return for their scheduled week 26 efficacy evaluations . Effects on cognition were assessed using the Alzheimer 's Disease Assessment Scale-Cognitive subscale ( ADAS-Cog ) . RESULTS The results for the Novartis US Pivotal Trials and for the 3 studies combined ( Novartis studies B352 , B351 , and B303 ) are reported . In the US pivotal trial , RDO patients in the 6- to 12-mg/d group had been not receiving the drug ( to be called " off drug " ) for 102 ( 57.7 ) days ( mean [ SD ] ) compared with 68 ( 51.7 ) days in the RDO placebo group . In these RDO analyses , a statistically significantly greater worsening on the ADAS-Cog mean change score was observed in the placebo group ( n = 17 ) compared with the rivastigmine 6- to 12-mg/d group ( n = 33 ) at week 26 ( MMSE score , -8.2 vs -3.0 ; P = .009 ) . In the pooled studies , the mean ( SD ) number of days off treatment was 95 ( 52.0 ) days for the rivastigmine 6- to 12-mg/d group and 66 ( 52.7 ) days for the placebo group . The RDO analysis also showed a statistically significantly greater decline in cognitive function as measured by the ADAS-Cog mean change score in the placebo group ( n = 38 ) compared with the rivastigmine 6- to 12-mg/d group ( n = 88 ) at week 26 ( MMSE score , -5.69 vs -2.5 ; P = .004 ) . A significantly greater proportion of patients in the placebo group exhibited at least a 4-point and 7-point worsening in ADAS-Cog scores at week 26 compared with the rivastigmine 6- to 12-mg/d group in both the Novartis US Pivotal Trials ( P = .007 , P = .009 ) and the pooled studies ( P = .002 , P = .017 ) . CONCLUSIONS After discontinuation of therapy , rivastigmine-treated patients exhibited less deterioration in cognitive function compared with placebo-treated patients . The less severe worsening of cognition after withdrawal of treatment in patients previously treated with rivastigmine suggests an effect on disease progression OBJECTIVE To develop a simple , readily administered and scored screening test for dementia utilizing the clock-drawing task . DESIGN Retrospective analysis of clock-drawing errors and prospect i ve validations . SETTING Hospital-based outpatient geriatric assessment clinic , rehabilitation service , apartment building for older adults , and long-term care facility . PARTICIPANTS Convenience sample of patients attending the geriatric assessment clinic , patients on the rehabilitation service , or residents of the above sites . MEASUREMENTS Sensitivity and specificity of a clock-scoring system in identifying patients with dementia and the comparison of this system with the Short Blessed Test ( SBT ) in the diagnosis of dementia and in the prospect i ve validation of the test . RESULTS Of the 10 clock-drawing errors evaluated , placement of digits in a pre-drawn circle had the greatest sensitivity and specificity in distinguishing patients with irreversible dementia from patients with other disorders who did not meet NINCDS-ADRDA criteria for probable dementia . The derived scoring system had a sensitivity of 87 % and a specificity of 82 % , compared with a sensitivity of 82 % and a specificity of 88 % for the SBT in identifying dementia . Test-retest reliability for the distinction between demented and non-demented was 82 % , with a Kappa of 0.63 for the clock completion , and 82 % , with a Kappa of 0.62 for the SBT . Inter-rater reliability for clock completion was 0.90 to 0.93 . CONCLUSION A simple , completely objective scoring system for a clock completion test has been developed which involves only the number of digits placed in the fourth quadrant of a pre-drawn circle . This readily administered test is as effective in screening for dementia as the longer six-item SBT Most cost-effectiveness studies using simulation modeling have demonstrated that donepezil , rivastigmine , and galantamine are cost effective for the treatment of mild-to-moderate Alzheimer disease ( AD ) . These conclusions are in large part based on the assumption that improvement in cognitive status , or prevention of cognitive and functional decline , reduces the amount of time patients spend institutionalized or receiving other full-time care . However , as discussed in this article , outcomes besides delay to institutionalization affect the costs of AD . In review s of utilization data from Medicare and managed care organizations , it was noted that hospitalization and post acute care in skilled nursing facilities accounted for the largest amount of excess direct costs , even among patients with mild or moderate AD . These utilization review s also suggest that many patients with AD and related dementias require inpatient care because they are not able to self-manage comorbid conditions . The improvements in cognitive status and daily functioning associated with acetylcholinesterase inhibitor ( AChEI ) therapy are expected to translate into improved management of comorbidities and reduced caregiver burden , thus reducing the total cost of care . To confirm these and other economic benefits of AChEIs , pharmacoeconomic outcomes should be evaluated routinely as part of r and omized , controlled trials and through well-controlled observational studies of AD patients in community and institutional setting BACKGROUND Although less likely to be reported in clinical trials than expressions of the statistical significance of differences in outcomes , whether or not a treatment has delivered a specified minimum clinical ly important difference ( MCID ) is also relevant to patients and their caregivers and doctors . Many dementia treatment r and omised controlled trials ( RCTs ) have not reported MCIDs and , where they have been done , observed differences have not reached these . METHODS As part of the development of the Statistical Analysis Plan for the DOMINO trial , investigators met to consider expert opinion- and distribution-based values for the MCID and triangulated these to provide appropriate values for three outcome measures , the St and ardised Mini-mental State Examination ( sMMSE ) , Bristol Activities of Daily Living Scale ( BADLS ) and Neuropsychiatric Inventory ( NPI ) . Only st and ard deviations ( SD ) were presented to investigators who remained blind to treatment allocation . RESULTS Adoption of values for MCIDs based upon 0.4 of the SD of the change in score from baseline on the sMMSE , BADLS and NPI in the first 127 participants to complete DOMINO yielded MCIDs of 1.4 points for sMMSE , 3.5 for BADLS and 8.0 for NPI . CONCLUSIONS Reference to MCIDs is important for the full interpretation of the results of dementia trials and those conducting such trials should be open about the way in which they have determined and chosen their values for the MCIDs This article reports the development and psychometric properties of the Alzheimer 's Disease Cooperative Study - Clinical Global Impression of Change ( ADCS-CGIC ) . At present , a number of unvali date d CGIC scales are used in clinical trials , with various methods for making ratings . The ADCS-CGIC was design ed on the basis of a survey of ADCS clinicians and by adapting existing instruments . It includes an organized but unstructured format , with which a clinician can address clinical ly relevant change . The instrument 's reliability and validity were assessed in a prospect i ve trial of Alzheimer 's disease ( AD ) and healthy subjects over a 12-month period . It showed good short-term reliability at 1 and 2 months , with 90 and 94 % of AD subjects , respectively , rated as having changed not at all or only minimally . The ADCS-CGIC 's face validity was demonstrated by untreated . AD subjects rated as having worsened over time at both 6 months ( 56 % rated as having worsened ) and 12 months ( 81 % rated as having worsened ) , whereas only 2 % of control subjects showed minimal worsening . As a measure of predictive validity , ADCS-CGIC ratings at 12 months were significantly associated with change on four severity scales . As with other measures , change ratings were sensitive to dementia severity . Moderately impaired subjects showed greater worsening than other subjects . ADCS-CGIC ratings of greater worsening were made after the informant interview , regardless of whether informants or subjects were interviewed first . The ADCS-CGIC is a valid and reliable instrument for use in clinical trials OBJECTIVE To estimate per-patient potential cost savings using rivastigmine in the treatment of Alzheimer 's disease ( AD ) in Canada . BACKGROUND In recent years , new members of a class of pharmaceuticals known as cholinesterase inhibitors have been introduced for the treatment of patients with AD . Two recent studies conducted in the United Kingdom and the United States estimated potential cost savings from the new cholinesterase inhibitor rivastigmine . The present study combined the disease-progression model used in those 2 studies with Canadian costs to estimate per-patient potential savings result ing from the treatment of AD in Canada . METHODS Efficacy data from 2 pivotal , phase III clinical trials of rivastigmine were used in a hazard model of disease progression to estimate long-term differences in cognitive functioning between patients receiving rivastigmine and patients receiving no treatment . We used the Mini-Mental State Examination ( MMSE ) score as our measure of disease progression . We also used Canadian costs of AD care , estimated as a function of MMSE score , to estimate cost savings experienced by treated patients compared with patients receiving no treatment . All costs and cost savings are presented in 1997 Canadian dollars . We used a societal perspective in this analysis . RESULTS Rivastigmine was estimated to delay the transition to more severe stages of AD by up to 188 days for patients with mild AD after 2 years of treatment . For patients with mild-to-moderate and moderate disease , this delay was estimated to be 106 and 44 days , respectively . For patients with the mild stage of AD , estimated average daily cost savings ( excluding the cost of rivastigmine ) ranged from Can $ 0.45 per patient per day at 6 months to Can $ 6.44 per patient per day after 2 years of treatment . For all patients , these estimated average daily cost savings ranged from a low of Can $ 0.71 per patient per day after 6 months of treatment to a high of Can $ 4.93 per patient per day after 2 years . CONCLUSION On average , treatment with rivastigmine yields savings in the direct cost of caring for AD patients that exceed the cost of the drug after 2 years of treatment Rivastigmine has demonstrated significant benefits in patients with mild to moderate Alzheimer 's disease ( AD ) . We aim ed to confirm whether rivastigmine was effective in patients with or without concurrent vascular risk factors ( VRF ) , as previously suggested . We chose to stratify the 725 patients involved in an international dose-ranging study according to the presence of arterial hypertension ( a marker of VRF ) at baseline . Efficacy in each subgroup was assessed using the ADAS-cog , a measure of cognitive performance , the Progressive Deterioration Scale ( PDS ) and the Clinician 's Interview-Based Impression of Change ( CIBIC ) with caregiver input . Patients receiving rivastigmine 6 - 12 mg/day showed better outcomes on the ADAS-cog than those receiving placebo , in both the hypertensive and non-hypertensive subgroups . Hypertensive patients receiving rivastigmine 6 - 12 mg/day also showed improvement over those receiving 1 - 4 mg/day ( p = 0.023 ) . Rivastigmine 6 - 12 mg/day also provided better outcomes than placebo on the PDS in the hypertensive ( p = 0.031 ) and non-hypertensive ( p = 0.035 ) subgroups . All patients receiving rivastigmine 6 - 12 mg/day had superior CIBIC-plus scores than those receiving placebo . There was a trend for lower incidences of nausea and vomiting in rivastigmine-treated patients with hypertension than in those without hypertension . No cardiac adverse events or drug-drug interactions were reported . Our data support the hypothesis that rivastigmine provides benefits to patients with or without hypertension , and contribute to the evidence that particular benefits may be observed in those with vascular risk factors |
13,649 | 24,793,445 | Sensitivity analyses using different values for the Intra-cluster coefficient ( ICC ) did not substantially alter the magnitude or significance of summary effect sizes .
All four domains of the conceptual framework were addressed , suggesting agreement on core components of cultural competence education interventions may be possible .
There was positive , albeit low- quality evidence , showing improvements in the involvement of CALD patients .
Findings either showed support for the educational interventions or no evidence of effect . | BACKGROUND Cultural competence education for health professionals aims to ensure all people receive equitable , effective health care , particularly those from culturally and linguistically diverse ( CALD ) background s. It has emerged as a strategy in high-income English-speaking countries in response to evidence of health disparities , structural inequalities , and poorer quality health care and outcomes among people from minority CALD background s. However there is a paucity of evidence to link cultural competence education with patient , professional and organisational outcomes .
OBJECTIVES To assess the effects of cultural competence education interventions for health professionals on patient-related outcomes , health professional outcomes , and healthcare organisation outcomes .
AUTHORS ' CONCLUSIONS Cultural competence continues to be developed as a major strategy to address health inequities . | BACKGROUND Increasing clinician awareness of racial disparities and improving communication may enhance diabetes care among black patients . OBJECTIVE To evaluate the effect of cultural competency training and performance feedback for primary care clinicians on diabetes care for black patients . DESIGN Cluster r and omized , controlled trial conducted between June 2007 and May 2008 . ( Clinical Trials.gov registration number : NCT00436176 ) SETTING : 8 ambulatory health centers in eastern Massachusetts . PARTICIPANTS 124 primary care clinicians caring for 2699 ( 36 % ) black and 4858 ( 64 % ) white diabetic patients . INTERVENTION INTERVENTION clinicians received cultural competency training and monthly race-stratified performance reports that highlighted racial differences in control of hemoglobin A(1c ) ( HbA(1c ) ) and low-density lipoprotein ( LDL ) cholesterol levels and blood pressure . MEASUREMENTS Clinician awareness of racial differences in diabetes care and rates of achieving clinical control targets among black patients at 12 months . RESULTS White and black patients differed significantly in baseline rates of achieving an HbA(1c ) level less than 7 % ( 46 % vs. 40 % ) , an LDL cholesterol level less than 2.59 mmol/L ( < 100 mg/dL ) ( 55 % vs. 43 % ) , and blood pressure less than 130/80 mm Hg ( 32 % vs. 24 % ) ( all P < 0.050 ) . At study completion , intervention clinicians were significantly more likely than control clinicians to acknowledge the presence of racial disparities in the 8 health centers as a whole ( 82 % vs. 59 % ; P = 0.003 ) , within their local health center ( 70 % vs. 51 % ; P = 0.020 ) , and among their own patients ( 63 % vs. 43 % ; P = 0.037 ) . Black patients of clinicians in the intervention and control groups did not differ at 12 months in rates of controlling HbA(1c ) level ( 48 % vs. 45 % ; P = 0.24 ) , LDL cholesterol level ( 48 % vs. 49 % ; P = 0.40 ) , or blood pressure ( 23 % vs. 25 % ; P = 0.47 ) . LIMITATION 11 % of primary care teams did not attend cultural competency training sessions . CONCLUSION The combination of cultural competency training and race-stratified performance reports increased clinician awareness of racial disparities in diabetes care but did not improve clinical outcomes among black patients As the percentage of older adults of diverse ethnicities increases in the United States , the call for culturally sensitive health care service strategies that target the special needs of older people grows . The present report describes methods used to adapt a health care program so that it would better meet the needs of a group of well , older M and arin-speaking Chinese residents of Los Angeles . The specific qualitative research procedures that we used to adapt the treatment program are described , along with the particular adaptations that emerged . Additionally , outcomes from a r and omized pilot experiment are presented that are consistent with the notion that the adapted program was effective in reducing health-related declines among older M and arin-speaking men and women . The overall outcome of this project is in agreement with other reports in the health care literature that address the importance of providing culturally sensitive health care service for elders Objectives . Aboriginal communities have a high prevalence of diabetes and heart disease , and limited re sources to address them . The objective of this study was to test the effectiveness of prioritizing care with audit and feedback on cholesterol management of diabetic patients . Study design . A controlled before-after intervention trial was conducted among health care providers in Oji-Cree reserves in Sioux Lookout Zone , Ontario . Two communities were r and omized to receive an interactive educational workshop and chart audit with feedback on cholesterol management ; 2 control communities received usual care . Methods . The primary outcome measure used was the proportion of patients on statins , and the secondary outcome measure was the proportion of patients with LDL>2.5 mmol/L or TC/HDL>4.0 on statins . Outcomes were assessed by chart review at baseline and 10 months post-intervention . Results . Patients in the 2 intervention communities ( n=170 ) and the 2 controls ( n=170 ) were comparable at baseline . The intervention did not increase the proportion of diabetic patients on statins overall or in the subset of patients with elevated cholesterol . The proportion of patients with elevated cholesterol on statins went from 46 % to 53 % ( p=0.48 ) in the intervention group and from 47 % to 50 % ( p=0.25 ) in the control group . Conclusions . Audit and feedback listing patients requiring treatment did not increase statin prescription rates in diabetic patients in remote Aboriginal setting s. This may be due to elevated baseline rates , the low intensity of feedback and the constraints of the practice environment , such as low staffing and high staff turnover INTRODUCTION Although depression can be treated effectively with Cognitive Behaviour Therapy ( CBT ) , only a small percentage of Chinese Australians access evidence -based treatment due to practical and cultural barriers . The present study examined the efficacy and acceptability of an Internet delivered CBT ( iCBT ) program to treat Chinese Australians with depression . METHODS The Chinese depression iCBT program ( the Brighten Your Mood Program ) is a culturally adapted version of the clinical ly efficacious Sadness iCBT Program . Fifty-five Chinese Australians with depression were r and omly allocated to either an immediate treatment group or to a waitlist control group . Treatment consisted of an 8 week program with 6 CBT online educational lessons , homework assignments , additional re sources presented in Chinese and English , and weekly telephone support with M and arin/Cantonese-speaking support personnel . An intention-to-treat model was used for data analyses . RESULTS Seventeen of twenty-five ( 68 % ) treatment group participants completed all lessons within the timeframe . Compared to controls , treatment group participants reported significantly reduced symptoms of depression on the Chinese versions of the Beck Depression Inventory ( CBDI ) and Patient Health Question naire-9 item ( CB-PHQ-9 ) . The within- and between-group effect sizes ( Cohen 's d ) were 1.41 and 0.93 on the CBDI , and 0.90 and 0.50 on the CB-PHQ-9 , respectively . Participants rated the procedure as acceptable , and gains were sustained at three-month follow-up . LIMITATIONS The study included several sub clinical participants and some measures that have not been previously vali date d with Chinese Australians . CONCLUSIONS Results provide preliminary support for the efficacy and acceptability of an iCBT program at reducing symptoms of depression in Chinese Australians BACKGROUND To investigate the feasibility and effectiveness of a needs-led , community-based intervention for treating individuals from black minority ethnic ( BME ) groups with common mental disorders . METHOD Forty eligible individuals from BME groups were r and omised to a needs-led package of care ( therapy based on the principles of cognitive behaviour therapy and ethnically matched therapists , advocacy and mentoring ; ' rapid access ' ) or to a 3-month waiting list control with information on local mental health services ( ' st and ard access ' ) . RESULTS At 3-month follow-up , individuals in the rapid access group showed significantly improved levels of depression ( GHQ-28 adjusted p<0.05 ) although there was no evidence for difference in general functioning ( GAF , p=0.87 ) . The intervention was found to be culturally appropriate and acceptable among users and did not result in significantly increased costs . LIMITATIONS The exploratory study sample was small with low power and therefore the statistical certainty may be limited . CONCLUSIONS Effective and culturally acceptable psychosocial interventions can be delivered in the community to individuals from BME groups with anxiety and depression with no significant cost implication Introduction : Although numerous studies have examined cultural competence training , debate still exists about efficacious approaches to this training . Furthermore , little focus has been placed on training and evaluating practicing physicians . Methods : A skills‐based course on culturally competent diabetes care was developed and subsequently tested in a controlled trial of primary physicians caring for patients enrolled in one state 's Medicaid program . We hypothesized that physicians completing the course would show higher levels of self‐reported cultural competence as measured by a Cultural Competence Assessment Tool ( CCAT ) than those in the control group . Differences in CCAT subscale scores were also compared . Results : Ninety physicians completed the study , with 41 in the control and 49 in the intervention group . Most were female ( 66 % ) , with an average age of 44 , and 12 years in practice . There were no significant differences on total CCAT score ( 212.7 ± 26.7 for control versus 217.2 ± 28.6 for intervention , p = .444 ) or subscales measuring cultural knowledge . There were significant positive differences on the subscales measuring physicians ' nonjudgmental attitudes/behaviors ( subscale score 2.38 ± 0.46 for control versus 2.69 ± 0.52 for intervention , p = .004 ) and future likelihood of eliciting patients ' beliefs about diabetes and treatment preferences ( 3.11 ± 0.53 for control versus 3.37 ± 0.45 for intervention , p = .014 ) . There was , however , a significant negative difference on the subscale measuring cultural self‐awareness ( 3.48 ± 0.36 for control versus 3.26 ± 0.48 for intervention , p = .018 ) . Discussion : A predominantly skills‐based approach to training physicians did not change aggregate measures of cultural competence , but did affect key attitudes and behaviors , which may better reflect the goals of cultural competence training BACKGROUND Patient navigators may increase colorectal cancer ( CRC ) screening rates among adults in underserved communities , but prior r and omized trials have been small or conducted at single sites and have not included substantial numbers of Haitian Creole-speaking or Portuguese-speaking patients . METHODS We identified 465 primary care patients from 4 community health centers and 2 public hospital-based clinics who were not up-to- date with CRC screening and spoke English , Haitian Creole , Portuguese , or Spanish as their primary language . We enrolled participants from September 1 , 2008 , through March 31 , 2009 , and followed them up for 1 year after enrollment . We r and omly allocated patients to receive a patient navigation-based intervention or usual care . Intervention patients received an introductory letter from their primary care provider with educational material , followed by telephone calls from a language -concordant navigator . The navigators offered patients the option of being screened by fecal occult blood testing or colonoscopy . The primary outcome was completion of any CRC screening within 1 year . Secondary outcomes included the proportions of patients screened by colonoscopy who had adenomas or cancer detected . RESULTS During a 1-year period , intervention patients were more likely to undergo CRC screening than control patients ( 33.6 % vs 20.0 % ; P < .001 ) , to be screened by colonoscopy ( 26.4 % vs 13.0 % ; P < .001 ) , and to have adenomas detected ( 8.1 % vs 3.9 % ; P = .06 ) . In prespecified subgroup analyses , the navigator intervention was particularly beneficial for patients whose primary language was other than English ( 39.8 % vs 18.6 % ; P < .001 ) and black patients ( 39.7 % vs 16.7 % ; P = .004 ) . CONCLUSIONS Patient navigation increased completion of CRC screening among ethnically diverse patients . Targeting patient navigation to black and non-English-speaking patients may be a useful approach to reducing disparities in CRC screening . TRIAL REGISTRATION clinical trials.gov Identifier : NCT01141114 PURPOSE The purpose of this study was to examine the effects of a cultural competence improvement program for maternity nurses . METHODS A quasi-experimental study using a non-equivalent control group pre and posttest design was used . Participants were 67 maternity nurses caring for multicultural pregnant women in G city . The cultural competence improvement program was developed based on the 3-D Puzzle Model and was provided using case-based small group learning methods for the experimental group ( n=31 ) . The control group ( n=36 ) did not receive any intervention . Data were collected using self-report structured question naires at two time points : prior to the intervention and after the intervention and were analyzed with descriptive statistics , χ²-test , and t-test . RESULTS Compared to the control group , the experimental group reported significant positive changes for cultural knowledge ( t=6.39 , p<.001 ) , cultural awareness ( t=3.50 , p<.001 ) , and cultural acceptance ( t=4.08 , p<.001 ) . However , change in cultural nursing behaviors ( t=0.92 , p=.067 ) was not significantly different between the two groups . CONCLUSION Findings from this study indicate that a cultural competence improvement program with case-based small group learning is a useful intervention strategy to promote multicultural maternity care . Further , strategies to improve cultural nursing behavior should be developed to promote culturally congruent nursing care OBJECTIVE Demonstrate the effective use of community-based evidence for health promotion by Lady Health Workers ( LHWs ) in Sindh , Pakistan . METHODS A baseline study on mothers and children provided local evidence for risk communication tools design ed and tested by LHWs . The communities were r and omized to intervention and control . LHWs visited women before and after childbirth to discuss safe practice s in pregnancy , in the intervention group LHW using the new tools and in the control group using their st and ard procedures . A household survey and focus groups permitted assessment of the impact of the intervention . RESULTS Women in the intervention communities were more likely to attend prenatal checkups , to stop routine heavy work during pregnancy , to give colostrum to newborn babies , and to maintain exclusive breastfeeding for four months . Community focus groups confirmed a positive reaction to the tools . CONCLUSION Discussion by lay health workers of local evidence underlying safe motherhood messages improved uptake of protective health practice s. PRACTICE IMPLICATION S Door-to-door health promotion based on culturally appropriate interaction around relevant evidence can have a positive impact on health practice s. Engaging health workers from the onset builds capacities , improves dialogue within the health system and performance of frontline health workers CONTEXT Despite unambiguous legal regulation and evidence for lack of effectiveness and safety , physical restraints are still frequently administered in nursing homes . OBJECTIVE To reduce physical restraint prevalence in nursing homes using a guideline - and theory-based multicomponent intervention . DESIGN , SETTING , AND PARTICIPANTS Cluster r and omized controlled trial of 6 months ' duration conducted in 2 German cities between February 2009 and April 2010 . Nursing homes were eligible if they had 20 % or more residents with physical restraints . Using external concealed r and omization , 18 nursing home clusters were included in the intervention group ( 2283 residents ) and 18 in the control group ( 2166 residents ) . INTERVENTION The intervention was based on a specifically developed evidence -based guideline and applied the theory of planned behavior . Components were group sessions for all nursing staff ; additional training for nominated key nurses ; and supportive material for nurses , residents , relatives , and legal guardians . Control group clusters received st and ard information . MAIN OUTCOMES MEASURES Primary outcome was percentage of residents with physical restraints ( bilateral bed rails , belts , fixed tables , and other measures limiting free body movement ) at 6 months , assessed through direct unannounced observation by blinded investigators on 3 occasions during 1 day . Secondary outcomes included restraint use at 3 months , falls , fall-related fractures , and psychotropic medication prescriptions . RESULTS All nursing homes completed the study and all residents were included in the analysis . At baseline , 30.6 % of control group residents had physical restraints vs 31.5 % of intervention group residents . At 6 months , rates were 29.1 % vs 22.6 % , respectively , a difference of 6.5 % ( 95 % CI , 0.6 % to 12.4 % ; cluster-adjusted odds ratio , 0.71 ; 95 % CI , 0.52 to 0.97 ; P = .03 ) . All physical restraint measures were used less frequently in the intervention group . Rates were stable from 3 to 6 months . There were no statistically significant differences in falls , fall-related fractures , and psychotropic medication prescriptions . CONCLUSION A guideline - and theory-based multicomponent intervention compared with st and ard information reduced physical restraint use in nursing homes . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N34974819 Background Disparities in health and healthcare are extensively documented across clinical conditions , setting s , and dimensions of healthcare quality . In particular , studies show that ethnic minorities and persons with low socioeconomic status receive poorer quality of interpersonal or patient-centered care than whites and persons with higher socioeconomic status . Strong evidence links patient-centered care to improvements in patient adherence and health outcomes ; therefore , interventions that enhance this dimension of care are promising strategies to improve adherence and overcome disparities in outcomes for ethnic minorities and poor persons . Objective This paper describes the design of the Patient-Physician Partnership ( Triple P ) Study . The goal of the study is to compare the relative effectiveness of the patient and physician intensive interventions , separately , and in combination with one another , with the effectiveness of minimal interventions . The main hypothesis is that patients in the intensive intervention groups will have better adherence to appointments , medication , and lifestyle recommendations at three and twelve months than patients in minimal intervention groups . The study also examines other process and outcome measures , including patient-physician communication behaviors , patient ratings of care , health service utilization , and blood pressure control . Methods A total of 50 primary care physicians and 279 of their ethnic minority or poor patients with hypertension were recruited into a r and omized controlled trial with a two by two factorial design . The study used a patient-centered , culturally tailored , education and activation intervention for patients with active follow-up delivered by a community health worker in the clinic . It also included a computerized , self- study communication skills training program for physicians , delivered via an interactive CD-ROM , with tailored feedback to address their individual communication skills needs . Conclusion The Triple P study will provide new knowledge about how to improve patient adherence , quality of care , and cardiovascular outcomes , as well as how to reduce disparities in care and outcomes of ethnic minority and poor persons with hypertension BACKGROUND Due to worldwide migration to Western countries , physicians are increasingly encountering patients with different ethnic background s. Communication problems can arise as a result of differences in cultural background s and poor language proficiency . AIMS To assess the effectiveness of an educational intervention on intercultural communication aim ed to decrease inequalities in care provided between Western and non-Western patients . DESIGN OF STUDY A r and omised controlled trial with r and omisation at the GP level and outcome measurements at the patient level . SETTING General practice in Rotterdam . METHOD Thirty-eight Dutch GPs in the Rotterdam region , with at least 25 % of inhabitants of non-Western origin , and 2407 visiting patients were invited to participate in the study . A total of 986 consultations were finally included . The GPs were educated about cultural differences and trained in intercultural communication . Patients received a videotaped instruction focusing on how to communicate with their GP in a direct way . The primary outcome measure was mutual underst and ing and the secondary outcomes were patient 's satisfaction and perceived quality of care . The intervention effect was assessed for all patients together , for the ' Western ' and ' non-Western ' patients , and for patients with different cultural background s separately . RESULTS An intervention effect was seen 6 months after the intervention , as improvement in mutual underst and ing ( and some improvement in perceived quality of care ) in consultations with ' non-Western ' patients . CONCLUSIONS A double intervention on intercultural communication given to both physician and patient decreases the gap in quality of care between ' Western ' and ' non-Western ' patients BACKGROUND AND OBJECTIVES Increased cultural competence is a tool in the fight to eliminate health disparities in people with diabetes . However , questions remain regarding the best cultural competence teaching , evaluation , and dissemination methods . An Internet-based approach requires less facilitator time and provides greater ease of dissemination . We developed and tested a skills-focused , Internet-based course on cultural competence in the context of type 2 diabetes . METHODS To test the effectiveness of the course , a r and omized controlled trial was conducted on a national sample of 122 family medicine residents . The primary outcome was measured by changes in score on the Cultural Competence Assessment Tool ( CCAT ) , a new self- assessment tool developed for this study . RESULTS Total CCAT score increased significantly after the completion of the Internet course for 58 residents in the experimental group ( 83.55 before the course , 192.09 after the course ) but did not change for the 64 residents in the control group ( 177.58 at baseline , 177.84 at end of study ) . On multivariate analysis , the only significant predictor of total CCAT score change was having taken the online course . CONCLUSIONS A skills-based course on cultural competence , delivered via the Internet , is an effective educational strategy . It has potential for dissemination of st and ardized content OBJECTIVE To test the hypothesis that a 20-h communication skills course based on the Four Habits model can improve doctor-patient communication among hospital employed doctors across specialties . METHODS Crossover r and omized controlled trial in a 500-bed hospital with interventions at different time points in the two arms . Assessment s were video-based and blinded . Intervention consisted of 20 h of communication training , containing alternating plenary with theory/debriefs and practical group sessions with role-plays tailored to each doctor . RESULTS Of 103 doctors asked to participate , 72 were included , 62 received the intervention , 51 were included in the main analysis , and another six were included in the intention-to-treat analysis . We found an increase in the Four Habits Coding Scheme of 7.5 points ( p = 0.01 , 95 % confidence interval 1.6 - 13.3 ) , fairly evenly distributed on subgroups . Baseline score ( SD ) was 60.3 ( 9.9 ) . Global patient satisfaction did not change , neither did average encounter duration . CONCLUSION Utilizing an outpatient-clinic training model developed in the US , we demonstrated that a 20-h course could be generalized across medical and national cultures , indicating improvement of communication skills among hospital doctors . PRACTICE IMPLICATION S The Four Habits model is suitable for communication-training courses in hospital setting s. Doctors across specialties can attend the same course An urgent need to improve Swedish primary child health-care nurses ' cultural competence was revealed by previous research among nurses working in , and immigrant parents visiting , primary child health-care services . The aim of this study was to evaluate the extent to which specific training affected how nurses rated their own cultural competence , difficulties , and concerns and to study how the nurses evaluated the training . Conducted as a r and omized controlled trial , the effects on a study sample of 51 nurses were assessed by question naires in a pre- and post- study design . The findings indicated that the 3 days of training were appreciated by the nurses and had some effects on their cultural competence , difficulties , and concerns . The training might have had positive effects on the nurses ' working conditions as they rated it to have an impact on their ability to cope with the dem and s of their work activities in the health services . These effects are presumed to contribute to an improved quality of the health services , with a reduction in the risk for health-care disparities among children of immigrant parents BACKGROUND There is sufficient research evidence in favour of cognitive therapy in western world . However , only limited research has been carried out on its effectiveness in other countries . It is suggested that adaptations in content , format and delivery are needed before CBT can be employed in non-western cultures . We describe a preliminary evaluation of culturally adapted CBT for depression in Pakistan . AIMS We aim ed to evaluate the efficacy of this culturally adapted CBT using a therapist manual . METHOD In a r and omized controlled trial we compared combination of CBT and antidepressants with antidepressants alone ( treatment as usual ) in primary care . Referred patients with ICD-10 diagnosis of depression were invited to participate and r and omized to the intervention and control groups . Hospital Anxiety and Depression Scale ( HADS ) and Bradford Somatic Inventory ( BSI ) were used to measure changes in depression , anxiety and somatic symptoms . RESULTS Seventeen patients each were r and omized to each arms of the trial . Except for financial status there were no differences between the two groups on various demographic variables . Patients receiving CBT showed statistically significant improvement on measures of depression ( p < .001 ) , anxiety ( p < .001 ) and somatic symptoms ( p < .000 ) as compared to antidepressant alone group . 82 % patients attended six or more sessions of therapy . CONCLUSIONS A culturally sensitive manualized CBT was effective in reducing symptoms of depression and anxiety in Pakistan OBJECTIVES Cluster r and omised trials , in which groups of individuals are r and omised , are increasingly being used in the health field . Adopting a clustered approach has implication s for the design of such trials , and sample size calculations need to be inflated to accommo date for the clustering effect . Reliable estimates of intracluster correlation coefficients ( ICCs ) are required for robust sample size calculations to be made ; however , little empirical evidence is available on their likely size , and on factors which influence their magnitude . The aim of this study was to generate empirical estimates of ICCs and to explore factors which may affect their magnitude . METHODS Empirical estimates of ICCs were calculated for both process variables and patient outcomes from a number of data sets of primary and secondary care implementation studies . RESULTS Estimates of ICCs varied according to setting and type of outcome . Estimates of ICCs for process variables were higher than those for patient outcomes , and estimates derived from secondary care were higher than those from primary care . ICCs for process variables in primary care were of the order of 0.05 - 0.15 , whilst those in secondary care were of the order of 0.3 . Estimates for patient outcomes in primary care were generally lower than 0.05 . CONCLUSIONS Adopting cluster r and omisation has implication s for the design , size and analysis of clinical trials . This study gives an insight into the potential size of ICCs in primary and secondary care , and provides a practical guide to research ers to aid the planning of future studies in this area OBJECTIVE To evaluate a health maintenance organization (HMO)-sponsored intervention to improve cancer screening in private physician practice s serving low-income , minority population s. DESIGN A r and omized controlled trial with preintervention and postintervention measurements . Measurements were obtained by abstract ing information from independent r and om sample s of medical charts ( N = 2316 at preintervention and 2238 at postintervention ) . SETTING Forty-seven primary care physician practice s located in low-income and minority urban neighborhoods in Chicago , Ill. INTERVENTION Practice s were encouraged to adopt an office chart reminder system and to use a patient health maintenance card . Activities to facilitate the adoption of these items and for compliance with cancer screening guidelines included on-site training and start-up assistance visits , a physician continuing medical education seminar , and quality assurance visits with feedback to physicians . MAIN OUTCOME MEASURES The proportions of patients with a chart-documented mammogram , clinical breast examination , Papanicolaou smear , or fecal occult blood slide test in the 2 years before preintervention and postintervention chart abstract ions . RESULTS Between baseline and postintervention , there was a net increase in the proportion of HMO members in the intervention , compared with the control practice s , who received in the preceding 2 years a Papanicolaou smear ( 11.9 % ) and a fecal occult blood slide test ( 14.1 % ) . There was a net increase in the proportion of non-HMO patients in the intervention compared with the control practice s who received a clinical breast examination ( 15.3 % ) and a fecal occult blood slide test ( 20.2 % ) . CONCLUSIONS Implementation of an HMO-mediated , multicomponent intervention to improve cancer screening was feasible and effective for the Papanicolaou smear , fecal occult blood slide test , and the clinical breast examination , but not for mammography The purpose of this two group intervention study ( N = 94 ) was to determine if RNs who participated in " culture school " improved levels of cultural competence to a greater extent than RNs who attended nursing informatics classes . The Giger and Davidhizar Transcultural Assessment Model/Theory ( GDTAMT ) was the study 's theoretical foundation ( Giger & Davidhizar , 1995 ) . A sample of 94 participants , was identified from a r and omized group of all Jefferson County , Alabama RNs . R and omly assigned participants ( stratified by race ) experienced 8.5 hours of either culture school or nursing informatics classes and completed survey tools in three phases ( pre-intervention , immediate post intervention , three week follow-up ) . The Cultural Self-Efficacy Scale ( CSES ) by Bernal and Froman ( 1987 ) , knowledge base questions by Rooda ( 1990 ) , and demographic profiles were used . Concepts empirically measured using these tools were analyzed by transcultural nursing experts for their congruence with GDTAMT . Using repeated measures analyses of convariance ( race ) , significant differences between groups for both scales were found . Culture school participants demonstrated significantly more cultural self-efficacy and cultural knowledge , and these improvements remained during phase three . Further research is recommended to allow for greater generalizability of findings , an examination of client perceptions , and actual nurse behaviors OBJECTIVE Ethnic minority patients often receive poorer quality care and have worse outcomes than white patients , yet practice -based approaches to reduce such disparities have not been identified . We determined whether practice -initiated quality improvement ( QI ) interventions for depressed primary care patients improve care across ethnic groups and reduce outcome disparities . STUDY SETTING The sample consists of 46 primary care practice s in 6 U.S. managed care organizations ; 181 clinicians ; 398 Latinos , 93 African Americans , and 778 white patients with probable depressive disorder . STUDY DEIGN : Matched practice s were r and omized to usual care or one of two QI programs that trained local experts to educate clinicians ; nurses to educate , assess , and follow-up with patients ; and psychotherapists to conduct Cognitive Behavioral Therapy . Patients and physicians selected treatments . Interventions featured modest accommodations for minority patients ( e.g. , translations , cultural training for clinicians ) . DATA EXTRACTION METHODS Multilevel logistic regression analyses assessed intervention effects within and among ethnic groups . PRINCIPAL FINDINGS At baseline , all ethnic groups Latino , African American , white ) had low to moderate rates of appropriate care and the interventions significantly improved appropriate care at six months ( by 8 - 20 percentage points ) within each ethnic group , with no significant difference in response by ethnic group . The interventions significantly decreased the likelihood that Latinos and African Americans would report probable depression at months 6 and 12 ; the white intervention sample did not differ from controls in reported probable depression at either follow-up . While the intervention significantly improved the rate of employment for whites and not for minorities , precision was low for comparing intervention response on this outcome . It is important to note that minorities remained less likely to have appropriate care and more likely to be depressed than white patients . CONCLUSIONS Implementation of quality improvement interventions that have modest accommodations for minority patients can improve quality of care for whites and underserved minorities alike , while minorities may be especially likely to benefit clinical ly . Further research needs to clarify whether employment benefits are limited to whites and if so , whether this represents a difference in opportunities . Quality improvement programs appear to improve quality of care without increasing disparities , and may offer an approach to reduce health disparities AIM To evaluate the effect of a community-oriented primary health care ( CPHC ) intervention on oral health behaviours of Indigenous preschool children living in remote communities of Australia 's Northern Territory . METHODS The study was a community-clustered r and omised controlled trial over two years , set in 30 remote Indigenous communities in the Northern Territory of Australia . Children aged 18 - 47 months at baseline were enrolled in the study . The intervention included fluoride varnish applications , training of primary care workers , and health promotion for oral health at an individual , family and community level . Intervention communities received six-monthly visits over two years and control communities were visited at baseline and two years later with no contact in the intervening period . The outcome measures reported in this paper are the impact of the intervention on two secondary endpoints : oral health promotion activities in the community and personal oral health practice of children . RESULTS The intervention did not produce any significant change in oral health behaviours , clinical measures of oral hygiene , or community programmes promoting oral health . Dental caries can be reduced but will continue to be a problem among young remote Indigenous children while they experience major social disadvantage PURPOSE To determine the effectiveness of cultural sensitivity training on the knowledge and attitudes of health care providers , and to assess the satisfaction and health outcomes of patients from different minority groups with health care providers who received training . DESIGN In this r and omised controlled trial , 114 health care providers ( nurses and homecare workers ) and 133 patients ( from two community agencies and one hospital ) were r and omly assigned to experimental ( training ) and control groups , and were followed for 18 months . METHODS Providers completed the Cultural Awareness Question naire and the Dogmatism Scale . Patients completed the Off-Axis-Ratio ( OAR ) Multidimensional Measure of Functional Capacity , the Client Satisfaction Question naire , the Physical and Mental Health Assessment Question naire , and the Health and Social Services Utilization Question naire . A qualitative analysis was conducted to identify and analyse themes from personal journals kept by participating nurses . FINDINGS Cultural sensitivity training result ed in increased open-mindedness and cultural awareness , improved underst and ing of multiculturalism , and ability to communicate with minority people . After 1 year patients of mostly European and British origin , who received care from trained providers , showed improvement in utilizing social re sources and overall functional capacity without an increase in health care expenditures . CONCLUSIONS The results of this study indicate that a cultural sensitivity training program not only improved knowledge and attitudes among health care providers , but it also yielded positive health outcomes for their patients OBJECTIVE To develop and evaluate a culturally adapted brief intervention for Indigenous people with chronic mental illness . DESIGN A mixed methods design in which an exploratory phase of qualitative research was followed by a nested r and omised controlled trial . SETTING Psycho-education re sources and a brief intervention , motivational care planning ( MCP ) , were developed and tested in collaboration with aboriginal mental health workers in three remote communities in northern Australia . PARTICIPANTS A total of 49 patients with mental illness and 37 carers were recruited to a r and omised controlled trial that compared MCP ( n = 24 ) with a clinical control condition ( treatment as usual , n = 25 ) . INTERVENTION The early treatment group received MCP at baseline and the late treatment group received delayed treatment at six months . MAIN OUTCOME MEASURES The primary outcome was mental health problem severity as measured by the health of the nation outcome scales . Secondary measures of well-being ( Kessler 10 ) , life skills , self-management and substance dependence were chosen . Outcome assessment s were performed at baseline , six-month , 12-month and 18-month follow up . RESULTS R and om effects regression analyses showed significant advantage for the treatment condition in terms of well-being with changes in health of the nation outcome scales ( P < 0.001 ) and Kessler 10 ( P = 0.001 ) , which were sustained over time . There was also significant advantage for treatment for alcohol dependence ( P = 0.05 ) , with response also evident in cannabis dependence ( P = 0.064 ) and with changes in substance dependence sustained over time . CONCLUSIONS These results suggest that MCP is an effective treatment for Indigenous people with mental illness and provide insight into the experience of mental illness in remote communities OBJECTIVE Findings of scarcely available studies indicate that there are substantial gaps in intercultural doctor-patient communication . In order to improve intercultural communication in medical practice in The Netherl and s , an educational intervention was developed . The aim of the present study was to examine the effects of this intervention on doctor-patient communication . METHODS Participants ( general practitioners : n=38 ; patients : n=124 ) were assigned at r and om to an intervention or a control group . GPs in the intervention group received 2.5 days training on intercultural communication . Patients in the intervention group were exposed to a videotaped instruction in the waiting room , right before the consultation . Data were collected through videotapes of visits of ethnic minority patients to their GP and home interviews with the patients after their medical visit . Communication behaviour was assessed using the Roter interaction analysis system ( RIAS ) . Interview length was assessed as well . RESULTS The length of the medical encounter increased significantly after having received the intervention . Total number of GP utterances increased significantly too . When comparing relative frequencies on affective and instrumental verbal behaviour of both patients and doctors , no significant changes could be detected . CONCLUSION It is concluded that there seems to be some change in doctor-patient interaction , but RIAS may not be suitable to detect subtle changes in the medical communication process . It is recommended to use other analysis methods to assess cultural differences in medical communication . PRACTICE IMPLICATION S Knowledge about possible antecedents of gaps in intercultural medical communication should be increased in order to be able to design effective interventions for intercultural doctor-patient communication BACKGROUND African Americans and persons with low socioeconomic status ( SES ) are disproportionately affected by hypertension and receive less patient-centered care than less vulnerable patient population s. Moreover , continuing medical education ( CME ) and patient-activation interventions have infrequently been directed to improve the processes of care for these population s. OBJECTIVE To compare the effectiveness of patient-centered interventions targeting patients and physicians with the effectiveness of minimal interventions for underserved groups . DESIGN R and omized controlled trial conducted from January 2002 through August 2005 , with patient follow-up at 3 and 12 months , in 14 urban , community-based practice s in Baltimore , Maryl and . PARTICIPANTS Forty-one primary care physicians and 279 hypertension patients . INTERVENTIONS Physician communication skills training and patient coaching by community health workers . MAIN MEASURES Physician communication behaviors ; patient ratings of physicians ’ participatory decision-making ( PDM ) , patient involvement in care ( PIC ) , reported adherence to medications ; systolic and diastolic blood pressure ( BP ) and BP control . KEY RESULTS Visits of trained versus control group physicians demonstrated more positive communication change scores from baseline ( −0.52 vs. −0.82 , p = 0.04 ) . At 12 months , the patient+physician intensive group compared to the minimal intervention group showed significantly greater improvements in patient report of physicians ’ PDM ( β = + 6.20 vs. −5.24 , p = 0.03 ) and PIC dimensions related to doctor facilitation ( β = + 0.22 vs. −0.17 , p = 0.03 ) and information exchange ( β = + 0.32 vs. −0.22 , p = 0.005 ) . Improvements in patient adherence and BP control did not differ across groups for the overall patient sample . However , among patients with uncontrolled hypertension at baseline , non-significant reductions in systolic BP were observed among patients in all intervention groups — the patient+physician intensive ( −13.2 mmHg ) , physician intensive/patient minimal ( −10.6 mmHg ) , and the patient intensive/physician minimal ( −16.8 mmHg ) , compared to the patient+physician minimal group ( −2.0 mmHg ) . CONCLUSION Interventions that enhance physicians ’ communication skills and activate patients to participate in their care positively affect patient-centered communication , patient perceptions of engagement in care , and may improve systolic BP among urban African-American and low SES patients with uncontrolled hypertension |
13,650 | 24,173,585 | We did not find a significant reduction in IA or Aspergillus colonization with universal anti-aspergillus prophylaxis .
There was no difference in the adverse events of inhaled amphotericin-B deoxycholate and lipid formulations of inhaled amphotericin-B. However , voriconazole was more hepatotoxic than itraconazole . | Aspergillus is the most common cause of invasive fungal infection in lung transplant recipients .
Most transplant centers employ routine antifungal prophylaxis to prevent the development of invasive aspergillosis ( IA ) . | Pulmonary fungal infection is diagnosed in up to 15 - 25 % of lung transplant recipients and frequently bears a fatal outcome . This prospect i ve uncontrolled study addresses the efficacy and safety of pre-emptive azole therapy against fungal infection in these patients . Fluconazole or itraconazole have been systematic ally used according to reported fungus sensitivity after the discovery of fungi in lower respiratory tract sample s. Patients were treated until the bronchial suture was normal and the cultures of the following bronchoscopy remained negative . Fungi were found post-transplantation in the lower respiratory tract specimens of 26 out of 31 ( 84 % ) patients , predominantly C and ida albicans ( 20 patients ) and Aspergillus fumigatus ( 16 patients ) . Mycelia characteristic of C and ida spp . or Aspergillus spp . were found in necrotic tissue at the bronchial suture of nine patients . The mean duration of the 38 treatments was 3.6+/-2.6 months ( range , 0.5 - 12 months ) . After a median follow-up of 16 ( range , 0 - 48 ) months , two cases of extended ulcerative and pseudo membranous Aspergillus fumigatus bronchitis were observed and healed under itraconazole treatment . In conclusion , pre-emptive azole therapy may be effective and well-tolerated in lung transplant patients where fungi are found in the airways or pleura BACKGROUND Invasive fungal infections ( IFIs ) are a major cause of morbidity and mortality among organ transplant recipients . Multicenter prospect i ve surveillance data to determine disease burden and secular trends are lacking . METHODS The Transplant-Associated Infection Surveillance Network ( TRANSNET ) is a consortium of 23 US transplant centers , including 15 that contributed to the organ transplant recipient data set . We prospect ively identified IFIs among organ transplant recipients from March , 2001 through March , 2006 at these sites . To explore trends , we calculated the 12-month cumulative incidence among 9 sequential cohorts . RESULTS During the surveillance period , 1208 IFIs were identified among 1063 organ transplant recipients . The most common IFIs were invasive c and idiasis ( 53 % ) , invasive aspergillosis ( 19 % ) , cryptococcosis ( 8 % ) , non-Aspergillus molds ( 8 % ) , endemic fungi ( 5 % ) , and zygomycosis ( 2 % ) . Median time to onset of c and idiasis , aspergillosis , and cryptococcosis was 103 , 184 , and 575 days , respectively . Among a cohort of 16,808 patients who underwent transplantation between March 2001 and September 2005 and were followed through March 2006 , a total of 729 IFIs were reported among 633 persons . One-year cumulative incidences of the first IFI were 11.6 % , 8.6 % , 4.7 % , 4.0 % , 3.4 % , and 1.3 % for small bowel , lung , liver , heart , pancreas , and kidney transplant recipients , respectively . One-year incidence was highest for invasive c and idiasis ( 1.95 % ) and aspergillosis ( 0.65 % ) . Trend analysis showed a slight increase in cumulative incidence from 2002 to 2005 . CONCLUSIONS We detected a slight increase in IFIs during the surveillance period . These data provide important insights into the timing and incidence of IFIs among organ transplant recipients , which can help to focus effective prevention and treatment strategies ABSTRACT Voriconazole prophylaxis is common following lung transplantation , but the value of therapeutic drug monitoring is unknown . A prospect i ve , observational study of lung transplant recipients ( n = 93 ) receiving voriconazole prophylaxis was performed . Serum voriconazole troughs ( n = 331 ) were measured by high-pressure liquid chromatography . The median initial and subsequent troughs were 1.91 and 1.46 μg/ml , respectively . The age of the patient directly correlated with initial troughs ( P = 0.005 ) . Patients that were ≥60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs , respectively . In 95 % ( 88/93 ) of patients , ≥2 troughs were measured . In 28 % ( 25/88 ) and 32 % ( 28/88 ) of these patients , all troughs were ≤1.5 μg/ml or > 1.5 μg/ml , respectively . Ten percent ( 10/93 ) and 27 % ( 25/93 ) of the patients developed invasive fungal infection ( tracheobronchitis ) and fungal colonization , respectively . The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 μg/ml ( P = 0.07 ) . Invasive fungal infections or colonization were more likely with troughs of ≤1.5 μg/ml ( P = 0.01 ) and among patients with no trough of > 1.5 μg/ml ( P = 0.007 ) . Other cutoff troughs correlated less strongly with microbiologic outcomes . Troughs correlated directly with aspartate transferase levels ( P = 0.003 ) , but not with other liver enzymes . Voriconazole was discontinued due to suspected toxicity in 27 % ( 25/93 ) of the patients . The troughs did not differ at the times of suspected drug-induced hepatotoxicity , central nervous system ( CNS ) toxicity , or nausea/vomiting and in the absence of toxicity . Voriconazole prophylaxis was most effective at troughs of > 1.5 μg/ml . A cutoff for toxicity was not identified , but troughs of > 4 μg/ml were rare . The data support a target range of > 1.5 to 4 μg/ml Lung transplant recipients have one of the highest rates of invasive aspergillosis ( IA ) in solid organ transplantation . We used a single center , nonr and omized , retrospective , sequential study design to evaluate fungal infection rates in lung transplant recipients who were managed with either universal prophylaxis with voriconazole ( n = 65 ) or targeted prophylaxis ( n = 30 ) with itraconazole ± inhaled amphotericin in patients at high risk ( pre‐ or posttransplant Aspergillus colonization [ except Aspergillus niger ] ) . The rate of IA at 1 year was better in lung transplant recipients receiving voriconazole prophylaxis as compared to the cohort managed with targeted prophylaxis ( 1.5 % vs. 23 % ; p = 0.001 ) . Twenty‐nine percent of cases in the targeted prophylaxis group were in patients colonized with A. niger who did not receive itraconazole . A threefold or higher increase in liver enzymes was noted in 37–60 % of patients receiving voriconazole prophylaxis as compared to 15–41 % of patients in the targeted prophylaxis cohort . Fourteen percent in the voriconazole group as compared to 8 % in the targeted prophylaxis group had to discontinue antifungal medications due to side effects . Voriconazole prophylaxis can be used in preventing IA in lung transplant recipients . Regular monitoring of liver enzymes and serum concentrations of calcineurin inhibitors are required to avoid hepatotoxicity and nephrotoxicity BACKGROUND Fungal infections are an important complication of lung transplantation , but no controlled studies of their management have been performed . Knowledge of actual anti-fungal strategies may aid in the design of future prospect i ve studies . METHODS Thirty-seven of 69 active lung transplant centers , accounting for 66 % of all US lung transplantations , responded to our survey . The survey focused on fungal surveillance , pre- and post-transplant prophylaxis , and approach to fungal colonization . RESULTS The median number of lung transplantations performed by the centers in 1999 was 14 per year ( range , 1 - 52 ) , and median time that centers were in in operation was 9 years ( range , 2 - 15 years ) . Seventy percent of centers had a transplant infectious diseases specialist . Pre-transplant fungal surveillance was performed by 81 % of centers , with 67 % of these surveying all patients and the remainder surveying only sub-sets of patients . Seventy-two percent of all centers started anti-fungal treatment if Aspergillus spp were isolated before transplantation . Itraconazole was the preferred agent ( 86 % ) . After transplantation , 76 % of centers gave anti-fungal prophylaxis , although 24 % of these did so only in selected patients . Prophylactic agents in order of preference were inhaled amphotericin B ( 61 % ) , itraconazole ( 46 % ) , parenteral amphotericin formulations ( 25 % ) , and fluconazole ( 21 % ) ; many centers used more than 1 agent . Prophylaxis was initiated within 24 hours by 71 % and within 1 week by all centers . Median duration of prophylaxis was 3 months ( range , < 1 month-lifetime ) . All 37 centers used anti-fungal therapy if colonization with Aspergillus spp was detected for a median duration of 4.5 months . Itraconazole was the preferred agent . Only 59 % of centers treated patients colonized with C and ida spp . In a statistical analysis , centers with larger volumes were less likely to treat pre-transplant colonization with C and ida spp but more likely to use agents other than itraconazole for post-transplant colonization with Aspergillus spp . Only 14 % of centers engaged in any anti-fungal research at the time of the survey . CONCLUSIONS The majority of surveyed lung transplant programs actively manage fungal infection with prophylaxis or pre-emptive therapy , despite the absence of controlled trials . This survey may provide an impetus and a basis for design ing prospect i ve studies We conducted a survey of 50 lung transplant centers across the world to evaluate the variation in antifungal prophylaxis practice s. These 50 centers performed 63 % of the world 's lung transplants reported in 2001 . Eighty-six percent ( 43/50 ) of the centers responded to the survey . Sixty-nine percent ( 30/43 ) of centers used universal antifungal prophylaxis . Aerosolized amphotericin B deoxycholate ( AmBd ) alone or in combination with itraconazole was used at 56 % ( 24/43 ) of centers . The median duration of prophylaxis with aerosolized AmBd and itraconazole was 30 and 90 days , respectively . Seventy-four percent of the centers surveyed agreed to participate in future research prophylaxis protocol s , which they felt should include both diagnostic and therapeutic arms . Our survey is the first documentation of the international variation in antifungal prophylactic strategies in lung transplant recipients , and underscores the need for multicenter , r and omized trials of antifungal prophylaxis in lung transplant recipients BACKGROUND Itraconazole is often given for fungal prophylaxis to lung transplant recipients after transplantation . The aim of this study was to determine the extent of interaction between tacrolimus and itraconazole in lung transplant recipients and the efficacy of itraconazole prophylaxis . METHODS The study group included 40 lung transplant recipients followed for at least 12 months . All received prophylactic itraconazole , 200 mg twice a day , for the first 6 months after transplantation . Tacrolimus levels and dosage requirements were compared during and after itraconazole therapy . Rejection rate , fungal infection rate , and renal function were assessed . The mean cost per daily treatment of the itraconazole/tacrolimus combination and tacrolimus alone was calculated . RESULTS The mean tacrolimus dose during itraconazole treatment was 3.26 + /- 2.1 mg/day compared with 5.74 + /- 2.9 mg/day after itraconazole was stopped ( p < 0.0001 ) for a mean total daily dose elevation of tacrolimus of 76 % . When the cost of itraconazole was taken into account , the average total daily cost of the combined treatment was US5.86 dollars less than the treatment with tacrolimus alone . No differences in the rejection or fungal infection rate , or in renal toxicity , were observed between the periods with and without itraconazole treatment , although less positive fungal isolates were identified during itraconazole therapy . CONCLUSION Prophylaxis therapy with itraconazole is highly effective . Itraconazole reduces the dose of tacrolimus and therefore lowers the cost of therapy without causing an increase in rejection rate and with renal function preservation Since July 1993 , amphotericin B ( 5 mg TID to be increased up to 20 mg TID within 5 days after surgery ) has been given as inhalation throughout the posttransplant hospital stay . This group consists of 126 patients ( mean age 39.8 years , 79 men , 47 women , 22 LTx , 27 HLTx , and 75 HTx ) . The incidence and spectrum of fungal infections were compared with a similar cohort of 101 patients ( = control , mean age 40.0 years , 73 men , 28 women , 12 LTx , 12 HLTx , and 77 HTx ) who were transplanted within a similar time period before introduction of ampho-prophylaxis . Both groups received the same triple-drug immunosuppressive protocol . The two groups were compared with regard to the spectrum of fungal , bacterial , viral , and protozoa1 infections as well as the incidence of acute rejection and level of renal function . The two-tailed f test was used to compare the linearized rate of events after the first 3 and 12 months , and the Gehan-test was used for statistical comparison of the actuarial incidence data in both groups Background . Fungal infections remain an important cause of morbidity and mortality in lung transplant recipients . Aerosolized amphotericin B lipid complex ( ABLC ) may be more efficacious than conventional amphotericin B in the prevention of fungal infections in animal models , but experience with aerosolized ABLC in humans is lacking . Methods . We conducted a prospect i ve , noncomparative study design ed to evaluate safety of aerosolized ABLC in lung or heart-lung transplant recipients . Results . A total of 381 treatments were administered to 51 patients . Complete spirometry records were available for 335 treatments ( 69 in intubated patients , 266 in extubated patients ) . ABLC was subjectively well tolerated in 98 % of patients . Pulmonary mechanics worsened by 20 % or more posttreatment in less than 5 % of all treatments . There were no significant adverse events related to study medication in any patient , and 1-year survival for all enrolled patients was 78 % . Conclusion . Administration of nebulized ABLC is safe in the short-term and well-tolerated in lung transplant recipients . Additional prospect i ve , r and omized studies are needed to determine the efficacy of aerosolized ABLC alone or in conjunction with systemic therapies in the prevention of fungal infections in lung transplant recipients Background . Inhaled amphotericin preparations have been used for prophylaxis against invasive aspergillosis in lung transplant recipients . However , no published data exist regarding the pharmacokinetic profile of amphotericin B lipid complex in lung transplant recipients . Methods . We prospect ively determined the concentrations of amphotericin B in the epithelial lining fluid ( ELF ) and plasma after aerosolized nebulization ( AeroEclipse ) , of amphotericin B lipid complex at 1 mg/kg every 24 hr for 4 days in 35 lung transplant recipients . One brochoalveolar lavage sample and a simultaneous blood sample were collected at various time points after the fourth dose from each subject . High-performance liquid chromatography and high-performance liquid chromatography-MS-MS were used to measure amphotericin B. Results . Concentrations of amphotericin B in ELF ( median , 25–75 IQR ) were at 4 hr ( n=5 ) 7.20 & mgr;g/mL ( 1.3–17.6 ) , 24 hr ( n=6 ) 8.26 & mgr;g/mL ( 3.9–82.7 ) , 48 hr ( n=5 ) 2.15 & mgr;g/mL ( 1.4–5.5 ) , 72 hr ( n=4 ) 1.25 & mgr;g/mL ( 0.75–5.5 ) , 96 hr ( n=6 ) 0.86 & mgr;g/mL ( 0.55–1.4 ) , 120 hr ( n=4 ) 1.04 & mgr;g/mL ( 0.44–1.6 ) , 144 hr ( n=1 ) , 4.25 & mgr;g/mL , 168 hr ( n=3 ) 1.14 & mgr;g/mL , and 192 hr ( n=1 ) 1 & mgr;g/mL. The plasma concentration of the drug remained below 0.08 & mgr;g/mL at all time points . During the study , the side effects noted included wheezing , coughing , and 12 % decline in forced expiratory volume in 1 sec. Conclusions . We conclude that administration through aerosolized nebulization of amphotericin B lipid complex every 24 hr for 4 days in lung transplant recipients achieved amphotericin B concentrations in ELF above minimum inhibitory concentration of the Aspergillus nearly at 168 hr after the last inhaled dose and is well tolerated Contemporary epidemiology and outcomes of invasive fungal infections ( IFIs ) in solid organ transplant ( SOT ) recipients are not well described . From March 2004 through September 2007 , proven and probable IFIs were prospect ively identified in 17 transplant centers in the United States . A total 429 adult SOT recipients with 515 IFIs were identified ; 362 patients received a single and 67 patients received > or=2 organs . Most IFIs were caused by C and ida species ( 59.0 % ) , followed by Aspergillus species ( 24.8 % ) , Cryptococcus species ( 7.0 % ) , and other molds ( 5.8 % ) . Invasive c and idiasis ( IC ) was the most frequently observed IFI in all groups , except for lung recipients where invasive aspergillosis ( IA ) was the most common IFI ( P<0.0001 ) . Almost half of IC cases in liver , heart , and lung transplant recipients occurred during the first 100 days post transplant . Over half of IA cases in lung recipients occurred > 1 year post transplant . Overall 12-week mortality was 29.6 % ; liver recipients had the highest mortality ( P=0.05 ) . Organ damage , neutropenia , and administration of corticosteroids were predictors of death . These results extend our knowledge on the epidemiology of IFI in SOT recipients , emphasizing the occurrence of IC early after non-lung transplant , and late complications with molds after lung transplant . Overall survival appears to have improved compared with historical reports Between January 2002 and December 2003 all 157 patients ( pts ) that underwent lung transplantation ( LTx ) at our institution were prospect ively screened for invasive aspergillosis ( IA ) during their perioperative hospital stay . Patients were regarded as IA positive , if they met the EORTC criteria for ' probable ' or ' proven ' IA . Records of pts were screened retrospectively for antimycotic prophylaxis . Eight of the 157 pts developed ' probable ' or ' proven ' IA ( 5.1 % ) within 17 + /- 10 days after LTx . This was associated with a 14-fold increased mortality compared with all pts without aspergillosis ( P < 0.01 , OR 13.8 , CI(95 % ) 2.5 - 82 ) . Preoperative colonization with Aspergillus was a significant risk factor for IA ( P < 0.001 , OR 21.9 , CI(95 % ) 4.9 - 97 ) . We switched our prophylactic strategies to the primary administration of voriconazole in high risk pts ( pre-LTx colonization ) starting in December 2002 . Six pts ( 6 % ) of 101 pts receiving itraconazole for antimycotic prophylaxis beginning at postoperative day ( POD ) one developed IA , of which three pts showed cerebral aspergillosis . One pt ( 5 % ) of 18 pts receiving voriconazole prophylaxis developed IA , while 10 pts showed pretransplant colonization with Aspergillus species . Thirty-eight pts received itraconazole prophylaxis at a later time point ( > POD 14 ) . By switching our prophylactic strategy to the use of voriconazole in high risk pts , we have decreased the incidence of IA from 8 % ( six of 75 ) in 2002 to 2 % ( two of 82 ) in 2003 . This study shows a high incidence of IA during the very early postoperative course after LTx of 5 % . This is associated with a significantly increased risk for mortality . Voriconazole prophylaxis appears to be superior to itraconazole , especially in high risk pts with pretransplant Aspergillus colonization BACKGROUND Nebulized amphotericin B deoxycholate ( n-ABD ) is used to prevent Aspergillus infection in lung transplantation . Nebulized liposomal amphotericin B ( n-LAB ) is another option ; however , no clinical data are available on the results of n-LAB for this purpose . METHODS In an observational study performed in 2 centers to assess the feasibility , tolerability , and outcomes of n-LAB prophylaxis , 104 consecutive patients undergoing prophylaxis with n-LAB were compared with 49 historical controls who received n-ABD . Patient follow-up lasted 12 months . The n-LAB prophylaxis regimen was 25 mg thrice weekly starting on the first post-operative day and continuing to 60 days , 25 mg once weekly from 60 to 180 days , and the same dose once every 2 weeks thereafter . RESULTS Aspergillus infection developed in 8 of 104 patients ( 7.7 % ) with n-LAB prophylaxis ( 5 colonization , 1 simple tracheobronchitis , 1 ulcerative tracheobronchitis , and 1 invasive pulmonary infection ) . Ulcerative tracheobronchitis and invasive pulmonary aspergillosis were regarded as invasive disease ; hence , the rate of invasive disease was 1.9 % ( 2 patients ) . The control group had similar rates of Aspergillus infection ( 10.2 % ; p = 0.6 ) and invasive disease ( 4.1 % ; p = 0.43 ) . In 3 patients ( 2.9 % ) , n-LAB was withdrawn due to bronchospasm in 2 and nausea in 1 . In the control group , prophylaxis was stopped in 2 patients ( 4.1 % ) because of bronchospasm ( p = 0.7 ) . CONCLUSIONS At the dose and frequency described , n-LAB seems effective , safe , and convenient for the prevention of Aspergillus infection in lung transplant patients Background . Aerosolized administrations of amphotericin B deoxycholate ( AmBd ) and amphotericin B lipid complex ( ABLC ) in lung transplant recipients were compared for safety and tolerability . The incidence of invasive fungal infections in patients receiving aerosolized amphotericin B formulations as sole prophylaxis was determined . Methods . A prospect i ve , r and omized ( 1:1 ) , double-blinded trial was conducted with 100 subjects . AmBd and ABLC were administered postoperatively by nebulizer at doses of 25 mg and 50 mg , respectively , which were doubled in mechanically ventilated patients . The planned treatment was once every day for 4 days , then once per week for 7 weeks . Treatment-related adverse events and invasive fungal infections were quantitated for 2 months after study drug initiation . Results . Intent-to-treat analysis revealed study drug was discontinued for intolerance in 6 of 49 ( 12.2 % ) and 3 of 51 ( 5.9 % ) patients in the AmBd- and ABLC-treated groups , respectively ( p = 0.313 ) . Subjects receiving AmBd were more likely to have experienced an adverse event ( odds ratio 2.16 , 95 % confidence interval 1.10 , 4.24 , p = 0.02 ) . Primary prophylaxis failure within 2 months of study drug initiation was observed in 7 of 49 ( 14.3 % ) AmBd-treated patients and 6 of 51 ( 11.8 % ) ABLC-treated patients . No fungal pneumonias were observed . Only two ( 2 % ) patients experienced documented primary prophylaxis failure with Aspergillus infections within the follow-up period . Conclusions . Both aerosol AmBd and ABLC appear to be associated with a low rate of invasive pulmonary fungal infection in the early posttransplant period . Patients receiving ABLC were less likely to experience a treatment-related adverse event |
13,651 | 28,841,894 | Conclusion Although we could distill various components of the Intervention- Context -Actor-Mechanism- Outcome analytic tool from different studies exploring group-based programmes , we could not , however , identify a salient programme theory based on the Intervention- Context -Actor-Mechanism- Outcome heuristic analysis . | Introduction It is increasingly acknowledged that differentiated care models hold potential to manage large volumes of patients on antiretroviral therapy ( ART ) .
Various group-based models of ART service delivery aim ed at decongesting local health facilities , encouraging patient retention in care , and enhancing adherence to medication have been implemented across sub-Saharan Africa .
Evidence from the literature suggests that these models of ART service delivery are more effective than corresponding facility-based care and superior to individual-based models .
Nevertheless , there is little underst and ing of how these care models work to achieve their intended outcomes .
The aim of this study was to review the theories explicating how and why group-based ART models work using a realist evaluation framework . | BACKGROUND Minimizing death and ensuring high retention and good adherence remain ongoing challenges for human immunodeficiency virus ( HIV ) treatment programs . We examined whether the addition of community-based accompaniment ( characterized by daily home visits from a community health worker , directly observed treatment , nutritional support , transportation stipends , and other support as needed ) to the Rw and a national model for antiretroviral therapy ( ART ) delivery would improve retention in care , viral load suppression , and change in CD4 count , relative to the national model alone . METHODS We conducted a prospect i ve observational cohort study among 610 HIV-infected adults initiating ART in 1 of 2 programs in rural Rw and a. Psychosocial and clinical characteristics were recorded at ART initiation . Death , treatment retention , and plasma viral load were assessed at 1 year . CD4 count was evaluated at 6-month intervals . Multivariable regression models were used to adjust for baseline differences between the 2 population s. RESULTS Eighty-five percent and 79 % of participants in the community-based and clinic-based programs , respectively , were retained with viral load suppression at 1 year . After adjusting for CD4 count , depression , physical health quality of life , and food insecurity , community-based accompaniment was protective against death or loss to follow-up during the first year of ART ( hazard ratio , 0.17 ; 95 % confidence interval [ CI ] , .09-.35 ; P < .0001 ) . In a second multivariable analysis , individuals receiving accompaniment were more likely to be retained with a suppressed viral load at 1 year ( risk ratio : 1.15 ; 95 % CI , 1.03 - 1.27 ; P = .01 ) . CONCLUSIONS These findings indicate that community-based accompaniment is effective in improving retention , when added to a clinic-based program with fewer patient support mechanisms Abstract Introduction : Successful population ‐level antiretroviral therapy ( ART ) adherence will be necessary to realize both the clinical and prevention benefits of antiretroviral scale‐up and , ultimately , the end of AIDS . Although many people living with HIV are adhering well , others struggle and most are likely to experience challenges in adherence that may threaten virologic suppression at some point during lifelong therapy . Despite the importance of ART adherence , supportive interventions have generally not been implemented at scale . The objective of this review is to summarize the recommendations of clinical , research , and public health experts for scalable ART adherence interventions in re source ‐limited setting s. Methods : In July 2015 , the Bill and Melinda Gates Foundation convened a meeting to discuss the most promising ART adherence interventions for use at scale in re source ‐limited setting s. This article summarizes that discussion with recent up date s. It is not a systematic review , but rather provides practical considerations for programme implementation based on evidence from individual studies , systematic review s , meta‐analyses , and the World Health Organization Consoli date d Guidelines for HIV , which include evidence from r and omized controlled trials in low‐ and middle‐income countries . Interventions are categorized broadly as education and counselling ; information and communication technology‐enhanced solutions ; healthcare delivery restructuring ; and economic incentives and social protection interventions . Each category is discussed , including descriptions of interventions , current evidence for effectiveness , and what appears promising for the near future . Approaches to intervention implementation and impact assessment are then described . Results and discussion : The evidence base is promising for currently available , effective , and scalable ART adherence interventions for re source ‐limited setting s. Numerous interventions build on existing health care infrastructure and leverage available re sources . Those most widely studied and implemented to date involve peer counselling , adherence clubs , and short message service ( SMS ) . Many additional interventions could have an important impact on ART adherence with further development , including st and ardized counselling through multi‐media technology , electronic dose monitoring , de central ized and differentiated models of care , and livelihood interventions . Optimal targeting and tailoring of interventions will require improved adherence measurement . Conclusions : The opportunity exists today to address and resolve many of the challenges to effective ART adherence , so that they do not limit the potential of ART to help bring about the end of AIDS Background : Current service delivery systems do not reach all people in need of antiretroviral therapy ( ART ) . In order to inform the operational and service delivery section of the WHO 2013 consoli date d antiretroviral guidelines , our objective was to summarize systematic review s on integrating ART delivery into maternal , newborn , and child health ( MNCH ) care setting s in countries with generalized epidemics , tuberculosis ( TB ) treatment setting s in which the burden of HIV and TB is high , and setting s providing opiate substitution therapy ( OST ) ; and de central izing ART into primary health facilities and communities . Design : A summary of systematic review s. Methods : The review ers search ed PubMed , Embase , PsycINFO , Web of Science , CENTRAL , and the WHO Index Medicus data bases . R and omized controlled trials and observational cohort studies were included if they compared ART coverage , retention in HIV care , and /or mortality in MNCH , TB , or OST facilities providing ART with MNCH , TB , or OST facilities providing ART services separately ; or primary health facilities or communities providing ART with hospitals providing ART . Results : The review ers identified 28 studies on integration and de central ization . Antiretroviral therapy integration into MNCH facilities improved ART coverage ( relative risk [ RR ] 1.37 , 95 % confidence interval [ CI ] 1.05–1.79 ) and led to comparable retention in care . ART integration into TB treatment setting s improved ART coverage ( RR 1.83 , 95 % CI 1.48–2.23 ) and led to a nonsignificant reduction in mortality ( RR 0.55 , 95 % CI 0.29–1.05 ) . The limited data on ART integration into OST services indicated comparable rates of ART coverage , retention , and mortality . Partial de central ization into primary health facilities improved retention ( RR 1.05 , 95 % CI 1.01–1.09 ) and reduced mortality ( RR 0.34 , 95 % CI 0.13–0.87 ) . Full de central ization improved retention ( RR 1.12 , 95 % CI 1.08–1.17 ) and led to comparable mortality . Community-based ART led to comparable rates of retention and mortality . Conclusion : Integrating ART into MNCH , TB , and OST services was often associated with improvements in ART coverage , and de central ization of ART into primary health facilities and communities was often associated with improved retention . Neither integration nor de central ization was associated with adverse outcomes . These data contributed to recommendations in the WHO 2013 consoli date d antiretroviral guidelines to integrate ART delivery into MNCH , TB , and OST services and to de central ize ART Background Non‐compliance with Antiretroviral Therapy is a major public health concern and further challenged by interaction of various social and clinical obstacles . So ; near perfect pill taking is desirable in order to maximise its benefits . Objectives To systematic ally search , appraise and synthesis e the best available evidence on determinants of non‐compliance with Antiretroviral Therapy among adults living with HIV/AIDS and provide direction to future how to increase compliance with Antiretroviral Therapy . Inclusion criteria Types of participants The systematic review considered studies with 18 years and above year old adults living with HIV/AIDS . Focus of the review Determinants of non‐compliance with Antiretroviral Therapy among adults living with HIV/AIDS . Types of studies Quantitative study design s were considered for inclusion . Types of outcomes Socio‐economic , Health service , Psychosocial and behavioural and Clinical related outcomes . Search strategy English language articles published between January1997 and December 2011 were sought across major data bases . Method ological quality Method ological quality was assessed using Joanna Briggs Institute Meta Analysis of Statistical Assessment and Review Instrument critical appraisal tools . Data collection Data were extracted from papers included in the review by using a st and ardized data extraction tool . Data synthesis Meta‐ analysis was conducted using fixed and r and om effects model with mantel Haenszel method using Revman5 software . Heterogeneity between the studies was assessed using & khgr;2 test at a p‐value of < 0.05 . Summary statistics were expressed as adjusted odds ratio or adjusted risk ratio with 95 % confidence intervals at a p‐value of < 0.05 . Results Nine studies ( seven cross‐sectional , one cohort study and one case‐control study ) were included in the review . Results from meta analysis showed that white race adults living with HIV/AIDS were 1.38 times more likely to non‐comply with Antiretroviral Therapy when compared with black adults living with HIV/ AIDS ( Adjusted Relative Risk=1.38 ; 95%CI=1.21 , 1.58 , p value<0.00001 ) . Non‐depressed adults living with HIV/AIDS were 1.77 times more likely to non‐comply with Antiretroviral Therapy when compared with depressed adults living with HIV/AIDS ( Adjusted Odds ratio = 1.77 ; 95%CI=1.17 , 2.69 , p value=0.007 ) . Substance non‐user adults living with HIV/ AIDS were 2.04 times more likely to non‐comply with Antiretroviral Therapy when compared with substance user adults living with HIV/ AIDS ( Adjusted Relative Risk = 2.04 ; 95%CI=1.51 , 2.74 , p value=<0.00001 ) . Adults living with HIV/ AIDS with baseline CD4 count ≥200cells/ml were 1.8 times more likely to non‐comply with Antiretroviral Therapy when compared with adults livings with HIV/ AIDS with baseline CD4 count ≥200cells/ml ( Adjusted Odds ratio=1.84 ; 95%CI=1.08 , 3.15 , p value=0.03 ) . Conclusion We found the base line CD4 count ≥200cells/ml , not being depressed ; not using substances and being white in race were associated with non‐compliance with Antiretroviral Therapy . Implication s for practice Behavioural change via counselling should be encouraged as a way to increase compliance . Reminders to take mediations regularly , on time , offering encouragement to keep going , helping to keep clinic appointments and providing emotional support for adults living with HIV/AIDS is important . Implication s for research Further research utilizing more robust experimental methods would help to further explore the findings of this review |
13,652 | 16,989,671 | Studies of office/hospital-based telemedicine suggest that telemedicine is most effective for verbal interactions , e.g. videoconferencing for diagnosis and treatment in specialties like neurology and psychiatry . | Telemedicine services are being increasingly used .
Although insurers and other payers are covering some services in the USA , the rationale for these coverage decisions is not always evidence -based .
We review ed the literature for telemedicine services that substitute for face-to-face medical diagnosis and treatment .
Store- and -forward services have been studied in many specialties , the most common being dermatology , wound care and ophthalmology .
The evidence for their efficacy is mixed . | The aim of this study was to determine if a teledermatology consult system , using store- and -forward digital imaging technology , results in patients achieving a shorter time from referral date to date of initial definitive intervention when compared to a traditional referral process . Patients being referred to the dermatology consult service from the primary care clinics at the Durham VA Medical Center were r and omized to either a teledermatology consultation or usual care . A usual care consultation consisted of a text-based electronic consult request . A teledermatology consultation included digital images and a st and ardized history , in addition to the text-based electronic consult . Time to initial definitive intervention was defined as the time between referral date and the date the patient was scheduled for a clinic visit for those patients that the consultant requested a clinic-based evaluation , or the time between referral date and the date the consult was answered by the consultant if a clinic visit was not required . Patients in the teledermatology arm of the study reached a time to initial definitive intervention significantly sooner than did those patients r and omized to usual care ( median 41 days versus 127 days , p = 0.0001 , log-rank test ) . Additionally , 18.5 % of patients in the teledermatology arm avoided the need for a dermatology clinic-based visit compared to zero patients avoiding a dermatology clinic visit in the usual care arm of the study ( p < 0.001 , z-test ) . Teledermatology consult systems can result in significantly shorter times to initial definitive intervention for patients compared to traditional consult modalities , and , in some cases , the need for a clinic-based visit can be avoided In a retrospective review , the telemedical management of 65 out patients from a r and omized controlled trial ( RCT ) of telemedicine for non-urgent referrals to a consultant neurologist was compared with the management of 76 patients seen face to face in the same trial , with that of 150 out patients seen in the neurology clinics of district general hospitals and with that of 102 neurological out patients seen by general physicians . Outcome measures were the numbers of investigations and of patient review s. The telemedicine group did not differ significantly from the 150 patients seen face to face by neurologists in hospital clinics in terms of either the number of investigations or the number of review s they received . Patients from the RCT seen face to face had significantly fewer investigations but a similar number of review s to the other 150 patients seen face to face by neurologists ( the disparity in the number of investigations may explain the negative result for telemedicine in that RCT ) . Patients with neurological symptoms assessed by general physicians had significantly more investigations and were review ed significantly more often than all the other groups . Patients from the RCT seen by telemedicine were not managed significantly differently from those seen face to face by neurologists in hospital clinics but had significantly fewer investigations and follow-ups than those patients managed by general physicians . The results suggest that management of new neurological out patients by neurologists using telemedicine is similar to that by neurologists using a face-to-face consultation , and is more efficient than management by general physicians OBJECTIVE To study the validity and feasibility of transferring images of cutaneous biopsy specimens via e-mail to remote physicians active in dermatopathology for teleconsultation . DESIGN Twenty skin specimens previously diagnosed at the Department of Dermatology , University of Graz , Austria , were subsequently sent for teleconsultation using the store- and -forward method . For each case , 3 or 4 images at different magnifications were sent by e-mail to 16 colleagues ( 11 dermatopathologists and 5 pathologists ) in 15 centers in 6 different countries . Six weeks later each observer received the hematoxylin-eosin-stained specimens to render a conventional diagnosis . SETTING Dermatopathology and pathology units within institutional and private setting s. MATERIAL Twenty small skin biopsy specimens of cutaneous diseases were selected r and omly from a study set of 80 . MAIN OUTCOME MEASURE Concordance between telepathologic diagnoses and conventional histopathologic diagnoses of 20 skin specimens . RESULTS On average , 78 % of the telediagnoses were correct ( range , 60%-95 % ) , whereas 85 % of the conventional diagnoses were correct ( range , 60%-95 % ) . A perfect diagnostic concordance was obtained in 7 ( 35 % ) of 20 cases , and a significant difference was identified in only 1 case . CONCLUSIONS Results suggest that telepathology performed by physicians active in dermatopathology may serve as a reliable technique for the diagnosis of cutaneous diseases when experts in dermatopathology are not available locally . Furthermore , teledermatopathology is attractive because it provides an opportunity to obtain timely consultation on difficult cases PURPOSE To evaluate the use of remote reading of digital retinal photographs in the diagnosis of severe ( referral-warranted ) retinopathy of prematurity ( ROP ) during longitudinal screening for ROP . STUDY DESIGN Prospect i ve , longitudinal cohort study . SUBJECTS Forty-four consecutive premature infants at risk for ROP . METHODS All infants were examined longitudinally , over a series of examinations , by indirect ophthalmoscopy ( gold st and ard ) and digital photography using the RetCam-120 Digital Retinal Camera ( Massie Research Laboratories Inc. , Dublin , CA ) equipped with an ROP lens . Images were stored and read remotely by a masked reader . Referral-warranted ROP was defined as ROP in zone 1 , the presence of plus disease or the presence of any stage 3 ROP . We determined whether and when referral-warranted ROP was diagnosed for each eye , of each infant , on each examination , during the course of each of the infant 's screening . RESULTS Severe ( referral-warranted ) ROP was diagnosed in 23 eyes by indirect ophthalmoscopy during their series of examinations . Digital photography had a sensitivity of 100 % and a specificity of 96 % in detecting referral-warranted ROP . The positive predictive value of digital photography was 92 % , and the negative predictive value was 100 % . In 87 % of eyes , referral-warranted ROP was diagnosed by digital photography before or at the same time as indirect ophthalmoscopy . CONCLUSIONS Longitudinal remote reading of digital photographs using the RetCam-120 system has excellent specificity and sensitivity in detecting referral-warranted ROP . This pilot study has shown that remote reading of digital photographs has promise for telemedicine strategies in ROP screening OBJECTIVE To evaluate the reliability of strabismus assessment using telemedicine ( TM ) technology . DESIGN Two prospect i ve interobserver agreement studies . One study compared the agreement between a st and ard and a TM examination , whereas the other assessed agreement between two independent st and ard examinations . PARTICIPANTS Strabismus patients over 4 years of age examined at a remote community clinic and patients assessed in a strabismologist 's urban practice . METHODS Forty-two patients were examined in person by a pediatric ophthalmologist at the remote community and independently by a pediatric ophthalmology fellow by means of TM ( TM-st and ard study ) . The TM examination was performed with the help of a qualified ophthalmic assistant at the remote telecommunication center using a Power Cam 100 camera , a Picture Tel Concorde 4500 teleconferencing system , and a 224 kilobyte b and width . For comparison , independent in person examinations were performed on 43 patients by both examiners ( st and ard-st and ard study ) . Agreement was measured using unweighted kappa ( k ) for categorical data , the intraclass correlation coefficient ( ICC ) for continuous data , and percent agreement . The odds of disagreement with TM ( comparing the TM-st and ard versus st and ard-st and ard studies ) was assessed with logistic regression analysis . MAIN OUTCOME MEASURES Three parameters were assessed : ( 1 ) category of strabismus , determined by observation without cover test ; ( 2 ) angle of deviation at 0.33 and 6.0 m ; and ( 3 ) ocular muscle action . RESULTS Agreement on the category of strabismus was good ( k > 0.61 ) other than for vertical deviations . However , there was good to excellent agreement between TM and st and ard examinations on the vertical ( ICC = 0.78 ) and horizontal ( ICC = 0.79 ) angles of deviation with 6-m fixation with the cover test . Muscle ratings agreed within one point for the lateral , superior , and inferior rectus muscle actions in more than 90 % of the eyes examined . Although good agreement was observed in the TM-st and ard study , it was inferior to the agreement in the st and ard-st and ard study . Examination by TM increased the odds of disagreement compared with examination in person by twofold to threefold . CONCLUSIONS Strabismus examination can be performed with a good level of reliability with the use of medium b and width video teleconferencing equipment . However , reduced reliability has been noted in the detection of small vertical deviations by inspection and in evaluating oblique muscle actions BACKGROUND Outcomes related to chronic heart failure ( HF ) remain relatively poor , despite advances in pharmacological therapy and medical and nursing care . Experts agree that outpatient care may be among the factors that affect HF outcomes . We hypothesized that the method by which outpatient care is delivered may affect outcomes in this patient population . METHODS A prospect i ve , r and omized design was used to compare HF outcomes from 216 patients r and omized to 1 of 2 home health care delivery methods for 3 months after discharge . Care was delivered by the home nurse visit ( HNV ) or the nurse telemanagement ( NTM ) method . In the latter , patients used transtelephonic home monitoring devices to measure their weight , blood pressure , heart rate , and oxygen saturation . These data were transmitted daily to a secure Internet site . An advanced- practice nurse worked collaboratively with a cardiologist and subsequently treated patients via the telephone . Both delivery methods used the same HF-specific clinical guidelines to direct care . Outcomes include HF readmissions and length of stay , anxiety , depression , self-efficacy , and quality of life . Data were primarily tested using a 2-group analysis of variance ( ANOVA ) . We used a repeated- measures ANOVA to conduct preintervention-postintervention analyses . RESULTS After 3 months , patients in the NTM group ( n = 108 ; mean + /- SD age , 62.9 + /- 13.2 years ; 83 % African American ; 64 % female ) had fewer HF readmissions ( 13 vs 24 ; P</=.001 ) with shorter lengths of stay ( 49.5 vs 105.0 days ; P</=.001 ) compared with the HNV group ( n = 108 ; mean + /- SD age , 63.2 + /- 12.6 years ; 89 % African American ; 62 % female ) . Hospitalization charges at 3 months were less in the NTM group compared with the HNV group ( $ 65 023 vs $ 177 365 ; P</=.02 ) . At 6 and 12 months , cumulative readmission charges in the NTM group were also less ( $ 223 638 vs $ 500 343 [ P<.03 ] and $ 541 378 vs $ 677 710 [ P</=.16 ] , respectively ) compared with the HNV group . Quality of life was significantly improved for both groups when we compared postintervention and preintervention scores . CONCLUSION The adaptation of state-of-the-art computerized technology to closely monitor patients with HF with advanced- practice nurse care under the guidance of a cardiologist significantly improves HF management while reducing the cost of care This study compared health-related outcomes , during a 1-year period , for two groups of frail elders-one that received care coordination via distance monitoring ( home-telehealth ) and one that received no intervention . A case-control design was employed . The home telehealth intervention group was made up of 111 male veterans who were enrolled in a Veterans Health Administration project . The control group consisted of 115 men who were referred from either senior service agencies or hospital rehabilitation programs , but did not receive home-telehealth . Subjects in both groups had primary diagnoses of hypertension , diabetes , respiratory disease , or heart disease . The two groups were similar in terms of age , race , marital status , and independence in instrumental activities of daily living ( IADL ) at baseline . A paired t-test was used to study the before-after ( baseline to 12-month follow-up ) improvements in the outcome measures within each group . Regression models were used to compare the outcome improvements between the two groups . Over 1 year , the intervention group improved 2.2 points more in IADL , 14.4 points more in FIM motor scores , and 2.7 points more in FIM cognitive scores than the control group ( p < 0.0001 ) . This evidence supports the use of a specific home-telehealth strategy for care coordination to improve functional independence in non-institutionalized veterans with chronic disease . A r and omized controlled trial should be employed to confirm these findings OBJECTIVE To test the hypothesis that telemedicine for new patient referrals to neurological out patients is as efficient and acceptable as conventional face to face consultation . METHODS A r and omised controlled trial between two groups : face to face ( FF ) and telemedicine ( TM ) . This study was carried out between a neurological centre and outlying clinics at two distant hospitals linked by identical medium cost commercial interactive video conferencing equipment with ISDN lines transmitting information at 384 kbits/s . The same two neurologists carried out both arms of the study . Of the 168 patients who were suitable for the study , 86 were r and omised into the telemedicine group and 82 into the face to face group . Outcome measures were ( 1 ) consultation process : ( a ) number of investigations ; ( b ) number of drugs prescribed ; ( c ) number of patient review s and ( 2 ) patient satisfaction : ( a ) confidence in consultation ; ( b ) technical aspects of consultation ; ( c ) aspects surrounding confidentiality . Diagnostic categories were also measured to check equivalence between the groups : these were structural neurological , structural non-neurological , non-structural , and uncertain . RESULTS Diagnostic categories were similar ( p>0.5 ) between the two groups . Patients in the telemedicine group had significantly more investigations ( p=0.001 ) . There was no difference in the number of drugs prescribed ( p>0.5 ) . Patients were generally satisfied with both types of consultation process except for concerns about confidentiality and embarrassment in the telemedicine group ( p=0.017 and p=0.005 respectively ) . CONCLUSION Telemedicine for new neurological out patients is possible and feasible but generates more investigations and is less well accepted than face to face examination BACKGROUND The current model of general practitioner referral of patients to hospital specialists in the UK is sometimes associated with unnecessary duplication of investigations and treatments . We aim ed to compare joint teleconsultations between general practitioners , specialists , and patients ( virtual outreach ) with st and ard outpatient referral . METHODS Virtual outreach services were established in London and Shrewsbury . The general practitioners referred 3170 patients , of whom 2094 consented to participate in the study and were eligible for inclusion . 1051 patients were r and omly assigned virtual outreach , and 1043 st and ard outpatient appointments . We followed up the patients for 6 months after their index consultation . The primary outcome measure was the offer of a follow-up outpatient appointment . Analysis was by intention to treat . FINDINGS More patients in the virtual outreach group than the st and ard group were offered a follow-up appointment ( 502 [ 52 % ] vs 400 [ 41 % ] , odds ratio 1.52 [ 95 % CI 1.27 - 1.82 ] , p<0.0001 ) . Significant differences in effects were observed between the two sites ( p=0.009 ) and across different specialties ( p<0.0001 ) . Virtual outreach increased the offers of follow-up appointments more in Shrewsbury than in London , and more in ear , nose , and throat surgery and orthopaedics than in the other specialties . Fewer tests and investigations were ordered in the virtual outreach group by an average of 0.79 per patient ( 0.37 - 1.21 , p=0.0002 ) . Patients ' satisfaction ( analysed per protocol ) was greater after a virtual outreach consultation than after a st and ard outpatient consultation ( mean difference 0.33 scale points [ 95 % CI 0.23 - 0.43 ] , p<0.0001 ) , with no heterogeneity between specialties or sites . INTERPRETATION The trial showed that allocation of patients to virtual outreach consultations is variably associated with increased offers of follow-up appointments according to site and specialty , but leads to significant increases in patients ' satisfaction and substantial reductions in tests and investigations . Efficient operation of such services will require appropriate selection of patients , significant service reorganisation , and provision of logistical support OBJECTIVE To determine whether diabetes education can be provided as effectively through telemedicine technology as through in-person encounters with diabetes nurse and nutrition educators . RESEARCH DESIGN AND METHODS A total of 56 adults with diabetes were r and omized to receive diabetes education in person ( control group ) or via telemedicine ( telemedicine group ) and were followed prospect ively . The education consisted of three consultative visits with diabetes nurse and nutrition educators . The in-person and telemedicine groups were compared using measures of glycemic control ( HbA(1c ) ) and question naires to assess patient satisfaction and psychosocial functioning as related to diabetes . Outcome measures were obtained at baseline , immediately after the completion of diabetes education , and 3 months after the third educational visit . RESULTS Patient satisfaction was high in the telemedicine group . Problem Areas in Diabetes scale scores improved significantly with diabetes education ( adjusted P < 0.05 , before vs. immediately after education and 3 months after education ) , and the attainment of behavior-change goals did not differ between groups . With diabetes education , HbA(1c ) improved from 8.6 + /- 1.8 % at baseline to 7.8 + /- 1.5 % immediately after education and 7.8 + /- 1.8 % 3 months after the third educational visit ( unadjusted P < 0.001 , P = 0.089 adjusted for BMI and age ) , with similar changes observed in the telemedicine and in-person groups . CONCLUSIONS Diabetes education via telemedicine and in person was equally effective in improving glycemic control , and both methods were well accepted by patients . Reduced diabetes-related stress was observed in both groups . These data suggest that telemedicine can be successfully used to provide diabetes education to patients Background and Purpose — Despite Food and Drug Administration approval of tissue-type plasminogen activator for stroke , obstacles in the US healthcare system prevent its widespread use . The Remote Evaluation for Acute Ischemic Stroke ( REACH ) program was developed to address these issues in rural setting s. A key component of stroke assessment in the REACH system is the National Institutes of Health Stroke Scale ( NIHSS ) evaluation . We sought to determine whether , using the REACH system , NIHSS values of bedside and remote evaluators would correspond . Methods — Twenty patients were recruited . On obtaining consent , a neurologist performed a bedside NIHSS evaluation on each patient . Within 1 hour , using any broadb and -connected workstation — either office or home personal computer and a l and line phone to speak with the patient — a second neurologist remotely evaluated the patient through the REACH system . Paired t tests and Pearson correlation coefficients were used to examine NIHSS reliability performed bedside and remotely . Results — NIHSS ranged from 1 to 24 . Correlations between bedside and remote locations ( r = 0.9552 , P = 0.0001 ) were very strong , and t tests indicate that the means were not different . Conclusions — The NIHSS can be reliably performed over the REACH system . This supports our endeavor to bring stroke expertise to rural community hospitals Background and Purpose — In acute stroke care , rapid but careful evaluation of patients is m and atory but requires an experienced stroke neurologist . Telemedicine offers the possibility of bringing such expertise quickly to more patients . This study tested for the first time whether remote video examination is feasible and reliable when applied in emergency stroke care using the National Institutes of Health Stroke Scale ( NIHSS ) . Methods — We used a novel multimedia telesupport system for transfer of real-time video sequences and audio data . The remote examiner could direct the set-top camera and zoom from distant overviews to close-ups from the personal computer in his office . Acute stroke patients admitted to our stroke unit were examined on admission in the emergency room . St and ardized examination was performed by use of the NIHSS ( German version ) via telemedicine and compared with bedside application . Results — In this pilot study , 41 patients were examined . Total examination time was 11.4 minutes on average ( range , 8 to 18 minutes ) . None of the examinations had to be stopped or interrupted for technical reasons , although minor problems ( brightness , audio quality ) with influence on the examination process occurred in 2 sessions . Unweighted & kgr ; coefficients ranged from 0.44 to 0.89 ; weighted & kgr ; coefficients , from 0.85 to 0.99 . Conclusions — Remote examination of acute stroke patients with a computer-based telesupport system is feasible and reliable when applied in the emergency room ; interrater agreement was good to excellent in all items . For more widespread use , some problems that emerge from details like brightness , optimal camera position , and audio quality should be solved Effective cognitive-behavioral treatments for childhood depression have developed over the last decade , but many families face barriers to such care . Telemedicine increases access to psychological interventions by linking the child and the clinician using videoconferencing ( VC ) . The current study evaluated an 8-week , cognitive-behavioral therapy ( CBT ) intervention for childhood depression either face-to-face ( F2F ) or over VC . The telemedicine setup included two PC-based PictureTel systems at 128 kilibits per second ( kbps ) . Success was defined by ( 1 ) decreasing depressive symptoms at similar rates in both the VC group and the F2F group and ( 2 ) demonstrating the feasibility of a r and omized controlled trial in telemental health . Children were assessed for childhood depression using the mood section of the Schedule for Affective Disorders and Schizophrenia for School Age Children-Present Episode ( K-SADS-P ) . Twenty-eight children were r and omized to either F2F or VC treatment . The participants completed the K-SADS-P and the Children 's Depression Inventory ( CDI ) at pre- and post-treatment . The CBT treatment across the two conditions was effective . The overall response rate based on post-evaluation with the K-SADS-P was 82 % . For the CDI total score , both the Time and the Group by Time effects were significant ( p < 0.05 ) . The interaction effect reflected a faster rate of decline in the CDI total score for the VC group . The study serves as a model for building on past research to implement a r and omized controlled trial . This information provides persuasive research data concerning treatment effectiveness for clinicians , families , and funders This study reports on secondary data , depression , fatigue and health-related quality of life ( HRQOL ) , collected on people with advanced multiple sclerosis ( MS ) as part of a larger study of the impact of a telerehabilitation intervention on people with severe mobility impairment . People with spinal cord injuries ( SCIs ) ( n=111 ) and the prevention of pressure sores were the primary group of interest of the project . The focus here is on data collected from people with advanced MS ( n=27 ) , who were included as an exploratory cohort , as they experience increased risk of pressure ulcer development as their level of mobility declines . The study consisted of a nine-week intervention with three r and omized groups : video , telephone , and st and ard care . Aside from information on pressure sores , data were also collected on fatigue , depression , and HRQOL for a two-year follow-up period . For the video group HRQOL scores trended higher and fatigue and depression scores lower for 24 months . Fatigue scores were significantly lower for the video group at month six , 12 , and 18 . In the sample overall , fatigue symptoms were far more prominent than depressive symptoms and affected 100 % higher rates of depression than women . At baseline , controlling for Extended Disability Status Score ( EDSS ) , depression and fatigue were correlated . However , contrary to indications from previous cross-sectional studies , no consistent relationship was observed over time between the two . Telerehabilitation interventions for people with advanced MS warrant further investigation . Findings here suggest that such interventions may be beneficial , although the results need affirmation through larger sample s. In addition , the higher prevalence of male depression merits serious attention The Telehealth program at East Carolina University has developed a system for real-time assessment of auditory thresholds using computer driven control of a remote audiometer via the Internet . The present study used 45 adult participants in a double-blind study of 2 different systems : a conventional audiometer and an audiometer operated remotely via the Internet . The audiometric thresholds assessed by these 2 systems varied by no more than 1.3 dB for air conduction and 1.2 dB for bone conduction . The results demonstrated the feasibility of this new " telehearing " audiometric system . With the rapid development of Internet-based applications , telehealth has the potential to provide important healthcare coverage for rural areas where specialized audiological services are lacking OBJECTIVE To determine whether radiologists ' interpretations of images are biased by their context and by prevalence of disease in other recently observed cases . METHODS A test set of 24 right pulmonary arteriograms with a 33 % prevalence of pulmonary emboli ( PE ) was assembled and embedded in 2 larger groups of films . Group A contained 16 additional arteriograms , all showing PE involving the right lung , so that total prevalence was 60 % . Group B contained 16 additional arteriograms without PE so that total prevalence was 20 % . Six radiologists were r and omly assigned to see either group first and then " cross over " to review the other group after a hiatus of at least 8 weeks . The direction of changes in a 5-point rating scale for the 2 readings of each film in the test set was compared with the sign test ; mean sensitivity , specificity , and areas under receiver operating characteristic ( ROC ) curves were compared with the paired t test . RESULTS In the context of group A 's higher disease prevalence , radiologists shifted more of their diagnoses toward higher suspicion than expected by chance ( P=.03 , sign test ) . In group A , mean sensitivity for diagnosing PE was significantly higher ( 75 % vs 60 % ; P=.04 ) , and area under the ROC curve was significantly larger ( 0.88 vs 0.82 ; P=.02 ) . CONCLUSIONS Radiologists ' diagnoses are significantly influenced by the context of interpretation , even when spectrum and verification bias are avoided . This " context bias " effect is unique to the evaluation of subjectively interpreted tests , and illustrates the difficulty of obtaining unbiased estimates of diagnostic accuracy for both new and existing technologies Abstract Objectives To assess the accuracy and efficiency of telemedicine in diagnosing and managing eye problems presenting to accident and emergency departments . Design A controlled trial with a face-to-face and telemedicine phases , each involving 40 patients undergoing two consecutive consultations . In the face-to-face phase , both consultations were in person ; in the telemedicine phase , observer 1 used videoconferencing technology at 384 kbit/s ( separate nonslit lamp – torchlight and slit lamp examinations ) and observer 2 saw the patient face to face . Setting The accident and emergency department at Moorfields Eye Hospital . Participants In total , 80 consenting new patients presenting to the department . Main outcome measures ( 1 ) Agreement levels between the two observers for each phase ( judged by an independent masked investigator ) , ( 2 ) length of consultation , and ( 3 ) number of unnecessary recalls . Results Agreement rates were as follows . Face-to-face phase : total agreement ( 30/40=75 % ) , trivial disagreement ( 8/40=20 % ) , clinical ly important disagreement ( 2/40=5 % ) . Telemedicine phase ( torchlight ) : complete agreement ( 16/40=40 % ) , trivial disagreement ( 20/40=50 % ) , clinical ly important disagreement ( 4/40=10 % ) . Telemedicine phase ( slit lamp ) : total agreement ( 23/40=58 % ) , trivial disagreement ( 15/40=37 % ) , clinical ly important disagreement ( 2/40=5 % ) . Agreement levels in the telemedicine phase with torchlight examination were significantly lower ( χ2=10.07 , P=0.007 ) for any disagreement . Telemedicine consultations erred on the side of clinical caution and were no slower than face-to-face consultations ( mean 6 min for observer 1 in both phases ) . Recalls were more likely ( χ2=5.16 , P=0.02 ) after telemedicine consultations with torchlight only ( 9/40 ) compared with face-to-face consultations ( 2/40 ) . Although there were more significant disagreements using the telemedicine , in each case the telemedicine diagnosis and management erred on the side of safety ; hence , no patient would have suffered by wrong management because of the consultation using telemedicine . Conclusions Telemedicine was found to be an accurate , safe , and efficient method of diagnosing and managing these patients , especially if slit lamp images were used . Advice using telemedicine erred on the side of caution , which result ed in more recalls We carried out a pilot study on the feasibility and accuracy of store- and -forward teledermatology based on patient-provided images and history as a triage tool for outpatient consultation . Patients referred by their general practitioner provided a history and images via the Internet . The information was review ed by one of 12 teledermatologists and the patient then visited a different dermatologist in person within two days . Three independent dermatologists compared the remote and in-person diagnoses in r and om order to determine diagnostic agreement . Broader agreement was also measured , by comparing the main disease groups into which the two diagnoses fell . The teledermatologists indicated whether an in-person consultation or further investigations were necessary . There were 105 eligible patients , aged four months to 72 years , who were willing to participate . For the 96 cases included in the analysis , complete diagnostic agreement was found in 41 % ( n= 39 ) , partial diagnostic agreement in 10 % ( n= 10 ) and no agreement in 49 % ( n= 47 ) . There was disease group agreement in 66 % of cases ( n= 63 ) . Nearly a quarter ( 23 % ) of participating patients could have safely been managed without an in-person visit to a dermatologist We conducted a r and omized case control study of referrals from a primary care centre in Finl and . All the consultations and referrals from seven general practitioners ( GPs ) dealt with by internists and surgeons at Satakunta Central Hospital in Pori and geriatricians at Satalinna Hospital in Harjavalta over five months were included . For patients in the control group , a conventional referral letter was sent to the hospital outpatient clinic . For patients in the intervention group , the GPs had to decide whether they wanted an electronic consultation with the hospital or wanted to refer the patient ( i.e. to transfer responsibility for treatment ) . Communication with the hospital specialist was then via a secure Web-based system . Ninety-three patients consented to participate in the study . None refused , although there were 15 non-attenders . Satisfaction data were collected from question naires completed by the patients and doctors . All the patients treated by teleconsultation said that they wanted the same procedure in future and 63 % of the control group said they would prefer a teleconsultation next time . The doctors quickly learned to exploit the telemedicine model successfully . The responsibility for treatment was maintained in the health centre in 52 % of cases using teleconsultation , without any visit to hospital being required . The GPs and the hospital doctors agreed on the follow-up treatment . Telereferral increased the possibility of the GP maintaining responsibility for the treatment . The reduced number of hospital visits in the telemedicine model should produce significant cost savings Recent advances in information and communication technology allow the design and testing of new models of diabetes management , which are able to provide assistance to patients regardless of their distance from the health care providers . The M2DM project , funded by the European Commission , has the specific aim to investigate the potential of novel telemedicine services in diabetes management . A multi-access system based on the integration of Web access , telephone access through interactive voice response systems , and the use of palmtops and smart modems for data downloading has been implemented . The system is based on a technological platform that allows a tight integration between the access modalities through a middle layer called the multi-access organizer . Particular attention has been devoted to the design of the evaluation scheme for the system : A r and omized controlled study has been defined , with clinical , organizational , economic , usability , and users ' satisfaction outcomes . The evaluation of the system started in January 2002 . The system is currently used by 67 patients and seven health care providers in five medical centers across Europe . After 6 months of usage of the system no major technical problems have been encountered , and the majority of patients are using the Web and data downloading modalities with a satisfactory frequency . From a clinical viewpoint , the hemoglobin A1c ( HbA1c ) of both active patients and controls decreased , and the variance of HbA1c in active patients is significantly lower than the control ones . The M2DM system allows for the implementation of an easy-to-use , user-tailored telemedicine system for diabetes management . The first clinical results are encouraging and seem to substantiate the hypothesis of its clinical effectiveness Abstract Aim To evaluate interobserver agreement for clinical signs in trabeculectomized eyes when examined face-to-face with slit-lamp biomicroscopy ( SL ) or by remote examination using telemedicine ( real-time remote video imaging ; TM ) . Method A system for examining trabeculectomized eyes was devised and vali date d. A prospect i ve r and omized interobserver agreement study was then undertaken to compare st and ard SL biomicroscopy and TM . Remote examination was performed using a 384 kbps Sony 5100 videoconferencing system . Three ophthalmologists each examined 40 eyes of 40 patients , who had previously undergone trabeculectomy . In rotation , two examiners used SL biomicroscopy . The third examined the eye remotely by TM . Analysis was performed to determine the variability in clinical signs and the presence or absence of systematic bias between ophthalmologists and examination methods . Results High levels of agreement were observed for paired examinations by SL biomicroscopy ( SL/SL ) for bleb vascularity ( score range 0–10 ) with no systematic bias . Paired examination by SL and TM ( SL/TM ) also showed good levels of agreement for bleb vascularity , although the spread of disagreement was wider ( 95 % limits of agreement 2.57 vs 2.98 ( P=0.054 ) ) . For anterior chamber depth , observers agreed within ±10 % of anterior chamber depth for 68 % of eyes ( SL/SL ) and 51 % of eyes ( SL/TM ) ( P=0.68 ) . Agreement was ‘ good ’ for wall thickness ( κ=0.63±0.08 ) , bleb height ( κ=0.67±0.1 ) , and the existence of bleb leak ( κ=0.63±0.19 ) , but poor for bleb morphology ( κ=0.26±0.12 ) . For the SL/TM comparison , agreement was fair for wall thickness ( κ=0.39±0.13 ) , poor for bleb height ( κ=0.17±0.12 ) , good for bleb leak ( κ=0.56±0.19 ) , and fair for bleb morphology ( κ=0.31±0.12 ) . Microcysts were not reliably detected using either technique . Conclusion SL biomicroscopy and TM telemedicine examination may permit reliable clinical assessment of trabeculectomized eyes . However , remote examination with TM is more limited with respect to assessing bleb height and bleb wall thickness . The assessment of bleb morphology and microcysts was unreliable with both instruments . We propose that TM examination of trabeculectomized eyes appears safe and appropriate in situations where face-to-face examination by an ophthalmologist is not practical The efficacy of telemedicine technology was tested for equivalence of nursing assessment with chronic congestive heart failure ( CHF ) home care patients ( N = 28 ) . The equivalence of nurses ' physical assessment findings was estimated using an innovative two-way , telemedicine audiovisual system . Nurses were r and omly assigned to a method of client assessment : on-site ( real time ) or telemedicine ( monitor time ) . Each assessment was performed within 10 minutes of each other . Assessment variables compared were auscultation of lung sounds , heart sounds , rate and rhythm , blood pressure , weight , edema , respiratory effort , and client 's face , lip , and nail color . Eighteen physiological parameters were analyzed , using either the Wilcoxon signed ranks test or the McNemar test . Results indicate few significant differences between the assessment s of the real time and monitor time nurses . The monitor nurse was more likely to cl aim abnormality than the real nurse was when assessing the color of nails ( p = .048 ) . The real nurse picked up ankle edema ( p = .024 ) , pedal edema ( p = .099 ) , and inspiratory wheeze ( p = .01 ) more frequently than did the monitor nurse . Kappa coefficients to determine the extent of agreement between nurse 's assessment s were significant . Nurses ' comments were favorable , but they recommended altering the interview to elicit symptoms not easily observed by the monitor nurse such as diaphoresis . Exit interviews of the elderly patients revealed a favorable reaction to using the telemedicine monitor , citing a quick connection to a nurse and response to their concerns and questions . Both nurses and patients reported the need to have real nurse home visits along with telemedicine visits BACKGROUND Gastrointestinal ( GI ) endoscopy is an effective tool to screen for cancers of the digestive tract . However , access to endoscopy is limited in many parts of South Carolina . This trial is a part of a prospect i ve multi-part study for remote cancer screening in coastal South Carolina . This pilot study was to evaluate the quality of tele-endoscopy for cancer screening . METHODS 10 patients scheduled for endoscopic procedures were observed simultaneously by the endoscopist and a remote observer connected over a 512 kbps ISDN line . Findings by both were compared for concordance on malignant or premalignant lesions . RESULTS The image quality was adequate to support remote diagnosis of GI cancer and abnormal lesions by an experienced observer . However , assessment of the esophagogastric junction for Barrett 's esophagus was equivocal . CONCLUSIONS Overall , our tele-endoscopy setup shows great promise for remote supervision or observation of endoscopic procedures done by nurse endoscopists . Tele-endoscopy is both adequate and feasible for diagnosis of most gastrointestinal lesions . Subtle lesions still may be missed in our current setup . However , improvements are being made in our setup to address the problem with resolution prior to further evaluation BACKGROUND Patients with chronic heart failure characteristically have multiple hospital admissions for symptom control , deleteriously affecting their quality of life and imposing a burden on national healthcare costs . We assessed the effect of a novel transtelephonic monitoring and follow-up program on the admission rate and length of hospital stay as well as changes in their subjectively rated quality of life of patients with chronic heart failure . METHODS This prospect i ve 1-year study was conducted on compliant subscribers to ' SHL ' , a telecardiological service with > 60,000 subscribers , who were admitted > or = 2 times during the previous year for recurrent pulmonary edema or deterioration in heart failure . Their heart rate , blood pressure and body weight measurements were now automatically transmitted daily to ' SHL"s data bank and added to stored and up date d medical records . A question naire survey acquired information on their quality of life . RESULTS The study cohort included 118 patients , mean age 75 years ( range 49 - 89 years ) , 65 % males , a II-IV class functional capacity and a 25 % ( range 10 - 39 % ) mean ejection fraction . There was a 66 % reduction in the total hospitalization days ( from 1623 in the year preceding study entry to 558 during the study period , p<0.0001 ) . Although only 38/118 patients were hospitalized , most participants reported a significant subjective improvement in their quality of life . CONCLUSIONS Data are provided to demonstrate that a transtelephonic system allowing primary care at the patient 's home can significantly reduce hospitalization rate and length of stay and significantly enhance the quality of life of patients with chronic heart failure OBJECTIVE To determine the relative efficacy of store- and -forward teledermatology vs face-to-face dermatology consultations in triage decisions about the need for a biopsy of neoplastic skin changes . DESIGN Prospect i ve study of consecutive patients judged by an internist to require dermatologic consultation for a skin growth . SETTING Private primary care and dermatology practice s and an academic dermatology practice . PATIENTS Patients requiring dermatology consultation for evaluation of skin growths . Patients were seen by a single primary care physician between July 10 , 1998 , and August 4 , 2000 . INTERVENTION Digital photographs of skin growths were obtained by the primary care physician and evaluated by a teledermatologist . The patient was then seen face-to-face by a dermatologist . A biopsy was performed if either dermatologist favored biopsy . MAIN OUTCOME MEASURES Decisions to perform a biopsy . Agreement between the dermatologists was assessed . RESULTS Of the 49 patients with evaluable photographs , the face-to-face dermatologist and teledermatologist recommended a biopsy for the same 26 patients , yielding a sensitivity of the teledermatologist of 1.00 ( 95 % confidence interval [ CI ] , 0.87 - 1.00 ) and a specificity of 1.00 ( 95 % CI , 0.85 - 1.00 ) . The agreement between the dermatologists ( kappa ) was 1.00 ( 95 % CI , 0.72 - 1.00 ) . CONCLUSION Store- and -forward teledermatology may provide an accurate and cost-effective method of determining whether skin growths in patients presenting to primary care physicians should undergo biopsy BACKGROUND Canada 's vast size and remote rural communities represent a significant hurdle for successful monitoring and evaluation of diabetic retinopathy . Teleophthalmology may provide a solution to overcome this problem . We investigated the application of Joint Photographic Experts Group ( PEG ) compression to digital retinal images to determine whether JPEG compression could reduce file sizes while maintaining sufficient quality and detail to accurately diagnose diabetic retinopathy . METHODS All 20 patients with type 2 diabetes mellitus assessed at a 1-day teleophthalmology clinic in northern Alberta were enrolled in the study . Following pupil dilation , seven 30 degrees fields of each fundus were digitally photographed at a resolution of 2008 x 3040 pixels and saved in uncompressed tagged image file format ( TIFF ) . The files were compressed approximately 55x and 113x their original size using JPEG compression . A review er in Edmonton r and omly viewed all original TIFF images along with the compressed JPEG images in a masked fashion for image quality and for specific diabetic retinal pathology in accordance with Early Treatment Diabetic Retinopathy Study st and ards . The level of diabetic retinopathy and recommendations for clinical follow-up were also recorded . Exact agreement and weighted kappa statistics , a measure of reproducibility , were calculated . RESULTS Exact agreement between the compressed JPEG images and the TIFF images was high ( 75 % to 100 % ) for all measured variables at both compression levels . Reproducibility was good to excellent at both compression levels for the identification of diabetic retinal abnormalities ( K = 0.45 - 1 ) , diagnosis of level of retinopathy ( kappa = 0.73 - 1 ) and recommended follow-up ( kappa = 0.64 - 1 ) . INTERPRETATION The application of JPEG compression at ratios of 55:1 and 113:1 did not significantly interfere with the identification of specific diabetic retinal pathology , diagnosis of level of retinopathy or recommended follow-up . These results indicate that JPEG compression at ratios as high as 113:1 has the potential to reduce storage requirements without interfering with the accurate and reproducible teleophthalmologic diagnosis of diabetic retinopathy . This pilot project demonstrates the potential for JPEG compression within a digital teleophthalmology viewing system Home monitoring by lung transplant recipients has been effective for early detection of clinical problems . This study used an electronic diary for home monitoring by lung transplant c and i date s to improve communication between c and i date s and the transplant team . C and i date s were r and omized into control ( 52 subjects following st and ard telephone reporting procedures ) and intervention ( 67 subjects using an electronic diary to record and transmit a range of health-related measures ) groups . Outcome measures were monitoring adherence and level of communication ( for monitor acceptability and utilization ) , hospital length of stay after transplantation and survival at 4 months ( for clinical effectiveness ) . Subjects used the diary without difficulty and with good adherence . Subjects and coordinator contacts were similar between groups ; intervention group subjects were positive regarding contact based on diary use . There were no significant differences in clinical outcomes between groups . Changing diary questions might improve the effectiveness of electronic monitoring for lung transplant c and i date Background : Heart murmurs are common in children , and they are often referred to a specialist for examination . A clinical ly innocent murmur does not need further investigation . The referral area of the University Hospital is large and sparsely populated . A new service for remote auscultation ( telemedicine ) of heart murmurs in children was established where heart sounds and short texts were sent as an attachment to e-mails . Aim : To assess the clinical quality of this method . Methods : Heart sounds from 47 patients with no murmur ( n = 7 ) , with innocent murmurs ( n = 20 ) , or with pathological murmurs ( n = 20 ) were recorded using a sensor based stethoscope and e-mailed to a remote computer . The sounds were repeated , giving 100 cases that were r and omly distributed on a compact disc . Four cardiologists assessed and categorised the cases as having “ no murmur ” , “ innocent murmur ” , or “ pathological murmur ” , recorded the assessment time per case , their degree of certainty , and whether they recommended referral . Results : On average , 2.1 minutes were spent on each case . The mean sensitivity and specificity were 89.7 % and 98.2 % respectively , and the inter-observer and intra-observer variabilities were low ( kappa 0.81 and 0.87 ) , respectively . A total of 93.4 % of cases with a pathological murmur and 12.6 % of cases with an innocent murmur were recommended for referral . Conclusion : Telemedical referral of patients with heart murmurs for remote assessment by a cardiologist is safe and saves time . Skilled auscultation is adequate to detect patients with innocent murmurs The purpose of this pilot study was to ( a ) determine the feasibility of providing a heart failure disease management program through an in-home telehealth communication device ( Health Buddy ® ) and ( b ) compare the effectiveness of the Health Buddy ® with traditional home management strategies ( telephonic , home visit ) in achieving selected patient outcomes ( self-efficacy , functional status , depression , and health-related quality of life ) . Ninety participants completed the study through 2 months . Thirty percent of participants were either eliminated prior to or withdrawn after enrollment from the study based on Health Buddy ® issues . A mixed model ANOVA revealed those who received telephonic disease management experienced decreased confidence in their ability to manage their heart failure whereas all other groups experienced increased confidence . Further ANOVA analyses indicated improvement over time with no group differences for functional status , depression , or health-related quality of life . These findings suggest that delivering a disease management program through a telehealth communication device is feasible and may be as effective as traditional methods BACKGROUND Web-based home care monitoring systems can assess medication compliance , health status , quality of life , and physiologic parameters . They may help overcome some of the limitations associated with current congestive heart failure management models . OBJECTIVES This pilot study compared the effects of a self-care and medication compliance device , linked to a Web-based monitoring system , to the effects of usual care alone on compliance with recommended self-care behaviors ; medication taking ; quality of life ; distance walked during a 6-minute walk test ; and New York Heart Association Functional Class . We also assessed patient experiences living with the compliance device . METHODS We enrolled 18 patients with Functional Class II-III congestive heart failure in an urban VA Medical Center . The patients were r and omized into 2 groups . Group A received usual care plus the compliance device . Group B ( controls ) received usual care only . Data were collected using the compliance device , the Heart Failure Self-Care Behavior Scale , pill counts , 6-minute walk test , and the Minnesota Living with Heart Failure Question naire at baseline and at 3 months follow-up . RESULTS At baseline and at 3 months , there were no differences between the compliance device group and the usual care group in self-care behaviors , pill counts , 6-minute walk-test distance , or Functional Class . However , quality of life improved significantly from baseline to 3-month follow-up ( ANOVA , P = .006 ) . This difference was due to an improvement in quality of life for the monitor group ( P = .002 ) but not the usual care only group ( P = .113 ) . Patients in the compliance device group had a 94 % medication compliance rate , 81 % compliance with daily blood pressure monitoring , and 85 % compliance with daily weight monitoring as compared to 51 % for blood pressure monitoring and 79 % for weight monitoring in the usual care group ( P = NS ) . CONCLUSION These are promising pilot results that , if replicated in a larger sample , may significantly improve care and outcomes for patients with heart failure The objective was to evaluate digital images of the retina from a h and held fundus camera ( Nidek NM-100 ) for suitability in telemedicine screening of diabetic retinopathy . A h and held fundus camera ( Nidek ) and a st and ard fundus camera ( Zeiss ) were used to photograph 49 eyes from 25 consecutive patients attending our diabetic clinic . One patient had cataracts , making it impossible to get a quality image of one of the eyes ( retina ) . The Nidek images were digitized , compressed , and stored in a Fujix DF-10 M digitizer supplied with the camera . The digital images and the photographs were presented separately in a r and om order to three ophthalmologists . The quality of the images was ranked as good , acceptable or unacceptable for diabetic retinopathy diagnosis . The images were also evaluated for the presence of microaneurysms , blot hemorrhages , exu date s , fibrous tissue , previous photocoagulation , and new vessel formation . kappa Values were computed for agreement between the photographs and digital images . Overall agreement between the photographs and digital images was poor ( kappa < 0.30 ) . On average , only 24 % of the digital images were grade d as being good quality and 56 % as having an acceptable quality . However , 93 % of the photographs were grade d as good- quality images for diagnosis . The results indicate that the digital images from the h and held fundus camera may not be suitable for diagnosis of diabetic retinopathy . The images shown on the liquid crystal display ( LCD ) screen of the camera were of good quality . However , the images produced by the digitizer ( Fujix DF-10 M ) attached to the camera were not as good as the images shown on the LCD screen . A better digitizing system may produce better quality images from the Nidek camera INTRODUCTION In patients with acute myocardial infa rct ion ( AMI ) , considerable time elapses from symptom onset until initiation of thrombolytic therapy or primary percutaneous coronary intervention . Prehospital diagnosing can reduce time delays , and remote diagnosing using telemedicine may be appropriate in areas and countries where ambulances are not staffed with physicians . OBJECTIVES To evaluate whether it was technically feasible for physicians at a remote university hospital to diagnose ST-segment-elevation-AMI ( AMI(STelev ) ) in patients suspected of AMI , who were transported by ambulances to a local hospital . To determine associated prehospital delays and in-hospital treatment delays . METHODS Patients carried in telemetry equipped ambulances had 12-lead electrocardiograms ( ECGs ) acquired as soon as possible . En route to the local hospital the ECGs were transmitted to a remote university hospital , by use of the GSM-system . The physician on call at the university hospital interviewed the patients , who were provided with cellular phone headsets , and alerted the local hospital if signs of AMI(STelev ) , bundle-branch-block-AMI or malignant arrhythmia were detected . Patients transported by traditional ambulances were included in a prospect i ve control group . RESULTS In 214 ( 86 % ) of 250 patients prehospital diagnosing was successful . Geographically related transmission problems were the primary reason for failure . Ninety-eight per cent of transmitted electrocardiograms and obtained history takings were technically acceptable for diagnostic purpose s. Door-to-needle times were shorter amongst patients with AMI(STelev ) who were subjected to prehospital diagnosing ( n = 13 ) as compared with patients transported by traditional ambulances ( n = 14 ) ( 38 vs. 81 min ) ( P = 0.004 ) . CONCLUSIONS It was technically feasible to use telemedicine for remote prehospital diagnosing of patients suspected of AMI . Patients subjected to prehospital diagnosing had shorter door-to-needle times compared with a prospect i ve control group We studied whether consultations via videoconferencing and traditional outpatient clinic visits differ in terms of the implementation of the patient management plan during a one-year follow-up . First-admission and follow-up orthopaedic patients were r and omly allocated to an outpatient visit at the surgical department of Oulu University Hospital or to videoconferencing at a health centre in Pyhäjärvi . In a prospect i ve one-year study , there were 145 consecutive orthopaedic patients who met the inclusion criteria : 84 referred for their first visit to a specialist and 61 of them for follow-up . There were 66 males ( 46 % ) in the study population . Over half the patients had some form of regenerative arthritis : 15 % had hip arthritis , 33 % knee arthritis and 4 % other arthritis . There were no differences in the implementation of the management plan between the two groups . The study showed that videoconferencing is a valid alternative to outpatient clinic visits for orthopaedic specialist consultations OBJECTIVE The purpose of this study is to determine the impact of a home communication intervention ( HCI ) for ischemic heart failure Coronary Artery Bypass Graft ( CABG ) patients > /= 65 years of age on self-efficacy , coronary artery disease risk factor modification and functioning posthospitalization . DESIGN A r and omized clinical trial with repeated measures was used . SAMPLE A sub sample of ischemic heart failure CABG surgery patients ( n = 35 ) was drawn from the parent study of 180 CABG patients . RESULTS HCI participants ( n = 18 ) had significantly higher adjusted mean self-efficacy scores [ F(1 , 29 ) = 6.40 , P < .05 ] and adjusted mean levels of functioning ( physical , general health , mental , and vitality functioning ) compared with the routine care group ( n = 17 ) , using repeated measures analysis of covariance with baseline scores as covariates . There were also significant effects of time on bodily pain and role emotional functioning . Significantly higher exercise adherence ( t = 3.09 , P < .01 ) and lower reported stress ( t = 3.77 , P < .01 ) at 3 months after surgery was reported by HCI subjects . CONCLUSIONS Data from this pilot study can be used to strengthen the HCI intervention with more tailored strategies for vulnerable subgroups of CABG patients ABSTRACT This trial compared 3 post-hospitalization nursing care models for reducing congestive heart failure ( CHF ) readmission charges during 180-days of follow-up . Subjects received in-person visits at baseline and 60 days plus 1 of 3 care modalities in the interim : ( a ) video-based home telecare ; ( b ) telephone calls ; and ( c ) usual care . CHF-related read-mission charges were > 80 % lower in the telenursing groups compared to usual care , and these groups also had significantly fewer CHF-related emergency visits . In-person visits were more than 3 times longer than telenursing visits ( p < 0.0001 ) , only partially due to added travel time . Patient self-care adherence , medications , health status , and satisfaction did not significantly differ between groups . Telenursing can reduce CHF hospitalizations and allow increased frequency of communication with patients BACKGROUND Dementia is a common but frequently undiagnosed problem in aging . Barriers to early diagnosis include a lack of routine screening for dementia and a lack of access to specialty consultative services . We conducted a pilot study to see if telemedicine could provide reliable , accurate geriatric consultative services to evaluate patients for dementia who were residing at remote sites . METHODS This was a prospect i ve cohort study that compared the diagnostic reliability of telemedicine to an in-person examination for dementia . Eligible subjects were residents of a Washington State Veterans ' Home , age 60 years or older , with no prior diagnosis of dementia . Eligible subjects were screened for dementia using the 7-Minute Screen . Veterans who screened positive and consented to participate in the study received an in-person neuropsychiatric evaluation at baseline , and then both telemedicine and in-person examinations for dementia conducted by experienced geriatric psychiatrists . The accuracy of the telemedicine diagnosis was estimated by comparing it to the diagnosis from the clinical examination . Three geriatric psychiatrists who were blinded to the results of the clinical examination conducted the telemedicine and in-person examinations . We also assessed attitudes of the subjects and geriatric psychiatrists towards the telemedicine sessions . RESULTS Eighteen of 85 subjects screened were ' positive ' for dementia on the 7 Minute Screen . Of these , 16 consented to participate in the telemedicine study . Twelve of the 16 subjects were subsequently diagnosed with dementia by the telemedicine examination . The telemedicine diagnoses were in 100 % agreement with the diagnoses from the in-person clinical examinations . Moreover , the subjects reported a high degree of satisfaction with the telemedicine experience and that they would like to have further care through telemedicine in the future . The geriatric psychiatrists reported technical difficulties with the audio-visual quality of telemedicine in the initial phases of the project that resolved as familiarity with the telemedicine equipment increased . None of these problems had an adverse impact on the diagnostic accuracy of telemedicine . CONCLUSIONS We found that telemedicine was as accurate as an in-person clinical examination in establishing the diagnosis of dementia . In addition , subjects reported a high degree of satisfaction with telemedicine and a willingness to participate in telemedicine clinical care in the future . Given the large increase in the aging population and the shortage of geriatric psychiatrists nationally , it appears that telemedicine may be a promising means to exp and the availability of geriatric psychiatric consultation to remote areas T elemedicine enables doctors in rural areas or areas with poor medical service to consult with experts at distant locations . Telecolposcopy and cervicography both enable remote diagnoses of the cervix . The 2 methods differ in equipment , operations , image format , timeliness of consultation , and probably cost . However , these diagnostic approaches have not been compared previously . The purpose of this study was to compare the accuracy of telecolposcopy and cervicography with on-site colposcopy in the remote evaluation of women with potential cervical neoplasia Patients with a diagnosis of heart failure , registered at the study practice , were recruited into the study . First , they had a cardiologist 's assessment . They were then r and omised into telemonitored patients who measured pulse , BP , weight and video consulted , and controls Delivering psychotherapy by videoconference could significantly increase the accessibility of empirically vali date d treatments . The aim of this study was to compare the effectiveness of cognitive-behavior therapy ( CBT ) for panic disorder with agoraphobia ( PDA ) when the therapy is delivered either face-to-face or by videoconference . A sample of 21 participants was treated either face-to-face or by videoconference . Results showed that CBT delivered by videoconference was as effective as CBT delivered face-to-face . There was a statistically significant reduction in all measures , and the number of panic-free participants among those receiving CBT by videoconference was 81 % at post-treatment and 91 % at the 6-month follow-up . None of the comparisons with face-to-face psychotherapy suggested that CBT delivered by videoconference was less effective . These results were confirmed by analyses of effect size . The participants reported the development of an excellent therapeutic alliance in videoconference as early as the first therapy session . The importance of these results for treatment accessibility is discussed . Hypotheses are proposed to explain the rapid creation of strong therapeutic alliances in videoconferencing BACKGROUND African Americans have a higher prevalence and greater severity of hypertension than do other minorities and whites . This fact is particularly problematic when one realizes that the rate of control and treatment of hypertension in the US population is getting worse rather than better . Alternative strategies to promote blood pressure control need to be tested . OBJECTIVES The purpose of this pilot study was to test the following hypothesis : Persons who participate in nurse-managed home telemonitoring ( HT ) plus usual care or who participate in nurse-managed community-based monitoring ( CBM ) plus usual care will have greater improvement in blood pressure from baseline to 3 months ' follow-up than will persons who receive usual care only . METHODS This study used a r and omized controlled design ; participants were r and omly assigned to 1 of 3 groups that were stratified by use or nonuse of antihypertension medication . One-way analysis of variance ( ANOVA ) and analysis of covariance ( ANCOVA ) controlling for age and body weight were used to determine changes in blood pressure from baseline to 3 months . The sample contained 26 African Americans with a mean age of 59 years . RESULTS Both the HT group and the CBM group had clinical ly and statistically significant ( P < .05 ) drops in systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ) at 3 months ' follow-up , with participants in the HT group demonstrating the greatest improvement ( HT : baseline SBP 148.8 + /- 13.8 , DBP 90.2 + /- 5.79 ; 3 months ' follow-up SBP 124.1 + /- 13.82 , DBP 75.58 + /- 11.4 ; CBM : baseline SBP 155.25 + /- 17.014 , DBP 89.42 + /- 10.95 ; 3 months ' follow-up SBP 142.3 + /- 12.1 , DBP 78.25 + /- 6.86 ) . There was little change in SBP or DBP at 3 months ' follow-up in the usual care only group . CONCLUSION These are important pilot results , which if replicated in a larger sample will significantly improve care for urban African Americans with hypertension OBJECTIVE : To determine if the management of forefoot ulcerations through telemedicine is medically equivalent to ulcer care at a diabetes foot program . DESIGN : Nonr and omized comparison of forefoot ulcer healing rates SETTING : The Louisiana State University Health Sciences Center Diabetes Foot Program , Baton Rouge , LA , and Lallie Kemp Medical Center , Independence , LA PARTICIPANTS : Twenty consecutive patients with diabetes were treated for neuropathic forefoot ulcerations via telemedicine consultation and 120 consecutive patients with diabetes were treated face-to-face at a diabetes foot program . INTERVENTIONS : Management of forefoot ulcers by a certified wound care nurse trained in the use of a staged management approach algorithm and alternative off-loading methods , supported by real-time interactive telemedicine consultation . MAIN OUTCOME VARIABLES : Forefoot ulcer healing time in days , percentage of wounds healed in 12 weeks , and healing time ratio ( adjusted for age , gender , ulcer duration , location , size , crossover , and grade ) . RESULTS : No differences were found between the telemedicine and diabetes foot program groups in the average forefoot ulcer healing time ( 43.2 + 29.3 vs. and 45.5 + 43.4 days , P = .828 ) , the percent of forefoot ulcers healed in 12 weeks ( 75 % vs. 81 % , P = .546 ) and the adjusted healing time ratio ( 1.40 vs 1.00 , P = .104 ) . CONCLUSION : These data appear to support the effectiveness of real-time interactive telemedicine consultation in the management of diabetes-related forefoot ulceration BACKGROUND Patients with insulin dependent diabetes require frequent advice if their metabolic control is not optimal . This study focuses on the fiscal and administrative aspects of telemanagement , which was used to establish a supervised autonomy of patients on intensified insulin therapy . METHODS A prospect i ve , r and omised trial with 43 patients on intensified insulin therapy was conducted . Travelling distance to the diabetes centre was 50 min one way ; all patients had undergone a diabetes education course with lessons in dose adaptation . Patients were r and omly assigned to telecare ( n=27 ) or conventional care ( n=16 ) . They used BG-meters with a storage capacity of 120 values ( Precision QID Abbott/Medisense ) and transmitted their data over a combined modem/interface via telephone line to the diabetes centre . Data were displayed and stored by a customised software ( Precision Link Plus , Abbott/Medisense ) . Advice for proper dose adjustment was given by telephone . RESULTS Average time needed for instruction in the telemedical system was 15 min . Data were transmitted every 1 - 3 weeks and a teleconsultation was performed by phone every 2 - 4 weeks , depending on the extent of specific problems . On average , personal visits in the control group were performed once a month . Physician 's time expenditure for telemanagement , compared to conventional advice was moderately higher ( 50 vs. 42 min per month ) . A substantial amount of time on the patients side could be saved through replacing personal communications by telephone contacts and data transmission reduction ( 96 vs. 163 min/month including data transmission time ) . Setting up an optimal telemanagement scenario , a cost analysis was carried out yielding savings of approximately 650 euro per year per patient . HbA(1c ) dropped significantly from 8.2 to 7.0 % after 8 months of observation , but there was no significant difference between the intervention and control groups . Major technical problems with the telematic system did not occur during the study . CONCLUSIONS Telemanagement of insulin-requiring diabetic patients is a cost and time saving procedure for the patients and results in metabolic control comparable to conventional outpatient management OBJECTIVE Telepsychiatry is an increasingly common method of providing psychiatric care , but r and omized trials of telepsychiatric treatment compared to in-person treatment have not been done . The primary objective of this study was to compare treatment outcomes of patients with depressive disorders treated remotely by means of telepsychiatry to outcomes of depressed patients treated in person . Secondary objectives were to determine if patients ' rates of adherence to and satisfaction with treatment were as high with telepsychiatric as with in-person treatment and to compare costs of telepsychiatric treatment to costs of in-person treatment . METHOD In this r and omized , controlled trial , 119 depressed veterans referred for outpatient treatment were r and omly assigned to either remote treatment by means of telepsychiatry or in-person treatment . Psychiatric treatment lasted 6 months and consisted of psychotropic medication , psychoeducation , and brief supportive counseling . Patients ' treatment outcomes , satisfaction , and adherence and the costs of treatment were compared between the two conditions . RESULTS Hamilton Depression Rating Scale and Beck Depression Inventory scores improved over the treatment period and did not differ between treatment groups . The two groups were equally adherent to appointments and medication treatment . No between-group differences in dropout rates or patients ' ratings of satisfaction with treatment were found . Telepsychiatry was more expensive per treatment session , but this difference disappeared if the costs of psychiatrists ' travel to remote clinics more than 22 miles away from the medical center were considered . Telepsychiatry did not increase the overall health care re source consumption of the patients during the study period . CONCLUSIONS Remote treatment of depression by means of telepsychiatry and in-person treatment of depression have comparable outcomes and equivalent levels of patient adherence , patient satisfaction , and health care cost The practical , operational issues of access to medical care services are pivotal to all patients . Unlike other marketplaces , where the consumer is the decision maker , employers , payers , and providersrather than patients primarily influence the way the health care system functions . Patients often find themselves on the outside of the system , such as when employers switch health plans and patients must scramble for new providers . Some consumers are leaving the mainstream system to obtain various medical services , for example , using concierge physicians who charge annual fees for upscale service , overseas hospitals for surgery , and walk-in radiology screening services . The fact that patients and providers are leaving the system threatens to make health care access and delivery even more difficult for those who remain ( 1 - 7 ) . Business school students learn that consumers eventually get what they want ; who will give it to them and when are the unknowns . Although health care had been able in the past to function with little attention to consumer preference , the diffusion of consumer forces into health care is giving momentum to this iron law of consumerism . Given the central role of access in health carenothing can happen without itproviders have good reason to consider access from the patient 's perspective . This article presents patient-centered access as a philosophy and integrated concept . We define patient-centered access , identify its primary characteristics , discuss its key principles , and consider its future evolution . Parts of this article will strike a familiar cord . What is different is a comprehensive discussion of access innovation from the patient 's perspective . Related literature usually focuses on a specific access initiative , for example , e-mail communications with patients . All such initiatives are better understood in the broader context of overall system access . Patient-Centered Access Patient-centered access refers to a patient 's ability to secure appropriate and preferred medical assistance when and where it is needed . Characteristics of patient-centered access include availability , appropriateness , preference , and timeliness . Availability involves fundamental access : can a patient obtain a medical service ? Availability is primarily a function of offering a needed service in the patient 's geographic area and within the patient 's financial means . At least 1 of 7 Americans is uninsured , and the adverse effects on personal health and the health care system are well documented ( 8) . Appropriateness involves obtaining the proper level of care . Appropriateness is complicated by the potential discrepancy between what a patient wants and what is medically indicated . Today 's patients have far more access to medical information via the Internet and media . However , patients often lack the knowledge with which to filter and interpret this information . Providers influenced by patient pressure may facilitate inappropriate care , creating additional stress for an already overburdened system . Preference concerns patient access to a preferred provider or specific medical service . Patients may base preferences on experience , the recommendations of others , physical proximity , or marketing messages ( such as direct-to-consumer prescription drug advertising ) . The substantial market shift in recent years from health maintenance organizations to less restrictive preferred-provider organizations illustrates the salience of preference ( 9 , 10 ) . Timeliness concerns receiving care when desired . Most medical services are inseparable from patients ' physical presence . Access for inseparable services is complex because patients and providers must coordinate the time and location of the service . This need for coordination often creates a scenario in which patients are required to wait multiple times : for the primary care appointment , in the medical office , and for specialty care or tests ( 11 ) . Principles of Patient-Centered Access In Crossing the Quality Chasm , the Institute of Medicine proposed 6 aims for improvement in the 21st century : safety , effectiveness , patient-centeredness , timeliness , efficiency , and equitability ( 12 ) . Improving health care access supports each of these aims . A patient 's ability to secure appropriate and preferred medical assistance when and where it is needed should enhance safety , effectiveness , and equity ; will require efficiency ; and reflects patient-centeredness and timeliness . Improving health care access is at the center of improving health care . Enhancing access requires systemic thinking . The goals of patients , providers , and payers must be aligned . Providers that have succeeded in substantially improving access had to rebuild rather than fine-tune their service delivery system ; they focused on changing dysfunctional habits and assumptions as well as on technical medical issues ( 13 ) . As shown in the Figure , implementing patient-centered access requires embracing 3 principles : work at the high end of expertise ; align care with need and preference ; and serve when service is needed . In developing these principles , we conducted a comprehensive literature review from 1985 using the MEDLINE and Academic Health Reference Center data bases and search ing a targeted set of refereed medical journals . Figure . Implementing patient-centered access . Work at the High End of Expertise Many assume that the labor-intensive nature of health care makes productivity gains difficult to realize . Physicians are not assembly-line workers . Regardless of technology , physicians still need to see patients and integrate history , physical examination , test results , judgment born of experience , and specialized medical knowledge to create therapeutic plans . Nonetheless , health care productivity and access gains can be achieved by rethinking the process of who performs specific tasks and how . Health care access can be improved ( and cost of care decreased ) when members of the health care team , including the patient , work up to their training , skills , and experience . When health care professionals consistently work below their level of expertise , scarce re sources are wasted , care is more costly , boredom and frustration increase , and access is impaired . Specialist physicians should do less of what generalist physicians can do , generalist physicians should do less of what nonphysician providers can do , and nonphysician providers should do less of what non clinical staff can do . Each caregiver also should do less of what appropriately instructed patients and families can do for themselves . The application of information technology , team-provided care , and alignment of skills with tasks are necessary to implement this principle . Dr. Charles Burger 's primary care practice in Bangor , Maine , illustrates these approaches . Electronic medical records , examination room terminals , computerized decision support , and e-mail patient communications facilitate nurse practitioners , registered nurses , medical assistants , and patients working at high rather than low levels of their expertise ( 14 ) . For example , when patients call with a medical concern , receptionists use sophisticated triage software to determine whether to schedule an office visit , how soon and by whom the patient should be seen , and how much time the office visit will require ( 15 ) . The Mayo Clinic uses specially trained nonphysician providers for diabetes management after a physician conducts the initial evaluation and creates the care plan . The nonphysician provider monitors the patient and involves the physician if the patient experiences problems . The patient sees the physician at least once every 2 years . Mayo compared the team-care model to the physician-care model in an internal study in 2000 . Among the results was more timely access for patients . Other research supports fuller use of nonphysician provider skills and training ( 16 , 17 ) . In 1 r and omized clinical trial , research ers assigned 1316 patients to a primary care physician or a nurse practitioner . They found only minimal differences in health outcomes and patient satisfaction between the patient groups , although design and sampling issues limit generalizability ( 18 , 19 ) . Align Care with Need and Preference The conventional office visit access model does not fully accommo date patient heterogeneity . The office visit model works best for patients who need to be seen in person and can be well served in the time allotted for the appointment . However , this model often results in system overuse , such as when a patient familiar to the physician makes an office visit only to ask several quickly answered questions , and system underuse , such as when a 20-minute appointment slot prevents the physician from covering all relevant issues with the patient . As family physician Gordon Moore commented : One of the biggest mistakes in primary care is n't what we do to patients but what we omit ( 20 ) . Studies show a relationship between shorter office visits and inappropriate prescribing ( 21 ) , patient reluctance to ask questions ( 22 ) , less attention to psychological concerns ( 23 ) and patient education ( 24 , 25 ) , and lower levels of patient confidence and coping ( 26 ) . As Davidoff has written : The sad truth is that our trillion-dollar medical care system seems to feel that time spent with patients is a luxury it simply ca n't afford ( 27 ) . Diverse patient needs and preferences require a more flexible service delivery model that offers multiple entry paths into the practice . What might this system include in addition to the office visit with a physician ? Each of the following access paths is being used in more practice s. Office Appointments with Nonphysician Providers The use of nonphysician providers as autonomous providers within physician-staffed medical practice s is growing ( 28 ) because of the prevalence of chronic illness and pressure to control health care costs . The Balanced Budget Act of 1997 exp and ed direct Medicare reimbursement for physician Objectives . The authors present preliminary results on health-related outcomes of a r and omized trial of telehealth interventions design ed to reduce the incidence of secondary conditions among people with mobility impairment result ing from spinal cord injury ( SCI ) . Methods . Patients with spinal cord injuries were recruited during their initial stay at a rehabilitation facility in Atlanta , They received a video-based intervention for nine weeks , a telephone-based intervention for nine weeks , or st and ard follow-up care . Participants are followed for at least one year , to monitor days of hospitalization , depressive symptoms , and health-related quality of life . Results . Health-related quality of life was measured using the Quality of Well-Being ( QWB ) scale . QWB scores ( n = 111 ) did not differ significantly between the three intervention groups at the end of the intervention period . At year one post discharge , however , scores for those completing one year of enrollment ( n = 47 ) were significantly higher for the intervention groups compared to st and ard care . Mean annual hospital days were 3.00 for the video group , 5.22 for the telephone group , and 7.95 for the st and ard care group . Conclusions . Preliminary evidence suggests that in-home telephone or video-based interventions do improve health-related outcomes for newly injured SCI patients . Telehealth interventions may be cost-saving if program costs are more than offset by a reduction in rehospitalization costs , but differential advantages of video-based interventions versus telephone alone warrant further examination Teledermatology is the practice of dermatology across distances ( and time ) and involves the transfer of electronic information . To be effective and safe , the teledermatology process needs to demonstrate an acceptable level of accuracy and reliability . Accuracy is reflected by the degree of concordance ( agreement ) between the teledermatology and face‐to‐face diagnoses . Reliability is dependent on how consistently a set of results can be reproduced across different operators . Mean concordance ( primary diagnoses ) achieved by four dermatologists study ing 53 store‐ and ‐forward diagnostic cases , originating from 49 referred patients , was 79 % ( range 73–85 % ) . When the differential diagnoses were taken into account , the variation across individual dermatologists narrowed further , with a mean of 86 % ( range 83–89 % ) . In contrast , the mean general practitioner ( GP ; n = 11 ) concordance ( GP face‐to‐face vs reference dermatologist store‐ and ‐forward diagnoses ) was 49 % . An interim review of all 49 teledermatology patients showed no adverse outcome at the end of 3 months . The ability to request face‐to‐face visits by dermatologists , combined with GPs maintaining primary care of the referred patient , serve as additional safeguards for patients using a telemedicine system . Our results indicate that teledermatology management of referred skin complaints is both accurate and reliable Home monitoring of spirometry has been advocated in lung transplant recipients for the early detection of acute infection and rejection of the allograft . We have developed a user-friendly , Internet-based telemonitoring system providing direct transmission of home spirometry to the hospital . In this prospect i ve study , we assessed patient adherence with the monitoring , agreement between home and hospital spirometry , intrasubject coefficient of variation ( CV ) for FEV(1 ) and FEF(25 - 75 ) , and sensitivity of these variables for the detection of acute complications . Twenty-two bilateral-lung and heart-lung transplant recipients were followed for a median of 473 d ( range , 60 - 822 ) , during which 13,833 measurements were obtained . Patient compliance was 55 % for two measurements a day and 84 % for one measurement a day . Agreement between home and hospital spirometry was within 4 % for FEV(1 ) and 6 % for FEF(25 - 75 ) . Mean CV was 3.2 % for FEV(1 ) and 7.5 % for FEF(25 - 75 ) . Using transbronchial lung biopsy and /or bronchoalveolar lavage as gold st and ards , the sensitivity of home spirometry was 63 % , and 23 % of true positives were detected by changes in FEF(25 - 75 ) alone . We conclude that home monitoring of pulmonary function in lung transplant recipients via the Internet is feasible and provides very reproducible data ; yet it has only a mild sensitivity for the detection of acute allograft dysfunction Many studies have been published recently on the effectiveness of teledermatology as a diagnostic tool ; however , much of the data comes from live 2-way video teleconferencing consultations and very little comes from more readily available " store and forward " consultations . Moreover , most published studies compare the diagnoses of 2 different dermatologists ( interobserver comparison ) . Given the lack of data on baseline interdermatologist diagnostic variability , the interpretation of currently available diagnostic correlation data is somewhat difficult . The objective of this study is to measure the degree of diagnostic concordance between a dermatologist seeing a patient via a teledermatology consult system and the same dermatologist seeing the same patient face-to-face in a dermatology clinic at a tertiary medical center . A r and om sample of 404 patients was selected from patients who had routine appointments at our dermatology clinic PURPOSE To assess three novel digital fundus cameras for diabetic retinopathy ( DR ) screening . METHODS Digital colour and red-free retinal imaging ( Topcon TRC 50 IA , Canon CR6 - 45NM , and MediTell ) was used to capture 427 images of 70 diabetes patients and control subjects . The images were grade d for DR by three readers in a r and omized and masked manner using a modified Early Treatment Diabetic Retinopathy Study classification . The reference st and ard was based on mydriatic ophthalmoscopy and colour and red-free images . RESULTS Digital 50 degrees red-free imaging had sensitivity of 97.7 % , two-field 50 degrees colour imaging 94.0 % , and two-field 45 degrees colour imaging sensitivity of 88.9 % . The specificity of these imaging modalities was 98.9 - 100 % , and un grade able images represented 1.2 - 1.6 % . The h and -held digital colour videocamera ( MediTell ) showed a sensitivity of 6.9 % and un grade able images represented 92.3 % . CONCLUSION Digital 50 degrees red-free and two-field 50 degrees or 45 degrees colour imaging were suitable for DR screening , whereas the h and -held digital videocamera did not fulfil the needs of DR screening Telemedicine promises to revolutionize medical care delivery in rural and remote areas . The ability to accurately evaluate physical impairment via the Internet is important to the possible future provision of Internet-based physiotherapy . This study evaluated the reliability and validity of assessing knee range of motion via the Internet . Two therapists evaluated knee angle on a single subject via two methods of assessment : the Internet and the traditional method ( face-to-face ) . Nine r and om positions of the knee were chosen with the principal examiner performing 20 face-to-face and two sets of 20 Internet measures in each position ( n=540 ) . The secondary therapist performed Internet assessment s only . The Internet connection was established at a readily available speed of 17 kbit/s . The Internet-based goniometer was found to be a valid tool for measuring both knee flexion and extension angles . It was shown to possess both high intra and inter-rater reliability . Difference average plots of the scores verified the consistency of measurement between both modes of assessment . The successful evaluation of the physical outcome measure of knee range of motion via the Internet assists the further development of Internet-based physiotherapy applications This pilot study examined the acceptability and feasibility of conducting a weight loss maintenance intervention over the Internet . Obese adults participated in a 15-week behavioral weight control intervention and were then r and omly assigned to one of the following three maintenance conditions : ( a ) in-person , therapist-led ( TL ) ; ( b ) Internet , therapist-led ( I ) ; and ( c ) control ( C ) . Both maintenance interventions met biweekly for 22 weeks using the same program content . Results showed that TL participants were more likely to attend their meetings and feel more satisfied with their group assignment . Ho wever , there were no differences between the TL and I groups in overall attrition or number of peer support contacts made . There was also no significant difference in weight loss between the groups . Thus , the Internet may hold promise as a method for maintaining contact with patients to facilitate long-term behavior change The adherence and disease-control outcomes associated with the use of an Internet-based store- and -forward video home telehealth system to manage asthma in children were studied . Pediatric patients with persistent asthma were provided with home computers and Internet access and monitored biweekly over the Internet . All patients were seen in the pediatric clinic at 0 , 2 , 6 , 12 , and 24 weeks . Half of the patients received asthma education in person and half via an interactive Web site . Adherence measures were assessed by therapeutic and diagnostic monitoring . Therapeutic monitoring included digital videos of patients using their controller medication inhaler . Diagnostic monitoring included an asthma symptom diary and a video of peak flow meter use . Videos were su bmi tted electronically twice a week by using in-home telemonitoring with store- and -forward technology . Feedback was provided electronically to each patient . Disease control was assessed by examining quality of life , utilization of services , rescue-therapy use , symptom control , satisfaction with home telemonitoring , and retention of asthma knowledge . Patients were r and omly assigned to an asthma education group ( Internet versus office ) , and the data were analyzed by comparing results for study days 0 - 90 and 91 - 180 . Ten children participated . A total of 321 videos of inhaler use and 309 videos of peak flow meter use were su bmi tted . Inhaler technique scores improved significantly in the second study period . Su bmi ssion of diagnostic monitoring videos and asthma diary entries decreased significantly . Peak flow values as a percentage of personal best values increased significantly . Overall , there was no change in quality of life reported by patients . However , the caregivers in the virtual-education group reported an increase in the patients ' quality -of-life survey scores . Emergency department visits and hospital admissions for asthma were avoided . Rescue therapy was infrequent . A high rate of satisfaction with home telemonitoring was reported . Internet-based , store- and -forward video assessment of children 's use of asthma medications and monitoring tools in their homes appeared effective and well accepted The aim of this study was to determine whether home telehealth , when integrated with the health facility 's electronic medical record system , reduces healthcare costs and improves quality -of-life outcomes relative to usual home healthcare services for elderly high re source users with complex co-morbidities . Study patients were identified through the medical center 's data base . Intervention patients received home telehealth units that used st and ard phone lines to communicate with the hospital . FDA -approved peripheral devices monitored vital signs and valid question naires were used to evaluate quality -of-life outcomes . Out-of-range data triggered electronic alerts to nurse case managers . ( No live video or audio was incorporated in either direction . ) Templated progress notes facilitated seamless data entry into the patient 's electronic medical record . Participants ( n = 104 ) with complex heart failure , chronic lung disease , and /or diabetes mellitus were r and omly assigned to an intervention or control group for 6 - 12 months . Parametric and nonparametric analyses were performed to compare outcomes for ( 1 ) subjective and objective quality -of-life measures , ( 2 ) health re source use , and ( 3 ) costs . In contrast to the control group , scores for home telehealth subjects showed a statistically significant decrease at 6 months for bed-days-of-care ( p < 0.0001 ) , urgent clinic/emergency room visits ( p = 0.023 ) , and A1C levels ( p < 0.0001 ) ; at 12 months for cognitive status ( p < 0.028 ) ; and at 3 months for patient satisfaction ( p < 0.001 ) . Functional levels and patient-rated health status did not show a significant difference for either group . Integrating home telehealth with the healthcare institution 's electronic data base significantly reduces re source use and improves cognitive status , treatment compliance , and stability of chronic disease for homebound elderly with common complex co-morbidities We investigated the use of videoconferencing in the examination of orthopaedic out patients . A consecutive sample of orthopaedic out patients was r and omized to examination either via videoconferencing ( n = 76 ) while attending a primary -care unit or at a conventional hospital outpatient clinic 160 km away ( n = 69 ) . Videoconferencing was found to be feasible and the equipment functioned well technically . There were somewhat more problems in examining the telemedicine patients than the clinic patients . The two patient groups were equally satisfied with the specialist service . The telemedicine patients were more willing to have their next visit by videoconferencing than the conventional patients . Videoconferencing between primary and secondary care can be used in the examination of orthopaedic patients whenever no dem and ing imaging technology is needed OBJECTIVE To determine whether modem technology allows for effective management of type 1 diabetes when used in lieu of a clinic visit . RESEARCH DESIGN AND METHODS A total of 70 adolescent patients with diabetes were prospect ively r and omized to either a control group or a modem group . Control group patients continued the st and ard of care of quarterly clinic visits , and modem group patients were instructed to transmit blood glucose data every 2 weeks for 6 months instead of a usual quarterly clinic visit . Health care providers analyzed the data received by modem and contacted patients to discuss diabetes treatment changes . GHbA(1c ) levels were determined at 0 and 6 months , and the number of high and low blood glucose levels and adverse events were tracked . Clinic visit costs , patient expenses , and health care provider times were tracked for cost analysis for both groups . RESULTS A total of 63 patients ( 33 control , 30 modem ) completed the 6-month study . The GHbA(1c ) values significantly decreased in both groups , with no statistically significant difference between groups ( P = 0.96 ) . The occurrence of mild-to-moderate hypoglycemic events were similar in the two groups , and there were no severe hypoglycemic events . The average cost of care for a clinic visit was $ 305.00 , whereas the cost for 6 months of modem transmission was $ 163.00 . CONCLUSIONS This study shows that electronic transmission of blood glucose levels and other diabetes data every 2 weeks-in lieu of a clinic visit- results in a similar level of glucose control and incidence of acute diabetes complications when compared with current st and ard care |
13,653 | 22,711,224 | They offer evidence of beneficial synergies between PMTCT programs and both STI prevention and early childhood immunization .
En conjunto , este material ofrece evidencia de sinergias beneficiosas entre los programas de PTMI , la prevención de ITS y la inmunización en la infancia temprana .
Otros datos , incluyendo información sobre el cuidado prenatal y parto , planificación familiar y suplementacion de la nutrición varian considerablemente entre los estudios que demuestran un impacto positivo y negativo de la PTMI . | There has been considerable debate about the effects of targeted global health assistance in low- and middle-income countries on health systems , specifically HIV/AIDS funding .
Recently , a h and ful of studies have emerged that describe the implementation of PMTCT programs , which have many theoretical links to maternal and child health .
Through a systematic review of research published between January 2000 and March 2011 , this paper synthesizes evidence evaluating the impact of these programs .
ResumenHay considerable debate acerca de los efectos de asistencia específica de la salud públicamundial aplicados a los sistemas de salud en países de bajos y medianos ingresos , en particular para financiacion de VIH/SIDA . | Objective : To describe pregnancy outcomes among clade C HIV-infected and uninfected women in South Africa . Design : A longitudinal cohort study . Methods : Pregnant women attending 9 rural/urban antenatal clinics were prospect ively recruited and followed up . Women were seen at the clinic or at home after delivery on 4 occasions after enrollment : 2 times within the first 2 weeks of the newborn 's life at home , and every 2 weeks thereafter until their first health clinic visit when the infant was 6 weeks old . Results : A total of 3465 women were enrolled ; 615 withdrew after delivery , moved away , or had a missing or indeterminate HIV status , leaving 2850 women ( 1449 HIV-infected women ) . Six women died after delivery and there were 17 spontaneous abortions and 104 stillbirths . An adverse pregnancy outcome was independently associated with HIV infection ( adjusted odds ratio [ AOR ] = 1.63 ; P = 0.015 ) , urban enrollment ( AOR = 0.39 ; P = 0.020 ) , and nonhospital delivery ( AOR = 13.63 ; P < 0.001 ) as well as with a CD4 count < 200 cells/mL among HIV-infected women ( AOR = 1.86 ; P = 0.127 ) . Among 2529 singleton liveborn babies , birth weight was inversely associated with maternal HIV ( AOR = 1.45 ; P = 0.02 ) and maternal middle upper arm circumference ( AOR = 0.93 ; P < 0.001 ) . Early infant mortality was not significantly associated with maternal HIV ( hazard ratio [ HR ] = 1.18 ; P = 0.52 ) but was with urban sites ( HR = 0.34 ; P = 0.045 ) . Low birth weight substantially increased mortality ( AOR = 8.3 ; P < 0.001 ) . HIV status of infants by 8 weeks of age ( 14.6 % , 95 % confidence interval : 12.5 % to 17.0 % ) was inversely associated with maternal CD4 cell count and birth weight . Conclusions : HIV-infected women are at a significantly increased risk of adverse pregnancy outcomes . Low-birth-weight infants of HIV-infected and uninfected women are at substantially increased risk of dying Objectives To study mortality in African children born to HIV-1-infected mothers exposed peripartum to zidovudine . Methods A r and omized placebo-controlled trial in Abidjan and Bobo-Dioulasso . Pregnant women received either 300 mg zidovudine twice daily from 36–38 weeks ’ gestation , 600 mg during labour , and 300 mg twice daily for 7 days post-partum or a matching placebo . Determinants of mortality were studied up to 18 months , overall and among the infected children : treatment , centre , timing of infection , mother and child HIV disease . Results There were 75 infant deaths among 407 live births . The risk of death at 18 months was 176/1000 in the zidovudine arm and 221 for placebo . Relative hazard ( RH , zidovudine versus placebo ) was 0.47 [ 95 % confidence interval ( CI ) 0.2–1.0 ] up to 230 days of life . Maternal CD4 lymphocyte count < 200/mm3 ( RH 2.92 ; CI 1.4–6.1 ) and child HIV-1 infection ( RH 12.6 ; CI 6.6–24.3 ) increased mortality of all children born to HIV-1-infected mothers . There were 101 children infected ( 40 in the zidovudine group ) , and 51 died . Their 18 month probability of death was 590/1000 in the zidovudine group and 510 in the placebo group . Among infected children , maternal zidovudine reduced the risk of death on or before day 230 ( RH 0.18 ; CI 0.1–0.5 ) . Maternal CD4 lymphocyte count < 200/mm3 ( RH 3.25 ; CI 1.3–8.4 ) , maternal death ( RH 9.65 ; CI 1.7–56.0 ) , diagnosis of paediatric infection on or before day 12 ( RH 18.1 ; CI 4.8–69.0 ) and between days 13 and 45 ( RH 7.63 ; CI 2.0–29.5 ) , clinical paediatric AIDS ( RH 5.37 ; CI 2.3–12.7 ) were risk factors for death in HIV-1-infected children . Conclusion Mother-to-child transmission reduction by zidovudine is safe and beneficial to African children . The mortality of HIV-1-infected children is high . Peripartum maternal zidovudine exerts a protective effect for at least 8 months Objective : Previous studies on the operational effectiveness of programmes to reduce transmission of HIV from mother-to-child ( PMTCT ) in Africa have generally been hospital-based pilot studies with short follow-up periods . Method : Prospect i ve cohort study to evaluate the routine operational effectiveness of the South African National PMTCT Programme , primarily measured by HIV-free survival at 36 weeks post-delivery . Three of eighteen pilot sites participating in the programme were selected as they reflected differences in circumstances , such as HIV prevalence , socioeconomic status and rural – urban location . A total of 665 HIV-positive mothers and their infants were followed . Results : HIV-free survival at 36 weeks varied significantly across sites with 84 % in Paarl , 74 % in Umlazi and 65 % in Rietvlei ( P = 0.0003 ) . Maternal viral load was the single most important factor associated with HIV transmission or death [ hazard ratio ( HR ) , 1.54 ; 95 % confidence interval ( CI ) , 1.21–1.95 ] . Adjusting for health system variables ( fewer than four antenatal visits and no antenatal syphilis test ) explained the difference between Rietvlei and Paarl ( crude HR , 2.27 ; 95 % CI , 1.36–3.77 ; adjusted HR , 1.81 ; 95 % CI , 0.93–3.50 ) . Exposure to breastmilk feeding explained the difference between Umlazi and Paarl ( crude HR , 1.74 ; 95 % CI , 1.06–2.84 ; adjusted HR , 1.41 ; 95 % CI , 0.81–2.48 ) . Conclusion : Ever breastfeeding and underlying inequities in healthcare quality within South Africa are predictors of PMTCT programme performance and will need to be addressed to optimize PMTCT effectiveness OBJECTIVES To identify potential predictors of mortality , to determine mortality rate and to identify prevalent causes of death in a cohort of HIV-1 exposed uninfected infants . DESIGN Prospect i ve cohort study . SETTING Kenyatta National Hospital , Nairobi , Kenya . SUBJECTS Three hundred and fifty one HIV-1 exposed uninfected post-neonatal infants who survived to one year of age . RESULTS Sixteen infants died ( post-neonatal mortality rate of 47/1000 live births ) , 14 ( 88 % ) before six months of age . The most frequently identified medical conditions at death included bronchopneumonia , diarrhoea and failure to thrive . In multivariate analysis , prematurity ( RR=10.5 , 95%CI 3.8 - 29.1 , p<0.001 ) , teenage motherhood ( RR=3.6 , Cl 1.0 - 13.2 , p=0.05 ) and symptomatic maternal HIV-1 disease ( RR=2.7 , CI 0.9 - 7.7 , p=0.06 ) were associated with infant mortality . CONCLUSION Prematurity , teenage motherhood and symptomatic HIV-1 maternal disease were important predictors for post-neonatal mortality in this cohort of HIV-1 exposed uninfected infants . These factors should be considered in monitoring and follow up in prevention of mother-to-child HIV-1 transmission ( PMTCT ) programs BACKGROUND HIV contributes substantially to child mortality , but factors underlying these deaths are inadequately described . With individual data from seven r and omised mother-to-child transmission ( MTCT ) intervention trials , we estimate mortality in African children born to HIV-infected mothers and analyse selected risk factors . METHODS Early HIV infection was defined as a positive HIV-PCR test before 4 weeks of age ; and late infection by a negative PCR test at or after 4 weeks of age , followed by a positive test . Mortality rate was expressed per 1000 child-years . We investigated the effect of maternal health , infant HIV infection , feeding practice s , and age at acquisition of infection on mortality assessed with Cox proportional hazards models , and allowed for r and om effects for trials grouped geographically . FINDINGS 378 ( 11 % ) of 3468 children died . By age 1 year , an estimated 35.2 % infected and 4.9 % uninfected children will have died ; by 2 years of age , 52.5 % and 7.6 % will have died , respectively . Mortality varied by geographical region , and was associated with maternal death ( adjusted odds ratio 2.27 , 95 % CI 1.62 - 3.19 ) , CD4 + cell counts < 200 per microL ( 1.91 , 1.39 - 2.62 ) , and infant HIV infection ( 8.16 , 6.43 - 10.33 ) . Mortality was not associated with either ever breastfeeding and never breastfeeding in either infected or uninfected children . In infected children , mortality was significantly lower for those with late infection than those with early infection ( 0.52 , 0.39 - 0.70 ) . This effect was also seen in analyses of survival from the age at infection ( 0.74 , 0.55 - 0.99 ) . INTERPRETATION These findings highlight the necessity for timely antiretroviral care , for support for HIV-infected women and children in developing countries , and for assessment of prophylactic programmes to prevent MTCT , including child mortality and infection averted OBJECTIVE To examine the relationships between maternal knowledge and concern about HIV status , adoption of preventive practice s and risk of acquiring HIV in Zimbabwe . METHODS Knowledge and behavioural data were collected via interview from 2595 mothers enrolled in ZVITAMBO , a r and omized trial of postpartum vitamin A supplementation that also offered education on safer infant feeding and sexual practice s. Mothers were tested for HIV at delivery ; those uninfected at baseline were retested during study follow-up . Logistic regression methods were used to identify variables associated with adoption of preventive behaviours and , for HIV-negative mothers , their relationship to risk of acquiring HIV post-delivery . RESULTS A total of 518 mothers ( 20 % ) reported practicing safer sex and 289 mothers ( 11 % ) reported modifying their feeding behaviour because of HIV . Fear of transmitting HIV ( 50.4 % ) and protecting the baby 's health ( 30.9 % ) were the most frequently cited reasons for behaviour change . Forty-nine HIV-negative mothers acquired HIV during the first postpartum year . After taking into account other significant covariates , mothers who were concerned about their own HIV status were 1.9 times more likely ( 95 % CI : 1.05 - 3.52 ; P = 0.03 ) , and those reporting safer sex practice s were 58 % less likely to become infected ( adjusted odds ratio : 0.42 ; 95 % CI : 0.17 - 1.04 ; P = 0.06 ) . Married women who reported practicing abstinence to prevent HIV were 3.2 times more likely to become infected than non-abstaining mothers ( P = 0.01 ) , while there were no new HIV infections among abstaining single mothers . CONCLUSIONS Greater emphasis should be given to safer sex practice s among women who test negative in mother-to-child HIV prevention programmes BACKGROUND The treatment of HIV infection during pregnancy significantly and substantially reduces the risk of mother-to-child transmission . Although triple therapy is the st and ard of care for management of HIV infection in adults , the safety of many approved antiretroviral agents in pregnancy is not currently established . METHODOLOGY An open-label pilot study conducted in Thail and and the UK of the safety of saquinavir soft-gel capsules 1200 mg three times daily administered in the second and third trimester of pregnancy in combination with local st and ard-of-care antiretroviral therapy . Infants received local st and ard-of-care antiretroviral therapy after delivery . Steady-state pharmacokinetics were performed in a subset of mothers at 4 weeks after the commencement of saquinavir therapy and paired sample s collected from the mother and infant cord blood at delivery . RESULTS Eighteen antiretroviral-naive pregnant women with a mean viral load of 4.2 log10 and CD4 cell count of 481/mm(3 ) were recruited . All patients received zidovudine and 3 ( all in the UK ) received lamivudine . There were no serious adverse events and no discontinuations due to adverse events . Viral load declined by 1.6 log10 at week 4 and was less than 400 copies/mL at delivery in 16/17 mothers . Sixteen live births were recorded , with two in utero deaths-one secondary to an accident and the second due to antiphospholipid syndrome . Both deaths were considered by investigators to be unrelated to study therapy . All infants were HIV negative at subsequent follow-up and no fetal abnormalities were observed . Pharmacokinetic data suggested that mothers had relatively low exposures to saquinavir despite an excellent virologic response . Saquinavir was not detected in cord blood . DISCUSSION Saquinavir soft-gel capsules are well tolerated during pregnancy and are not associated in this small study with birth abnormalities . Transmission of HIV infection from mother to child was successfully prevented in all cases . Low maternal exposures of saquinavir were noted . However , these did not appear to affect virologic efficacy of the combination . Sample s from cord blood indicate minimal fetal exposure to saquinavir Objectives : The extent to which HIV affects pregnancy-related mortality in countries with high HIV/AIDS and maternal mortality is poorly understood . The objectives of this study were to investigate the mortality of women of reproductive age by both HIV and pregnancy status , and quantify the excess mortality attributable to HIV during pregnancy in Pointe Noire , Congo . Design : Prospect i ve mortuary investigation of all deaths in women aged 15–44 years , during 112 consecutive days . Methods : Mortality rates by HIV and pregnancy were computed . During the study period , 378 corpses were examined , blood was tested for HIV and pregnancy , relatives were interviewed and hospital files were review ed . Denominators were obtained from a census with women-years assigned to pregnancy and /or HIV based on levels of fertility and HIV prevalence in the city . Results : The mortality rate was 32 times higher [ 95 % confidence interval ( CI ) , 25–39 ] among HIV-positive than among HIV-negative women . The relative increase in mortality associated with HIV was much higher in non-pregnant [ rate ratio ( RR ) , 41 ; 95 % CI , 32–52 ] than in pregnant women ( RR , 4 ; 95 % CI , 2–9 ) . Among HIV-positive women , pregnancy appeared to confer a survival benefit . Conclusion : These findings have important implication s for the interpretation of trends in maternal mortality in the context of HIV . The apparent survival benefit of pregnant HIV-positive women is largely due to their low fertility in the latest stage of the disease . As the HIV epidemic matures and more women become severely ill , any potential adverse effects associated with HIV and pregnancy may be increasingly offset by selection effects , and maternal mortality may not increase further Objective To assess the 24 month efficacy of a maternal short-course zidovudine regimen to prevent mother-to-child transmission ( MTCT ) of HIV-1 in a breastfeeding population in West Africa . Methods Data were pooled from two clinical trials : DITRAME-ANRS049a conducted in Abidjan , Côte d'Ivoire and Bobo-Dioulasso , Burkina-Faso and RETRO-CI , conducted in Abidjan . Between September 1995 and February 1998 , consenting HIV-1-seropositive women were r and omly assigned to receive zidovudine ( 300 mg ) or placebo : one tablet twice daily from 36–38 weeks ’ gestation until delivery , then in DITRAME only , for 7 more days . Paediatric HIV-1 infection was defined as a positive HIV-1 polymerase chain reaction , or if aged ⩾ 15 months , a positive HIV-1 serology . Cumulative risks ( CR ) of infection were estimated using a competing risk approach with weaning as a competing event . Results Among 662 live-born children , 641 had at least one HIV-1 test . All but 12 children were breastfed . At 24 months , overall CR of MTCT were 0.225 in the zidovudine and 0.302 in the placebo group , a 26 % significant reduction . Among children born to women with CD4 cell counts < 500/ml at enrolment , CR of MTCT were similar , 0.396 in the zidovudine and 0.413 in the placebo group . Among children born to women with CD4 cell counts ⩾ 500/ml , CR of MTCT were 0.091 in the zidovudine and 0.220 in the placebo group , a significant 59 % reduction . Conclusion A maternal short-course zidovudine regimen reduces MTCT of HIV-1 at age 24 months , despite prolonged breastfeeding . However , efficacy was observed only among women with CD4 cell counts ⩾ 500/ml . New interventions should be considered to prevent MTCT , especially for African women with advanced HIV-1 immunodeficiency |
13,654 | 30,471,226 | The presence of polyps improved the efficacy of the nebulization .
This way of delivery appears not convincing regarding antibiotics .
Few side effects were noted in the retrieved studies and only for nebulized antibiotics .
CONCLUSIONS This systematic review highlighted that based on the present literature nebulization is not better than nasal spray to the delivery of corticosteroids due to the positive results on symptoms , endoscopic appearance and histological outcomes .
For antibiotics delivery , the nebulization is not of added value | BACKGROUND Treatment of chronic rhinosinusitis ( CRS ) aims to treat the underlying inflammation or infection .
Although the optimal modality of administration remains controversial , inhalation route is usually preferred .
The aim of this systematic review was to summarize the efficacy of intranasal corticoisteroids or antibiotics delivery by nebulization on symptoms , histology , endoscopy scores , nasal obstruction , clinical outcomes and quality of life in CRS . | OBJECTIVE The aim of this study was to evaluate the clinical efficacy and the effects on decreasing the recurrence of AFRS ( allergic fungal rhinosinusitis ) of a budesonide inhalation suspension delivered via transnasal nebulization to patients following endoscopic sinus surgery . SUBJECTS AND METHODS Thirty-five patients were recruited into this study . Final diagnoses were reached using Bent and Kuhn 's criteria . The eligible patients were r and omly divided into two groups : the budesonide transnasal nebulization group ( group A ) and the topical nasal steroids group ( group B ) . Nasal symptoms , Lund-Mackay scores , and Kupferberg grade s were evaluated before surgery , after surgery and during the follow-up to assess the effects of these two approaches . RESULTS A total of 30 patients with AFRS who were eligible were included in the study . Four of the 15 patients in group B ( 26.67 % ) developed recurrent disease , whereas no patients in group A developed recurrent disease . This difference was statistically significant ( p=0.032 ) . CONCLUSION Nebulized budesonide is an effective and safe treatment for patients with AFRS following endoscopic sinus surgery , as evidence d by the reduced recurrence rate observed in the budesonide transnasal nebulization group relative to the topical nasal steroids group BACKGROUND There is little evidence on the efficacy of glucocorticoid transnasal nebulization therapy in patients with eosinophilic chronic rhinosinusitis with nasal polyps ( CRSwNP ) . OBJECTIVE We sought to evaluate the immunologic and remodeling effects of budesonide transnasal nebulization in patients with eosinophilic CRSwNP . METHODS Sixty patients with eosinophilic CRSwNP were r and omized to receive budesonide or placebo treatment for 14 days by means of transnasal nebulization in a double-blind manner . Endoscopic polyp size scores ( maximum = 6 points , Kennedy score ) and visual analog scale scores for nasal symptoms were assessed before and after treatment . Similarly , polyp sample s were evaluated for inflammatory cytokines , matrix metalloproteinases ( MMPs ) , and tissue inhibitors of metalloproteinases ( TIMPs ) by using an immunoassay ; collagen by using histochemistry ; eosinophils by using hematoxylin and eosin stain ; and T-cell subsets by using flow cytometry . RESULTS Budesonide transnasal nebulization significantly reduced polyp size compared with placebo ( mean difference between groups , -0.73 units ; 95 % CI , -1.15 to -0.32 units ; P = .002 ) and improved symptoms . Polyp IL-5 and eotaxin expression decreased significantly , whereas TGF-β and IL-10 expression increased . Expression of IFN-γ and IL-17 was not altered . Budesonide transnasal nebulization consistently reduced eosinophil infiltration and TH2 cell frequency and increased natural regulatory T-cell and type 1 regulatory T-cell frequencies . Indices of remodeling , including albumin , MMP-2 , MMP-7 , MMP-8 , and MMP-9 , were significantly decreased , whereas collagen deposition and TIMP-1 , TIMP-2 , and TIMP-4 levels were significantly increased . Budesonide transnasal nebulization did not suppress the hypothalamic-pituitary-adrenal axis or cause any serious side effects . CONCLUSION Short-term budesonide transnasal nebulization is an effective and safe treatment option in patients with eosinophilic CRSwNP , achieving clinical improvement by regulating remodeling , cytokine expression , and T-cell subset distribution tion of both CP and cisplatin . Hypersensitivity to mannitol was reported as a cause of apparent hypersensitivity to cisplatin . 6 In case 2 the result of a skin test with mannitol was negative , whereas the result of a skin test with the commercial formulation containing CP and mannitol was positive , suggesting that CP was solely responsible for the hypersensitivity reaction . In addition to the clinical tolerance induced by the desensitization protocol , skin responses to intradermal CP diminished . As shown in Table I , the ratio between wheal sizes of CP and histamine decreased more than 3.5 times after the desensitization . The observation of wheal- and -flare responses becoming negative has already been described in penicillin desensitization . 7 This phenomenon supports an antigen-specific desensitization . The rate at which the drug concentration increases in the extracellular fluid seems to be the most important factor in a successful outcome of desensitization . As suggested by our two patients , this rate can differ in each individual case . We conclude that the 4-hour desensitization protocol may not be suitable for all patients allergic to CP , whereas a modified prolonged protocol seems to be more tolerable . Until further data have been accumulated , the short protocol may be at tempted initially but should be replaced by the prolonged protocol if adverse effects appear . The prolonged protocol seems to be both safe and efficacious with regard to anti tumor activity Objectives : Rhinosinusitis and polyposis are difficult to treat in patients with Samter 's triad ; they commonly recur despite sinus surgery , antibiotics , and /or nasal steroids . The present study assesses the efficacy of a multimodal regimen that includes topical corticosteroids and antibiotics delivered through a hydroxyethyl cellulose gel and by nebulization . Methods : Eleven patients with Samter 's triad who had polyposis and rhinosinusitis that recurred despite endoscopic sinus surgery were treated with a 6-week course of multimodal topical therapy consisting of a hydroxyethyl cellulose gel that releases corticosteroids and antibiotics , topical nebulization of corticosteroids and antibiotics , saline solution rinses , and sinus debridement . Clinical outcomes were evaluated by Lund-Kennedy endoscopic and symptom scores . Histologic assessment was evaluated by hematoxylin and eosin staining before and after treatment . Results : Both Lund-Kennedy symptom and endoscopic scores showed a progressive and statistically significant decline throughout the course of treatment , reaching at 6 weeks 42 % of the pretreatment values ( p = 0.005 ) for the Lund-Kennedy symptom score and 34 % ( p = 0.002 ) for the endoscopic score , respectively ; however , the significance of the improvement was lost with time . Conclusions : Topical gel therapy improves clinical symptoms , endoscopic findings , and sinus membrane histologic features in patients with refractory Samter 's triad , but the improvement is transient , suggesting that a longer therapeutic period might be needed OBJECTIVES To compare the distribution patterns of topical medication delivery systems in the sinonasal region and upper respiratory tract after functional endoscopic sinus surgery . STUDY DESIGN Prospect i ve descriptive evaluation . METHODS Four topical delivery systems ( spray bottle , atomizer , nebulizer , and bulb syringe ) were studied . Using a dye solution as a marker , we independently applied the four topical delivery systems to a population of patients with chronic rhinosinusitis who had undergone functional endoscopic sinus surgery . The anatomic distributions were videotaped using flexible fiberoptic endoscopy . Three blinded observers independently rated the anatomic distribution of dye using a 4 point scale . Statistical analysis was performed using analysis of variance ( ANOVA ) and Dunn posttesting . RESULTS Seven participants completed the study . All participants had undergone bilateral maxillary antrostomies , bilateral total ethmoidectomies , and bilateral sphenoidotomies . Five sinonasal sites and the larynx were evaluated for dye deposition . Interobserver agreement reached 95.6 % . There was no statistical difference between the atomizer and spray bottle . The bulb syringe was statistically superior to the nebulizer in all sinonasal sites and statistically superior to the atomizer and spray bottle in the ethmoidal region . Dye was rarely seen within the larynx . CONCLUSIONS The delivery systems tested were shown to have significant differences in their capability to place dye in specific sinonasal areas . Because topical medications are commonly administered to postoperative patients , these differences may have important clinical implication OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity This study evaluated 1‐year outcomes in patients with chronic rhinosinusitis ( CRS ) who were considered surgical c and i date s by study criteria and elected either medical management or endoscopic sinus surgery ( ESS ) . In addition , some patients initially enrolled in the medical treatment arm crossed over to the surgery arm during the study period and their respective outcomes are evaluated BACKGROUND Systemic glucocorticoids are often used in the treatment of chronic rhinosinusitis with nasal polyps ( CRSwNP ) , and osteoporosis is a well-known complication to steroid treatment , associated with significant morbidity . Nevertheless , the burden of steroid induced osteoporosis is unknown in patients with CRSwNP . We aim ed to assess the risk of acquiring osteoporosis caused by oral steroids in patients with CRSwNP , and provide recommendations on future research and guidelines . METHODOLOGY Cochrane Review Data base , EMBASE , Ovid Medline , and PubMed were search ed for studies including adult patients with CRSwNP treated with oral steroids . Outcomes were Bone Mineral Density ( BMD ) and prevalence of fractures in relation to dose and duration of oral steroids . In addition , we review ed general guidelines for treatment with oral steroids . RESULTS We identified two studies ( n=243 ) that met the inclusion criteria . Doses and duration s of oral steroids were over 5 mg/day for more than 3 months and 1 mg/kg body weight/day for 6 to 10 days for 4 or more courses/year . The prevalence of low bone mass was 39 % and 61 % , respectively . It was not possible to quantify the overall risk of osteoporosis induced by oral steroids from the studies . No studies evaluated prevalence of fracture . CONCLUSIONS Registry studies and r and omized controlled trials would be needed to assess the risk of osteoporosis in CRSwNP patients and future guidelines should include recommendations regarding preventive treatment and recommendations on doses and duration s of oral steroids PURPOSE To quantify the amount of aerosol deposited in different parts of the airways with a commercially available nasal sonic jet nebulizer ( NJN ) using a sound effect , and to compare its performance with a new nasal mesh nebulizer ( NMN ) . METHODS Seven healthy non-smoking male volunteers aged 21 - 36 years with a mean weight of 77±10 kg were included in this single-center study . Both nebulizer systems were loaded with (99m)Tc-DTPA and scintigraphies were performed with a gamma camera . Particle size distribution of the aerosols produced by the two nebulizer systems was measured . RESULTS There was no statistical difference between the two nebulizers in terms of fraction of particles smaller than 5 μm ( 44±4 % vs 45±2 % ) ( p>0.9 ) . Aerosol deposition in the nasal region was 73±10 % ( % of aerosol deposited in airways ) with the NJN , and 99±3 % with the NMN ( p=0.01 ) . Total nasal deposition was 9.6±1.9 % of the nebulizer charge with the NJN and 28.4±8.9 % with the NMN ( p=0.01 ) . 0.5±0.3 % of the nebulizer charge was deposited in the maxillary sinuses with the NJN , compared to 2.2±1.6 % with the NMN ( p=0.01 ) . CONCLUSION Although the two nebulizers had the same particle size , NMN significantly improved aerosol deposition in nasal cavity and prevents deposition into the lungs CONTEXT Treatment of infected nasal polyposis . MATERIAL AND METHODS Multicenter interventional prospect i ve double-blind r and omized study with matched groups : treatment with tobramycin aerosol versus isotonic saline aerosol . The study population included 55 patients : 23 receiving isotonic saline aerosol and 32 receiving tobramycin . A novel device ( Easynose ® ) was used with an original principle limiting pulmonary deposition and ensuring homogeneous peripheral deposition in the nasal cavities . OBJECTIVES The principal objective was to compare bacteriological eradication between tobramycin 150mg/3ml versus isotonic saline , both administered by nebulization via the Easynose ® device . RESULTS AND CONCLUSION Tobramycin aerosol administered via the Easynose ® device showed significantly better bacteriological eradication than isotonic saline OBJECTIVE : To study the efficacy of nebulized topical saline-tobramycin solution in patients with chronic rhinosinusitis refractory to medical and surgical therapy . STUDY DESIGN AND SETTING : Twenty patients in whom endoscopic sinus surgery failed to relieve symptoms entered a r and omized , double-blind trial of tobramycin-saline solution or saline-only solution administered thrice daily to the nasal passages by means of a large-particle nebulizer apparatus for 4 weeks , followed by a 4-week observation period . Outcome measures of symptoms , quality of life , and endoscopic aspect of sinus mucosa were assessed . RESULTS : Both treatments were well tolerated and produced equivalent improvement in symptoms , quality of life , and mucosal aspect . Treatment with the tobramycin-saline solution gave more rapid improvement of pain , but led to the development of nasal congestion . CONCLUSION : Therapy with a 4-week course of large-particle nebulized aerosol therapy improves symptomatology and objective parameters of rhinosinusitis in patients refractory to surgical and medical therapies . Addition of tobramycin appears of minimal benefit . The mechanism of this effect is unexplained . SIGNIFICANCE : Large-particle nebulized aerosol therapy may offer a safe and effective management alternative for patients with refractory rhinosinusitis Nasal histamine challenge testing is a st and ard method of assessing upper airway hyperreactivity although there is still debate as to the best measure of response . The aim of the study was to evaluate peak nasal inspiratory flow rate ( PIFR ) as an endpoint during histamine challenge and compare this with rhinomanometry ( Rhino ) and acoustic rhinometry ( AR ) . Twenty two patients with perennial allergic rhinitis ( PAR ) were enrolled into a 2-way r and omised crossover study comparing placebo with intra-nasal mometasone furoate ( MF ) 200 mg once daily , with laboratory measurements of PIFR , AR and Rhino being made during histamine nasal challenge after each 10 - 14 day treatment period . Patients also recorded their domiciliary nasal symptoms and PIFR on a daily basis . With nasal challenge testing using PIFR PC30 there was a significant ( p < 0.05 ) difference between MF and placebo but not with PC30 AR or PC175 Rhino . There was also significant ( p < 0.05 ) improvement in terms of domiciliary total nasal symptom scores but not domiciliary PIFR . In conclusion PIFR after nasal challenge with histamine is a sensitive test of response to treatment with intra-nasal corticosteroids in PAR OBJECTIVES To conduct the first prospect i ve , r and omized controlled clinical trial comparing the efficacy of a drug-eluting stent ( DES ) ( the Relieva StratusTM MicroFlow Spacer ) and topical intranasal corticosteroid therapy in patients with chronic rhinosinusitis ( CRS ) . METHODS Sixty-three adult patients with ethmoiditis were r and omized into either the DES group ( n=34 ) or nasal spray group ( n=29 ) . The main outcome variable was the Sinonasal Outcome Test 22 , Visual Analogue Scale , nasal endoscopy , rhinometric measurements were performed at the beginning of the study , after three months and six months of follow-up . RESULTS Both treatments significantly improved quality of the life with no significant difference being found between the two groups . The VAS score decreased in both groups : improvements were significant at three and six months in the nasal spray group , but in the DES group a significant difference was noted only at three months . There was a statistically significant increase in total nasal cavity volumes in the corticosteroid spray group , but not in the DES group . CONCLUSION We found that patients benefitted from DES and the corticosteroid nasal spray . We could not find any significant difference between the treatments , except the greater increase in the total nasal cavity volumes favouring the nasal spray group . Because of the very good results for the nasal spray and the much higher material and operating room costs associated with DES , we can not recommend the use of DES over nasal spray as a monotherapeutic treatment for CRS BACKGROUND Olfactory dysfunction is deemed to be a significant contributor to poor quality of life in chronic rhinosinusitis ( CRS ) . OBJECTIVE To assess and to compare the effectiveness of three modalities of corticosteroids administration in patients with CRS . STUDY DESIGN A prospect i ve r and omized controlled study METHODS Thirty patients with CRS were r and omized in three groups depending on the route of corticosteroids administration : 16 days by oral route ( Medrol ( Pfizer , Belgique ) , 32 mg/8 days -16 mg/4 days-8 mg/4 days ) ; nasal spray ( Rhinocort ( AstraZeneca , Belgique ) , 2 × 2 × 64 µg/nostril ) ; or sonic nebulization ( Pulmicort ( AstraZeneca , Belgique ) , 2 × 1 mg/4 mL ) ( Sonic nebulizer , AOHBOX-NL11SN , DTF , France ) . Olfactory function was assessed using orthonasal threshold discrimination identification and retronasal psychophysical olfactory tests ( RNT ) before and after the treatment . Same intranasal modalities were previously tested for in vitro airways scintigraphic deposition . RESULTS In vitro differences in drug deposition pattern between both intranasal modalities were demonstrated . Threshold discrimination identification and RNT were similar between three groups at baseline . Threshold discrimination identification improved by 5.5 , 5.8 , and -1.1 for sonic nebulization , oral , and nasal spray groups , respectively ( P = 0.010 ) . This improvement was clinical ly relevant for oral and nebulized administration . It was similar between oral and nebulized administration but significantly higher than nasal spray administration . Retronasal psychophysical olfactory tests improved similarly for the three groups ( P = 0.231 ) CONCLUSION : Effectiveness of sonic nebulized and oral administration is demonstrated on orthonasal olfactory . The clinical benefit is better than with nasal spray Direct delivery of medication to the sinuses with st and ard nebulizers is difficult to achieve . The nasal inhalation of aerosolized medications is dependent on the size of the particles and the pressure with which they are delivered ; when the particles are too small or the pressure is too low , the drug can not reach the sinuses . The ability of topical medications to treat sinus disorders can be improved if the medication could be delivered directly to the sinuses . We tested the ability of the RinoFlow ™ nasal aerosol delivery device to deposit aerosol directly to the paranasal sinuses . Five normal , healthy subjects used the device to administer technetium Tc 99 m nasally . Nuclear scanning was used to detect deposition in the frontal and maxillary sinuses . Three subjects underwent additional testing after administration of a nasal decongestant . Three of the five subjects showed some evidence of direct delivery to the sinuses , although deposition was not uniform or complete . Pretreatment with a decongestant had no apparent effect on subsequent technetium delivery . We conclude that the results of this study are promising and that further study is warranted Hyaluronic acid is a major component of many extracellular matrices and plays a central role in the homeostasis of physiology in upper and lower airways . When topically administered following endoscopic sinus surgery , hyaluronic acid may be effective in functional recovery and in the prevention of recurrence of chronic rhinosinusistis . This pilot study was aim ed at evaluating the effects of nebulised 9 mg of sodium hyaluronate given for 15 days per months over 3 months in 46 patients aged > 4 years who underwent functional endoscopic sinus surgery ( FESS ) for rhino-sinusal remodelling . Eligible patients were r and omized to receive nebulised 9 mg sodium hyaluronate nasal washes plus saline solution or 5 ml saline alone ( 23 patients in each group ) , according to an open-label , parallel group design , with blind observer assessment . Treatment was administered by means of a nasal ampoule that allows nebulisation of particles with a median aerodynamic diameter > 10 micron , i.e. suitable for upper respiratory airways deposition . The efficacy variables included clinical ( presence of nasal dyspnoea ) , endoscopical ( ostium of paranasal sinuses , oedema , respiratory patency , synechiae , and appearance of nasal mucosa ) and cytological ( ciliary motility and presence of neutrophils , eosinophils , mast cells , bacteria , mycetes and bio film ) measures . At the end of the study , patients expressed an opinion on the overall tolerability of treatment . The two treatment groups were comparable at baseline . Treatment with 9 mg of sodium hyaluronate was associated with significantly greater improvements compared to controls in nasal dyspnoea ( p<0.001 ) , presence of mycetes ( p = 0.044 ) , ciliary motility ( p<0.001 ) and abnormalities in nasal secretions . A univariate logistic model , in which the odd ratio ( OR ) indicates the probability of success in the 9 mg sodium hyaluronate group compared to the control group , showed that the highest OR was observed for presence of nasal dyspnoea ( OR = 21.36 ; 95 % CI : 1.07 to 426.56 ) , normal mucosa at endoscopy ( OR : 9.62 ; 95 % CI : 1.82 to 50.89 ) , ciliary motility ( OR : 7.27 ; 95 % CI : 1.68 to 31.42 ) and presence of bio film ( OR : 4.41 ; 95 % CI : 1.26 to 15.40 ) . Treatment with 9 mg sodium hyaluronate plus saline was well tolerated . A 3-month intermittent treatment with 9 mg sodium hyaluronate plus saline solution nasal washes following FESS for rhino-sinusal remodelling was associated with significant improvements in nasal dyspnoea , appearance of nasal mucosa at endoscopy and ciliary motility compared to saline alone OBJECTIVE To evaluate the efficacy and safety of a short course of nebulized budesonide via transnasal inhalation in chronic rhinosinusitis with nasal polyps . METHOD Thirty patients with severe eosinophilic nasal polyps were r and omized into experimental group ( n=15 ) and control group ( n=15 ) . The experimental group received nebulised budesonide suspension ( 1 mg twice daily ) via transnasal inhalation for one week and control group-received budesonide nasal spray ( 256 microg twice daily ) . Visual analogue scales (VAS)of nasal symptoms ( including nasal obstruction , nasal discharge , loss of smell , and headache/facial pain ) and endoscopic polyp scores ( Kennedy scores ) and morning serum cortisol concentration were performed to both groups before and after the treatment . RESULT Nebulized budesonide inhalation caused a significant improvement in all nasal symptoms especially nasal obstruction ( baseline : 8.4 + /- 0.7 ; after treatment : 4.0 + /- 0.8 , P<0.01 ) and reduced polyp size compared with before treatment . Additionally , the patients treated with nebulized budesonide showed more obvious improvement in nasal symptoms and polyp size than control group . The morning serum cortisol concentration was mild decreased after one week treatment in nebulized steroid group [ baseline : ( 17.6 + /- 2.4 ) microg/dl , after treatment : ( 14.8 + /- 2.6 ) microg/dl , P<0.01 ] , but all values still were located in normal range ( normal range : 5 - 25 microg/dl ) . CONCLUSION A short course of nebulized budesonide transnasal inhalation can rapidly improve nasal symptoms , reduce polyp size , and does not cause obvious HPA axis suppression . Based on these , it is recommend that transnasal inhalation with nebulized budesonide suspension should be performed as a pre-operative routine in patients with nasal polyp Background This study was design ed to prospect ively evaluate the role of nebulized hyaluronic acid ( HA ) given for 10 days/mo over 3 months as adjunct treatment to minimize symptoms and preventing exacerbation of chronic rhinosinusitis ( CRS ) . Methods Thirty-nine eligible patients were r and omized to receive nebulized 9-mg sodium hyaluronate nasal washes plus saline solution ( 21 patients ) or 5 mL of saline alone ( 18 patients ) , according to an open-label , parallel-group design , with blind observer assessment . A question naire about main CRS discomfort and nasal endoscopy for mucous discharge and /or mucosal edema of nasal cavities was used to assess primary outcomes of treatments . Secondary outcome measures included side effects and satisfaction . Results HA significantly improved quality of life in CRS patients according to the CRS question naire ( 16± 3.72 versus 11.52 ± 4.28 ; p < 0.001 ) , contrary to saline group scores ( 18.92 ± 3.09 versus 18.21 ± 3.21 ; p = 0.55 ) . The HA group showed significantly reduced osteomeatal edema ( 2.42 versus 1.52 ; p < 0.001 ) and secretions ( 0.95 versus 0.42 ; p < 0.001 ) , whereas there was no statistically significant difference in the saline group he compliance to the treatment was similar in both groups and no side effects were recorded . Conclusion The results of this study suggested that intermittent treatment with topical 9-mg sodium hyaluronate plays a role in minimizing symptoms and could prevent exacerbations of CRS |
13,655 | 26,035,341 | Although Ballantyne 's meta- analysis found that PCA did have a small but statistically significant benefit upon pain intensity , a 2001 review by Walder et al did not find statistically significant differences in pain intensity or pain relief between PCA and groups treated with non-patient controlled analgesia .
There was no difference in the length of hospital stay .
This review provides moderate to low quality evidence that PCA is an efficacious alternative to non-patient controlled systemic analgesia for postoperative pain control | BACKGROUND This is an up date d version of the original Cochrane review published in Issue 4 , 2006 .
Patients may control postoperative pain by self administration of intravenous opioids using devices design ed for this purpose ( patient controlled analgesia or PCA ) .
A 1992 meta- analysis by Ballantyne et al found a strong patient preference for PCA over non-patient controlled analgesia , but disclosed no differences in analgesic consumption or length of postoperative hospital stay .
OBJECTIVES To evaluate the efficacy and safety of patient controlled intravenous opioid analgesia ( termed PCA in this review ) versus non-patient controlled opioid analgesia of as-needed opioid analgesia for postoperative pain relief . | Background : Pain after coronary artery bypass surgery persists for several days . A continuous intravenous infusion of an opioid adequately accomplishes good pain control in the intensive care unit , but it is often not suitable on the ordinary ward . Patient‐controlled analgesia ( PCA ) with intermittent injections delivered by one of the new devices now available could be an alternative to conventional nurse‐controlled analgesia ( NCA ) based on intermittent injections . The aim was to compare these two techniques with respect to efficacy and the amount of opioid used The pharmacy and nursing time requirements , quality of postoperative pain control , and cost of patient-controlled analgesia ( PCA ) and intramuscular ( i.m . ) analgesic therapy were studied . All timings were conducted with a stopwatch on a single nursing unit that primarily receives gynecologic surgery patients . The various work elements involved in each type of therapy were timed individually . Both quality of analgesia and cost were evaluated in a prospect i ve , r and omized study in hysterectomy patients . I.M. patients received meperidine hydrochloride 75 - 100 mg every three to four hours as needed . PCA patients had access to morphine sulfate 1 mg or meperidine hydrochloride 10 mg , with a six-minute lockout period . The patients scored their pain every four hours . Direct costs for PCA were calculated as drug cost plus tubing cost plus form cost plus maintenance cost plus depreciation cost . Direct costs for i.m . therapy consisted of the cost of drugs . The total mean nursing time per patient was 16.9 minutes for PCA and 10.7 minutes for i.m . therapy . Pharmacy time per patient was 5.1 minutes longer for PCA than for i.m . therapy . Thirty-six hysterectomy patients ( 17 i.m . and 19 PCA ) were enrolled in the study of pain control and cost . Among i.m . patients , 64 % of the pain scores were mild or worse , compared with 40 % for PCA patients . The median pain scores were moderate for i.m . patients and mild for PCA patients . Scores tended to be lower for PCA patients at 16 and 20 hours . Although equal numbers of patients in the two groups experienced nausea , i.m . patients needed more doses of antiemetics than PCA patients . ( ABSTRACT TRUNCATED AT 250 WORDS The purpose of this comparative study was to examine differences in pain intensity , sleep disturbance , sleep effectiveness , fatigue , and vigor between patients undergoing cholecystectomy who received either patient-controlled analgesia ( PCA ) or intramuscular ( IM ) injections of narcotics for postoperative pain . The PCA group consisted of 16 women , aged 22 - 58 ; the IM group consisted of 10 women , aged 22 - 60 . Data were collected on patients ' postoperative days 1 and 2 . Findings indicated that patients receiving PCA reported less pain on postoperative day 1 and less fatigue on postoperative day 2 than patients receiving IM injections of narcotics BACKGROUND In previous studies comparing patient-controlled-analgesia and intramuscular pain management have been unable to provide conclusive evidence of the benefits of either method of postoperative pain control . AIM The purpose of the study was to compare the efficacy and cost-effectiveness of intravenous patient-controlled-analgesia with intermittent intramuscular morphine for Chinese women in the first 24 hours following elective gynaecological surgery . METHODS A r and omized control design was used . The main outcomes were level of pain and cost for the two types of pain management . Participants indicated their level of pain at rest and when deep breathing or coughing on a 100 mm Visual Analogue Scale , on seven occasions within 24 postoperative hours . Costs for the two types of pain management were based on the costs of equipment , drugs and nursing time . RESULTS A total of 125 women participated in the study . Mean pain level over the 24 hours in the patient-controlled-analgesia group was significantly lower than in the intramuscular group ( P < 0.001 ) . Mean pain level over the seven occasions for the patient-controlled-analgesia group was 11.83 points ( 95 % CI 7.14 - 16.52 ) lower when at rest and 11.73 points ( 95 % CI 5.96 - 17.50 ) lower during motion than the intramuscular group . Cost per patient was $ 81.10 ( Hong Kong ) higher for patient-controlled-analgesia than for intramuscular pain management . Women in the patient-controlled-analgesia group had significantly greater satisfaction with pain management than those in the intramuscular group ( P < 0.001 ) , but reported significantly more episodes of nausea ( P < 0.05 ) . CONCLUSIONS While patient-controlled-analgesia was more costly , it was also more effective than conventional on-dem and intramuscular opioid injections after laparotomy for gynaecological surgery Purpose This prospect i ve study was undertaken to compare the effectiveness and safety of a multimodal pain control protocol with those of intravenous patient-controlled analgesia in rotator cuff repair . Methods Seventy patients scheduled for rotator cuff repair were r and omized to either a multimodal pain control group ( group 1 , 40 patients ) or an intravenous patient-controlled analgesia group ( group 2 , 30 patients ) . We compared these two groups with respect to level of pain before surgery to the fifth postoperative day , duration of postoperative rehabilitation , consumption of additional analgesics , and adverse effects . Results Mean visual analogue scale scores immediately after surgery ( day 0 ) and on postoperative days 1–5 were 6.9 , 5.5 , 4.3 , 3.3 , 3.0 , and 2.6 in group 1 and 7.8 , 5.9 , 4.4 , 4.7 , 4.3 , and 3.7 in group 2 . Pain relief was significantly better in group 1 on days 0 , 3 , 4 , and 5 ( P = 0.026 , 0.006 , 0.010 , and 0.009 , respectively ) . Furthermore , functional recovery occurred earlier in group 1 . No significant differences were observed between the two groups with respect to nausea , vomiting , urinary retention , and headache ( n.s . ) , but group 1 was found to be significantly less likely to experience dizziness or urticaria ( P = 0.007 , 0.017 , respectively ) . One other significant difference was observed : 1 patient ( 2.5 % ) in group 1 and 6 patients ( 20 % ) in group 2 discontinued regimen because of medication-related adverse effects ( P = 0.016 ) . Conclusion The multimodal pain control protocol was found to offer more effective postoperative pain control with fewer adverse effects than intravenous patient-controlled analgesia . However , achieving adequate pain control within the first 48 h of surgery remains challenging , and thus , the developments of more effective and safer multimodal pain control protocol s are required Background and Objectives : To compare the use of patient-controlled analgesia to intermittent intramuscular injections of morphine following major gynecological laparoscopic procedures in order to assess differences in level of pain , sedation , episodes of nausea and /or vomiting , hospitalization time and patient satisfaction with their postoperative analgesia . Methods : Seventy-two patients undergoing major gynecological laparoscopic surgery were r and omized to receive either postoperative analgesia via intermittent intramuscular injection of morphine ( Group 1 ) or patient controlled analgesia ( PCA - Group 2 ) . All patients received anesthesia via a st and ardized protocol . Postoperative pain levels were recorded via a 10 cm visual analogue scale , and sedation scores were recorded on a st and ard PCA form . Episodes of nausea and vomiting were also recorded on the same form . Results : There were no statistically significant differences between intramuscular analgesia and PCA for any of the factors studied . Most significantly it was found that most patients ceased to require either form of parenteral analgesia within 24 hours of their procedure , regardless of the operating time . Conclusion : It is important for the surgeon to be aware of the effects of postoperative analgesia on his or her patients ' level of satisfaction . We do not recommend the use of PCA analgesia following major laparoscopic gynecological surgery Abstract Variability in patients ' response to interventions in pain and other clinical setting s is large . Many explanations such as trial methods , environment or culture have been proposed , but this paper sets out to show that the main cause of the variability may be r and om chance , and that if trials are small their estimate of magnitude of effect may be incorrect , simply because of the r and om play of chance . This is highly relevant to the questions of ‘ How large do trials have to be for statistical accuracy ? ’ and ‘ How large do trials have to be for their results to be clinical ly valid ? ’ The true underlying control event rate ( CER ) and experimental event rate ( EER ) were determined from single‐dose acute pain analgesic trials in over 5000 patients . Trial group size required to obtain statistically significant and clinical ly relevant ( 0.95 probability of number‐needed‐to‐treat within ±0.5 of its true value ) results were computed using these values . Ten thous and trials using these CER and EER values were simulated using varying group sizes to investigate the variation due to r and om chance alone . Most common analgesics have EERs in the range 0.4–0.6 and CER of about 0.19 . With such efficacy , to have a 90 % chance of obtaining a statistically significant result in the correct direction requires group sizes in the range 30–60 . For clinical relevance nearly 500 patients are required in each group . Only with an extremely effective drug ( EER>0.8 ) will we be reasonably sure of obtaining a clinical ly relevant NNT with commonly used group sizes of around 40 patients per treatment arm . The simulated trials showed substantial variation in CER and EER , with the probability of obtaining the correct values improving as group size increased . We contend that much of the variability in control and experimental event rates is due to r and om chance alone . Single small trials are unlikely to be correct . If we want to be sure of getting correct ( clinical ly relevant ) results in clinical trials we must study more patients . Credible estimates of clinical efficacy are only likely to come from large trials or from pooling multiple trials of conventional ( small ) size After open prostatectomy , 52 patients were r and omly allocated to two treatment groups . Group A ( 26 patients ) received buprenorphine sublingually , and in group B ( 26 patients ) the analgesia was induced using a patient-controlled analgesia system with morphine . The total dose of morphine given during the first 24 h was 72 + /- 8 mg compared to 1.6 + /- 0.45 mg of buprenorphine . The total dose of buprenorphine on days 2 and 3 was significantly lower than the total dose of morphine ( p < 0.01 ) . There were no significant differences in visual pain scores , side effects , mean arterial blood pressure , pulse rate and respiration rate between the two groups . Sublingual application of buprenorphine offers an effective and easy alternative to the parenteral route of morphine for the management of postoperative pain A r and omized , controlled clinical trial was conducted on 66 patients undergoing elective cardiac surgery to compare patient-controlled analgesia ( PCA ) to nurse-controlled analgesia ( NCA ) with continuous morphine infusion . Hourly assessment of pain ( at rest and on movement ) using a visual analogue scale ( VAS ) , of respiratory rate , and level of sedation took place for the 24 h following extubation . The incidence of nausea was also recorded . Mean pain scores were calculated , and peak pain and sedation scores , together with lowest respiratory rates , were identified . Morphine consumption was measured at 24 h. No significant differences were found between the groups ' scores for pain or sedation . The PCA group had significantly lower respiratory rates ( P = 0.02 ) and a lower incidence of nausea ( P = 0.008 ) . The PCA group also consumed significantly more morphine ( P = 0.0001 ) . The study suggests a beneficial effect from PCA after cardiac surgery in reducing nausea , compared to NCA . It confirms nurse-controlled infusion analgesia as an effective form of pain relief in an intensive care and high-dependency setting We have evaluated the level of state and trait anxiety , neuroticism , extroversion and coping style as predictors of the effectiveness of patient-controlled analgesia ( PCA ) in 110 patients undergoing total abdominal hysterectomy . After operation patients were allocated to receive pain control with either PCA or i.m . injections ( IMI ) . Pain was assessed using the short form McGill pain question naire at 6 , 18 and 24 h after operation , and by recording the amount of analgesic consumed in the first 24 h after surgery . Both state anxiety and coping style were significant predictors of postoperative pain , irrespective of the method of analgesia used . Patients using PCA experienced significantly better pain control than those receiving IMI . However , it was those with high levels of state anxiety who experienced the greatest reduction in pain with PCA . In addition to achieving better pain control , patients who received PCA used significantly less analgesia and were discharged earlier than patients who received IMI We have compared patients ' and nurses ' assessment s of postoperative pain and anxiety after different analgesic treatments . Sixty orthopaedic patients were allocated r and omly to receive i.v . piritramide ( either nurse-controlled or patient-controlled ) or subarachnoid bupivacaine ( nurse-controlled or patient-controlled ) . Patients and nurses assessed pain and anxiety using a visual analogue scale ( VAS ; 1 - 100 mm ) . Pain and anxiety ratings of patients and nurses were significantly correlated ( Spearman 's r > or = 0.69 ; P < 0.001 ) . In general , patients ' pain scores were higher than nurses ' scores ( patients ' median VAS = 34 ( range 1 - 76 ) mm ; nurses VAS 21 ( 1 - 59 ) mm ) and for all groups except the patient-controlled subarachnoid bupivacaine group , where they were significantly higher ( P < 0.01 ) . Discrepancy in pain estimates between patients and nurses increased with the level of pain . The relationship between patients ' and nurses ' anxiety scores was less clearly defined and did not depend on the level of anxiety OBJECTIVES To assess the economics of patient-controlled analgesia ( PCA ) treatment versus regular intramuscular ( i.m . ) injections of opioid analgesia for pain management after hysterectomy . METHODS Cost-minimization analysis was used based on the comparable pain control results achieved in the two treatment groups . Observations were taken of treatment-related events with personnel ( mostly nursing ) time implication s during the trial . Times were then associated with these events in an independent study of personnel activity . Costs were linked by using average wage rates for the various personnel for the Montreal area during the time of the study . Drug and material costs were hospital acquisition costs for all items . The cost of the PCA pump itself was not included in the analysis . Several analyses were performed to test the sensitivity of the results to various assumptions . RESULTS The results for total costs of the two therapies generally showed PCA to be more costly than regular i.m . injections despite no costs of the pump being included in the analyses . These results were robust with respect to changes in assumptions . Even when intentionally biasing the analysis against i.m . therapy , it was difficult to obtain results that favored PCA . CONCLUSIONS Based upon the institutions and assumptions in this analysis , PCA offers no cost advantages over regular i.m . therapy in the pain management after hysterectomy . Regular i.m . injections provided less costly analgesia This prospect i ve , r and omized study compared the effects of two methods of morphine administration after abdominal surgery in 62 adults . All patients were offered intravenous morphine in the Postanesthesia Care Unit . On the ward , one group ( PCA-CI ) received a continuous infusion of morphine that could be supplemented by a patient-controlled bolus every 10 minutes . The other group ( IM ) received intramuscular morphine ( 0.08 - 0.12 mg/kg ) as often as every 3 hours when requested . During three postoperative interviews , patients were question ed about pain relief ( visual analogue scale ) , adverse opioid effects , and satisfaction with the method of analgesia . Total dose of morphine ( mg , mg/kg body weight ) , time to first oral analgesic medication , length of hospital stay , and cost were calculated following discharge . There was a wide interindividual variation in reported pain intensity and morphine usage in both groups . Comparison of both groups demonstrated no significant differences in analgesia , incidence of adverse opioid effects , 24 and 36 hour morphine dose , time to first oral analgesic medication , operating cost , and length of hospital stay . Patients in the PCA-CI group received a slightly greater dose of morphine in relation to body weight ( 24 hr , P = 0.03 ; 36 hr , P = 0.05 ) and reported a greater degree of satisfaction at each assessment ( P = 0.005 , P = 0.02 , P = 0.01 ) . These data support the greater patient satisfaction associated with patient-controlled analgesia but suggest that the wide range of reported pain scores and morphine requirements makes it difficult to demonstrate , in a small population , superior pain relief from patient-controlled analgesia when nurses are encouraged to administer intramuscular pain medication more effectively BACKGROUND To determine if oral oxycodone ( OOXY ) could provide equivalent postoperative analgesia and a similar side-effect profile to i.v . patient-controlled morphine in patients undergoing elective primary total hip replacement ( THR ) under spinal anaesthesia . METHODS We studied 110 consecutive patients aged 60 - 85 yr . After operation , patients were r and omly allocated to receive either oral controlled- and immediate-release OOXY or i.v . patient-controlled analgesia ( IVPCA ) with morphine . Both groups received regular co-analgesia and antiemetics . The primary outcome measures were : ( i ) postoperative pain at rest and movement and ( ii ) nausea score recorded 12 hourly . The secondary outcome measures were : ( i ) time to first mobilization , ( ii ) total amount of opioid consumed , ( iii ) number of additional antiemetic doses , and ( iv ) time to analgesic discontinuation . RESULTS There were no statistically significant differences in the primary outcome measures of pain at rest and movement ( P>0.05 , 95 % confidence intervals -0.41 , + 0.96 ) or nausea score ( P>0.5 ) . The secondary outcome measures showed no significant difference in the total amount of opioid consumed ( 102 vs 63 mg ; P>0.05 ) or time to mobilization ( 24.45 vs 26.6 h , P=0.2 ) . The number of antiemetic doses required in the first 24 h was significantly lower in the OOXY group ( 1.1 vs 1.4 , P<0.05 ) . The time to analgesic discontinuation was significantly shorter in the OOXY group ( 50.5 vs 56.6 h , P<0.05 ) . Oral analgesia with OOXY was approximately GBP 10 less expensive per patient than IVPCA . CONCLUSIONS Oral analgesia with OOXY after THR offers non-inferior analgesia to IVPCA and may offer some logistical and cost advantages The postoperative analgesia afforded after colonic surgery by IV opioid , clonidine and lignocaine given intra- and postoperatively was evaluated . In a double-blind r and omised trial , 80 male patients scheduled for colonic resection under general anaesthesia received fentany 15 μg.kg−1 at induction and another 4 μg.kg−1 before skin incision ( group A ) or fentanyl ( same dose ) plus clonidine 4 μg.kg−1 in 20 min + 2 μg.kg−1.h−1 ( group B , C ) or fentanyl plus clonidine ( same dosage ) plus lignocaine 2 mg.kg−1 before skin incision , repeated before peritoneal incision and retractor placement ( group D ) . In the four groups , intraoperative boluses of fentanyl 2 μg.kg−1 were given in response to the painful stimulation of the procedure . Postoperative pain was managed with PCA delivering 2 mg morphine per request in group A , 1.5 mg morphine in group B , 1.5 mg morphine + 15 μg clonidine in group C and 1.2 mg morphine + 15 μg clonidine + 23 mg lignocaine in group D. Postoperative analgesia was assessed by recording the analgesic dem and s ( met and unmet ) and the dose of morphine delivered at 6 , 12 , 18 , 24 , 36 hours . Side-effects , pain and sedation analogue scores were also recorded . A nalgesic dem and s and delivered morphine dose were reduced , at any time interval considered , in groups B , C , D , compared with A ( P < 0.001 ) . No differences were noted between the groups B , C , D. Pain analogue scores were better in groups B , C , D compared with group A ( P < 0.001 ) . Sedation and side-effects were not increased in groups B , C , D. Intraoperative clonidine was the major determinant of the reduction in analgesic dem and s and morphine delivered . Lignocaine , at the dose used , failed to afford any additional benefit This investigation evaluated patient – controlled analgesia ( PCA ) for subjective well – being and mood in the postoperative period in comparison with the intramuscular ( i m ) administration of morphine given on dem and . Patients scheduled for elective upper abdominal surgery were assigned at r and om to either PCA ( n = 17 ) or i m morphine ( n= 14 ) . The PCA group experienced significantly more pain relief and consumed more morphine than those who received i m morphine . The PCA patients suffered from more fatigue and showed less vigour than the i m group . Neither preoperative trait anxiety nor locus of control was associated with postoperative pain in either of the groups OBJECTIVE The purpose of this study was to determine whether oral analgesia with oxycodone-acetaminophen or a patient-controlled analgesia device with morphine provides superior analgesia after cesarean delivery . STUDY DESIGN Ninety-three patients with scheduled cesarean delivery were assigned r and omly to receive either oral analgesia with oxycodone-acetaminophen or a morphine patient-controlled analgesia device . At 6 and 24 hours after the procedure , pain was assessed on a visual analog pain scale of 0 to 10 . Nausea , sedation , pruritus , ambulation , emesis , and oral fluid intake were also assessed . RESULTS Patients who used oral analgesia without a patient-controlled analgesia device experienced less pain at 6 and 24 hours after cesarean delivery . They also had less nausea and drowsiness at 6 hours but slightly more nausea at 24 hours . CONCLUSION Oral analgesia with oxycodone-acetaminophen may offer superior pain control after cesarean delivery with fewer side-effects as compared with morphine patient-controlled analgesia . Consideration should be given to exp and ing the use of oral analgesia in patients immediately after cesarean delivery BACKGROUND : Acute pain services have received widespread acceptance and formal support from institutions and organizations , but available evidence on their costs and benefits is scarce . Although there is good agreement on the provision of acute pain services after many major surgical procedures , there are other procedures for which the benefits are unclear . Data are required to justify any expansion of acute pain services . In this r and omized , controlled clinical trial we compared the costs and effects of acute pain service care on clinical outcomes with conventional pain management on the ward . Patients included in the trial were considered by their anesthesiologist to have either arm be suitable for the procedure . METHODS : Four hundred twenty-three patients undergoing major elective surgery were r and omized either to an anesthesiologist-led , nurse-based acute pain service group with patient-controlled analgesia or to a control group with IM or IV boluses of opioid analgesia . Both groups were treated with medications to treat opioid-related adverse effects and received the usual care from health professionals assigned to the ward . The main outcome measures were quality of recovery scores , pain intensity measures , global measure of treatment effectiveness , and overall pain treatment cost . Cost-effectiveness acceptability curves were drawn to detect a difference in the joint cost-effect relationship between groups . RESULTS : There was no difference in quality of recovery score on postoperative day 1 between treatment and control groups ( mean difference , 0 ; 95 % confidence interval [ CI ] , −0.7 to 0.7 ; P = 0.94 ) or in the rate of improvement in quality of recovery score ( mean difference , −0.1 ; 95 % CI , −0.4 to 0.1 ; P = 0.34 ) . The proportion of patients with 1 or more days of highly effective pain management was higher in the acute pain service group than in the control group ( 86 % vs. 75 % ; P < 0.01 ) . Costs were higher in the acute pain service group ( mean difference , US$ 46 ; 95 % CI , $ 44 to $ 48 per patient ; P < 0.001 ) . A cost-effectiveness acceptability curve showed that the acute pain service was more cost effective than was control for providing highly effective pain management if the decision maker was willing to pay more than US$ 546 per patient per 1 day with highly effective treatment . CONCLUSION : In extending the role of the acute pain service to a specific group of major surgical procedures , the acute pain service was likely to be cost effective Pain control is an important consideration after any surgical procedures . Especially in children , more attention and care are needed during the period of postoperative pain control , which must be both sufficiently safe and effective . In this respect , intravenous patient-controlled analgesia provides improved titration of analgesic drugs , thereby maintaining optimal analgesic status with few side effects . Thirty pediatric patients were r and omly divided into two groups : the intravenous patient-controlled analgesia group ( with nalbuphine HCl and ketorolac tromethamine ) and the conventional pethidine HCl intramuscular group . The degree of analgesia was assessed every 4 hours until the second postoperative day . The intravenous patient-controlled analgesia group had significantly lower pain scores and took less time until they were able to walk to the bathroom , but as many side effects as the control group . We concluded that intravenous patient-controlled analgesia is safe and effective for pediatric patients who have moderate to severe pain after operations such as rib cartilage graft , iliac bone graft , and large flap surgeries To quantify the effects of postoperative pain relief on surgical stress response , 16 patients undergoing cholecystectomy were allocated r and omly to double-blind treatment with either fentanyl by patient controlled analgesia ( PCA ) with the Prominject plus saline given s.c . by nurses on dem and ( PCA group ) or saline by the infusion pump plus morphine 10 mg/70 kg s.c . by nurses on dem and ( control ) . Pain intensity ( VAS ) and plasma catecholamine , cortisol and glucose concentrations were measured 2-hourly for 12 h after operation . PCA improved postoperative pain intensity ( P less than 0.05 ) and reduced plasma cortisol ( P less than 0.05 ) , but not glucose and catecholamine concentrations compared with the control group . Thus improved postoperative pain relief per se by PCA with systemic opioids had no major influence on the catabolic response to abdominal surgery Pain after craniotomy remains a significant problem . The effect of morphine and tramadol patient‐controlled analgesia ( PCA ) on arterial carbon dioxide tension is unknown in patients having such surgery . Sixty craniotomy patients were r and omly allocated to receive morphine PCA , tramadol PCA or codeine phosphate 60 mg intramuscularly . Baseline values of pain score ( 0–10 ) , sedation and arterial carbon dioxide tension were recorded at the time of first analgesic administration and at 30 min , 1 , 4 , 8 , 12 , 18 and 24 h. Patient satisfaction was assessed at 24 h. There were no differences in arterial carbon dioxide tension or sedation between groups at any time , but in all three groups some patients had rises greater than 1 kPa . Morphine produced significantly better analgesia than tramadol at all time points ( p < 0.005 ) and better analgesia than codeine at 4 , 12 and 18 h. Patients were more satisfied with morphine than with codeine or tramadol ( p < 0.001 ) . Vomiting and retching occurred in 50 % of patients with tramadol , compared with 20 % with morphine and 29 % with codeine A r and omized investigation compared the efficacy and safety of nalbuphine administered by two methods , a patient-controlled infuser system and intramuscular ( IM ) injections , after major gynecologic surgery . Forty-seven patients were r and omly assigned to receive nalbuphine by either method . The 22 patients using the infuser were given a 2.0-mg , incremental dose with a 10-minute lock-out interval between doses . A similar group receiving 10 - 15 mg IM every three hours served as the control . Misprogramming , overdosage , depressed respiration and drug dependence were not encountered . Self-administration provided equally satisfactory sedation and more immediate pain relief without painful injections . Although patients with the infuser had the ability to self-administer more medication , they did not use higher doses of nalbuphine than did the IM group . The additional cost of the infuser system was offset by the satisfaction expressed by the patients and by the improved nursing efficiency . Nalbuphine administered with a patient-controlled infuser provided an effective balance between analgesia and sedation and offered advantages over IM injections CONTEXT Patient-controlled analgesia ( PCA ) with morphine is commonly used to provide acute postoperative pain control after major surgery . The fentanyl hydrochloride patient-controlled transdermal system eliminates the need for venous access and complicated programming of pumps . OBJECTIVE To assess the efficacy and safety of an investigational patient-controlled iontophoretic transdermal system using fentanyl hydrochloride compared with a st and ard intravenous morphine patient-controlled pump . DESIGN , SETTING , AND PATIENTS Prospect i ve r and omized controlled parallel-group trial conducted between September 2000 and March 2001 at 33 North American hospitals , enrolling 636 adult patients who had just undergone major surgery . INTERVENTIONS In surgical recovery rooms , patients were r and omly assigned to intravenous morphine ( 1-mg bolus every 5 minutes ; maximum of 10 mg/h ) by a patient-controlled analgesia pump ( n = 320 ) or iontophoretic fentanyl hydrochloride ( 40- microg infusion over 10 minutes ) by a patient-controlled transdermal system ( n = 316 ) . Supplemental analgesia ( morphine or fentanyl intravenous boluses ) was administered as needed before and for the first 3 hours after activation of the PCA treatments . Patients then used the PCA treatments without additional analgesics for up to 72 hours . MAIN OUTCOME MEASURES The primary efficacy variable was patient global assessment of the method of pain control during the first 24 hours . Additional efficacy measures were the proportion of patients discontinuing the study because of inadequate analgesia for any reason , patient-reported pain intensity scores on a 100-mm visual analog scale ( VAS ) , and patient global assessment s at 48 and 72 hours . Adverse effects were also recorded . RESULTS Ratings of good or excellent after 24 hours of treatment for the method of pain control were given by 73.7 % of patients ( 233/316 ) who used transdermal fentanyl PCA and 76.9 % of patients ( 246/320 ) who used intravenous morphine PCA ; treatment difference was -3.2 % ( 95 % confidence interval , -9.9 % to 3.5 % ; P = .36 ) . Early patient discontinuations ( 25.9 % fentanyl vs 25.0 % morphine ; P = .78 ) and last pain intensity scores ( 32.7 fentanyl vs 31.1 morphine on the VAS ; P = .45 ) were not different between the 2 treatments . With continued treatment for up to 48 or 72 hours , more than 80 % of patient assessment s in each treatment group were good or excellent . The incidence of opioid-related adverse events was similar between the groups . CONCLUSION An investigational PCA transdermal system using iontophoresis to deliver fentanyl provided postsurgical pain control equivalent to that of a st and ard intravenous morphine regimen delivered by a PCA pump & NA ; We have compared analgesic requirements , perceived pain , and self‐ assessment of ‘ health locus of control ’ for 72 h in 88 subjects after cholecystectomy , r and omized to either a st and ard technique of self‐administration of meperidine ( patient‐controlled analgesia , PCA ) or to intramuscular injections on dem and ( i.m . ) . Multivariate analysis revealed no statistical differences between group scores for pain ( over any 24 h period ) and only minor differences in total meperidine administered . However , the PCA group received significantly less analgesic in the first 24 h ( P < 0.01 ) and described significantly more pain over the first 4 h ( P < 0.01 ) . Assessment of ‘ health locus of control ’ did not show any marked changes . Analysis of patient question naires suggests more enthusiasm for patient‐controlled analgesia , but in this study , it was difficult to clearly demonstrate any significant advantage for pain management or amount of opiate administered BACKGROUND : Surgery of the posterior fossa often produces intense postoperative pain . However , this pain is infrequently treated because of concern that opioid administration may mask the postoperative neurologic examination and /or produce hypercarbia . In this prospect i ve , r and omized controlled trial , we sought to determine whether IV patient-controlled analgesia ( PCA ) would lead to reductions in postoperative pain after neurosurgical procedures of the posterior fossa compared with conventional IV nurse-administered as-needed ( PRN ) therapy . METHODS : Eighty patients ( age range , 18–82 years ) undergoing elective posterior fossa surgery were r and omized to receive postoperative IV fentanyl PRN 25 to 50 & mgr;g every 30 minutes or via PCA 0.5 & mgr;g/kg/dose , with a maximal dose limit of 50 & mgr;g , and 15-minute lockout ( 4 doses/hour ) . We measured pain ( Numerical Rating Scale , 0–10 ) , analgesic use , sedation ( Ramsay Sedation Scale and Glasgow Coma Scale ) , respiration , hemodynamics , and adverse events hourly . RESULTS : Sixty-five patients completed the study . Thirty-one patients received IV PCA and 34 received PRN analgesia . Patient demographics did not differ between groups . Patients in the PCA group reported less pain at rest ( mean [ 95 % confidence interval ] : 3.7 [ 3.0 , 4.4 ] vs 5.2 [ 4.5 , 5.8 ] , P = 0.003 ) and received more fentanyl ( mean [ 95 % confidence interval ] : 54.8 [ 42.1 , 67.6 ] vs 29.9 [ 24.2 , 35.7 ] & mgr;g/h , P = 0.002 ) than those in the PRN group . There were no differences in side effects and no adverse events related to analgesic therapy . CONCLUSIONS : IV PCA use result ed in reduction in postoperative pain compared with PRN analgesic therapy after surgery of the posterior fossa . Larger studies will be required to determine the safety of IV PCA in this patient population There are no comparisons of IV patient controlled analgesia ( IV PCA ) versus nurse-administered subcutaneous ( NA SC ) morphine for acute postoperative pain . We undertook a prospect i ve , r and omized , controlled clinical trial of 80 cardiac surgical patients to compare IV PCA with NA SC morphine for postoperative pain control . Visual analog scale ( VAS ) pain scores at rest and with movement , daily verbal pain relief scores , and side effect profiles were not significantly different . Total morphine requirements in the two groups were not significantly different . A physiotherapist 's evaluation of the effectiveness of analgesia for chest physiotherapy revealed no difference between the two groups . We conclude that NA SC morphine , administered as required ( up to hourly ) , is a satisfactory alternative to IV PCA morphine after cardiac surgery . Implication s : In a prospect i ve , r and omized study , we have shown that nurse-administered subcutaneous morphine is a satisfactory alternative to IV patient-controlled analgesia after cardiac surgery . ( Anesth Analg 1998;87:11 - 5 Recent reports have suggested that patient-controlled analgesia is an effective means of narcotic administration in postoperative patients . This prospect i ve investigation was undertaken to determine the efficacy and safety of patient-controlled anesthesia infusion after cesarean section . During a recent ten-month period , 130 patients were assigned r and omly to receive meperidine by pump or intramuscular injection . Meperidine consumption using the device varied widely to meet individual needs . Overdosage and drug dependence were not encountered with the prescribed drug concentrations . The patient-controlled analgesia method provided less sedation and more immediate pain relief without the need for painful injections . The additional cost of renting the infuser device was offset by combined patient and nursing satisfaction . We conclude that patient-controlled infusion of meperidine is safe and effective in satisfying individual patient needs after cesarean section A clinical trial compared the efficacy of a mechanical device to deliver patient-controlled analgesia ( PCA ) ( n = 25 ) with intramuscularly administered morphine ( n = 17 ) for postcesarean pain management . Hypotheses were : ( 1 ) patient-controlled administration of narcotics will be superior ( increased satisfaction , reduced pain , decreased sedation , increased ambulation , decreased length of stay ) , and ( 2 ) functional vital capacity will increase post-operatively with PCA . No differences in demographic variables were identified ( P = less than or equal to .001 ) . Differences in satisfaction ( greater in PCA group , P = less than or equal to .05 ) , ambulation ( greater in PCA group , P = less than or equal to .001 ) , amount of medication used ( greater in PCA group , P = less than or equal to .001 ) , and sedation level ( less in PCA group , P = less than or equal to .05 ) were identified . No differences in vital capacity were identified . The hypothesis related to the superiority of PCA was accepted , while the association between PCA and increased vital capacity was not supported . The use of mechanical PCA devices provides an effective and safe means of managing postcesarean pain OBJECTIVE To determine whether the use of patient-controlled analgesia vs intramuscular injections improves postoperative psychological parameters , particularly anxiety . DESIGN R and omized , controlled trial of patient-controlled analgesia vs as-needed intramuscular morphine with pre- and postoperative assessment s of pain , mental status , narcotic use , anxiety and mood states . SETTING General surgical wards and surgical intensive care unit at a Veterans Administration hospital . PATIENTS Eighty-three elderly , chronically ill males undergoing major elective surgery . INTERVENTION Subjects r and omized to receive postoperative patient-controlled analgesia vs as-needed intramuscular morphine . Pre- and postoperative assessment s of State-Trait Anxiety Inventory , McGill-Dartmouth Part IV and Short Portable Mental Status Question naire . Pain ( using linear analog scale ) , sedation score and narcotic use assessed every 4 hours for 72 hours . RESULTS No differences were found in state anxiety or self-perceived mood states . Postoperative state anxiety was found to relate most closely to preoperative anxiety and postoperative complications , rather than method of analgesia or severity of pain . However , patient-controlled analgesia subjects had significantly improved analgesia and increased satisfaction . CONCLUSION The use of patient-controlled analgesia does not significantly alter the measured psychological parameters , compared with intramuscular injections . Improved analgesia is the result of pharmacologic effects , independent of psychological factors We assessed the quality of assessment and reporting of adverse effects in r and omized , double-blind clinical trials of single-dose acetaminophen or ibuprofen compared with placebo in moderate to severe postoperative pain . Reports were identified by systematic search ing of a number of bibliographic data bases ( e.g. , MEDLINE ) . Information on adverse effect assessment , severity and reporting , patient withdrawals , and anesthetic used was extracted . Compliance with former guidelines for adverse effect reporting was noted . Fifty-two studies were included ; two made no mention of adverse effects . No method of assessment was given in 19 studies . Twenty trials failed to report the type of anesthetic used , eight made no mention of patient withdrawals , and nine did not state the severity of reported adverse effects . Only two studies described the method of assessment of adverse effect severity . When all adverse effect data were pooled , significantly more adverse effects were reported with active treatment than with placebo . For individual adverse effects , there was no difference between active ( acetaminophen 1000 mg or ibuprofen 400 mg ) and placebo ; the exception was significantly more somnolence/drowsiness with ibuprofen 400 mg . Ninety percent of trials reporting somnolence/drowsiness with ibuprofen 400 mg were in dental pain . All studies published after 1994 complied with former guidelines for adverse effect reporting . Different methods of assessing adverse effects produce different reported incidence : patient diaries yielded significantly more adverse effects than other forms of assessment . We recommend guidelines for reporting adverse effect information in clinical trials Background and Objectives . Patient-controlled analgesia ( PCA ) offers effective postoperative pain management . However , the evidence of economic benefits associated with its use is lacking . Although suggestive , the potential economic advantages of PCA in saving nursing time and shortening hospital stay need objective documentation . Methods . This study compared the effects of morphine administered by PCA systems with intra-muscular ( IM ) morphine injection on patient analgesic response , satisfaction , nursing time requirements , and postoperative recovery in 23 patients undergoing “ open ” cholecystectomy and 44 patients undergoing lumbar laminectomy and bony fusion . After the operation , patients in the PCA group received 1.5 - 2 mg morphine with a lockout of 5 - 10 minutes on dem and , whereas those in the IM group received 0.15 - 0.2 mg/kg every 4 hours on dem and . Visual analog scale ( VAS ) pain scores and satisfaction scores were evaluated at 4-hour intervals while nursing time spent on both analgesia-related and non-analgesia-related activities was recorded continuously by a team of independent observers on the ward . Recovery time profile for the return of bowel function , activities of daily living , ambulation without support , and length of hospital stay was also recorded . Results . It was found that morphine consumption , VAS , and satisfaction scores were similar in both PCA and IM treatment groups following both types of surgery . However , the delay in nurse response to IM morphine request ranged from 27.2 ± 3.2 to 42.1 ± 11.8 minutes . The dem and of nursing time on analgesia administration was less with PCA . The magnitude of time saving was 10 min/patient/d in chole-cystectomy patients and 13 min/patient/d in laminectomy patients . The speed of post-operative patient recovery was similar between the two analgesia groups . Length of hospital stay following cholecystectomy was shorter—92.0 ± 5.9 hours with PCA versus 128.6 ± 22.2 hours with IM ( not statistically significant)—whereas that following laminectomy was not different . Conclusions . Data in this study have demonstrated some beneficial effects of PCA on nursing time requirements when it was used following cholecystectomy and lumbar laminectomy at the University of Toronto ; however , the magnitude of these benefits was less than previously reported . The effects of PCA on postoperative recovery and hospital stay , however , were not significantly different from IM therapy To evaluate a possible opioid-sparing effect of intravenous lidocaine we conducted a r and omized , double-blind clinical trial . Patients undergoing intraabdominal surgery under general anesthesia were treated with patient-controlled analgesia ( PCA ) in three groups : Group 1 ( n = 100 ; morphine 1 mg/mL ) , Group 2 ( n = 44 ; morphine 1 mg/mL plus lidocaine 10 mg/mL ) , and Group 3 ( n = 51 ; morphine 1 mg/mL plus lidocaine 20 mg/mL ) . Pain was evaluated using a 0 - 10 visual analog scale in the postanesthesia care unit ( PACU ) during deep inhalation at 15 and 30 min , and at 1 , 2 , and 4 h after arrival in the PACU , and continued after PACU discharge every 4 h for 36 h. Patients whose pain was more than 4/10 in the PACU received 2.5 mL of the respective solutions every 7 min until pain was less than 4/10 ; then PCA was started . The number of bolus and cumulative drug doses during the study were recorded . Along with pain intensity , we assessed vital signs and side effects . Time to acceptance of oral liquids was also determined . Adding lidocaine 10 or 20 mg/mL to PCA morphine 1 mg/mL for acute pain treatment after abdominal surgery yielded no differences in opioid use , pain levels , or side effects . ( Anesth Analg 1996;83:102 - 6 The purpose of this study was to evaluate the effectiveness of patient-controlled analgesia ( PCA ) in patients undergoing spinal surgery . Sixty patients undergoing spinal surgery were r and omly assigned to receive PCA or the st and ard approach to postoperative analgesia ( intramuscular injections on an " as needed " basis ) . Information on pain intensity at rest and with activity , total daily amount of analgesia , presence of adverse effects , length of time to ambulation and length of hospital stay was collected on all patients . Patients in the PCA group reported lower levels of pain , both at rest and with activity , and were ambulating earlier than patients receiving st and ard analgesia . There were no differences between the groups in total daily analgesic intake , presence of adverse effects and length of hospital stay . These data suggest that PCA is a safe , effective approach to managing pain after spinal surgery We conducted a study to compare the effectiveness of patientcontrolled analgesia ( PCA ) technique to conventional analgesic therapy ( CAT ) after coronary artery bypass graft ( CABG ) . The PCA group received hydromorphone 0.1 mg · hr−1 basal infusion and bolus doses of 0.2 mg Q 5 min ( maximum 1.2 mg · hr−1 ) while the CAT group received morphine 2.5 mg iv Q 30 min prn until extubation followed by prn meperidine 1 mg · kg−1 i m Q4 hr or acetaminophen 325 mg with codeine 30 mg po ( 1 or 2 tablets ) when oral intake was possible . The degree of pain was assessed using a Visual Analogue Scale ( VAS ) starting after extubation and every 6–8 hr for the next 60 hr . Holter monitoring was initiated one hour after patient arrival in the Intensive Care Unit ( ICU ) and continued for 72 hr . Other measured variables were pulmonary function , sedation , side effects and total opioid requirements . Results show that the day-to-day VAS pain score decreased in the PCA group ( P < 0.001 ) while it remained unchanged in CAT patients . The PCA patients had lower VAS pain scores at extubation ( P < 0.05 ) . During the third postoperative day , the PCA group had a lower VAS pain score , a lower incidence of severe pain defined as a score > 5 on the VAS scale , and a reduced incidence of myocardial ischaemia ( P < 0.01 ) . However , there was no difference in the duration , severity , area under the curve ( AUC ) , or heart rate during ischaemic events . Postoperative pulmonary function was abnormal in both groups ( NS ) with minimal recovery by the fourth day . Opioid requirements , incidence of side effects and the degree of sedation were similar . We conclude that the PCA technique for analgesia provided slightly better results . The finding of a reduced incidence of myocardial ischaemia in the PCA group warrants further clinical investigation . RésuméNous avons effectué une étude comparative sur l’efficacité de l’analgésie contrôlée par le patient ( PCA ) par rapport au traitement analgésique conventionnel ( CAT ) chez des patients subissant une chirurgie de revascularisation myocardique . Après r and omisation , le groupe PCA ( n = 30 ) recevait une perfusion continue d’hydromorphone ( 0.1 mg · hr−1 ) avec des bolus de 0.2 mg Q 5 min ( maximum 1.2 mg · hr−1 ) , alors que le groupe CAT ( n = 30 ) recevait morphine 2.5 mg iv Q 30 min prn jusqu’à l’extubation , suivie par mépéridine 1 mg · kg−1 i m Q 4 hr prn ou acétaminophène 325 mg avec codéine 30 mg po ( 1–2 comprimés ) lorsque le patient pouvait s’alimenter . La perception de douleur fut évaluée à l’aide d’une échelle visuelle analogique ( VAS ) lorsque le patient fut extubé et à toutes les 6–8 hr pendant 60 hr . Un monitorage Holter de 72 hr fut débuté 1 hr après l’arrivée du patient aux soins intensifs . L’étude a aussi évalué les changements dans la fonction pulmonaire , la sédation , les effets secondaires et la quantité d’opiacés requise . Nos résultats démontrent que le degré de sévérité de la douleur a diminué significativement d’une journée à l’autre dans le groupe PCA ( P > 0.001 ) comparativement au groupe CAT A l’extubation , les patients PCA avaient moins de douleur ( P < 0.05 ) . Au troisième jour postopératoire , le groupe PCA avail moins de douleur ( P < 0.05 ) , aucune incidence de douleur sévère ( P < 0.01 ) et une incidence diminuée d’ischémie myocardique ( P < 0.01 ) . Toutefois , il n’y avail pas de différence dans la durée , l’intensité , la surface sous la courbe ( AUC ) et la fréquence cardiaque pendant les épisodes d’ischémie myocardique . La fonction pulmonaire postopératoire était anormale dans les deux groupes ( P = NS ) avec très peu de récupération après quatre jours . Les besoins en opiacés , l’incidence des effets secondaires et le degré de sédation étaient similaires . Nous concluons que la technique de PCA procure une analgésie légèrement supérieure . Le fait qu’il y avail une diminution dans l’incidence d’ischémie myocardique dans le groupe PCA nécessite d’autres investigations cliniques Though patient-controlled analgesia ( PCA ) has been in use for over a decade , it has been popularized only recently . Conventional techniques of intermittent intramuscular ( IM ) administration of analgesia have fallen short of meeting the needs of patients following major abdominal surgery . This has prompted a search for methods to improve postoperative pain management . Though PCA has been accepted in many hospitals , few studies comparing conventional IM administration of morphine with PCA have been performed . A prospect i ve r and omized study comparing IM- and PCA-administered morphine in 62 patients undergoing colon surgery was performed . A comparison of the efficacy of analgesia and extent of sedation using these approaches shows that PCA allows for analgesia with less sedation and less drug requirement than that of IM administration . No differences were noted in postoperative duration of ileus , duration of hospitalization , and total hospital costs . This study confirms the safety and efficacy of PCA , and should be considered the current optimal method of controlling pain following major colonic surgery BACKGROUND The goal of this study was to evaluate the effectiveness on postoperative pain , and cognitive impact , of patient-controlled analgesia ( PCA ) compared with subcutaneous ( s.c . ) injections of morphine in elderly patients undergoing total hip replacement ( THR ) . METHODS Forty patients older than 70 yr were r and omly assigned to two different postoperative analgesic techniques for 48 h : i.v . PCA morphine ( dose , 1 mg ; lockout interval , 8 min ; PCA group ) or regular s.c . morphine injections ( SC group ) . Postoperative pain was assessed at rest and when moving , using a visual analogue scale ( VAS ) every 4 h. A Mini Mental Status ( MMS ) examination was used to assess cognitive functions before surgery , at 2 h , 24 h and 48 h after surgery , and at hospital discharge . Side-effects were also recorded systematic ally during the first 48 h after surgery . RESULTS The PCA group showed significantly lower pain scores than the SC group both at rest and during mobilization . However , the clinical significance of pain scores was weak . There was no intergroup difference in postoperative MMS scores . The incidence of side-effects was similar in both groups . CONCLUSIONS We conclude that in healthy elderly subjects undergoing THR , the flexibility of the analgesic regimen is more important than the route of administration with regard to efficacy , adverse effects and recovery of cognitive function We conducted a r and omized , double-blind trial to compare analgesia and side effects produced by ketorolac and morphine during postoperative patient-controlled analgesia ( PCA ) . Fifty-one patients ( ASA classes I and II ) undergoing elective intraabdominal procedures were assigned to one of two groups . When postoperative pain first increased to 4/10 ( by visual analog scale [ VAS ] ) , patients were r and omly assigned to one of two groups . Group 1 ( n = 25 ) received up to two intravenous ( IV ) boluses of 5 mg of morphine followed by IV morphine PCA , whereas those in Group 2 ( n = 26 ) received up to two IV boluses of 30 mg ketorolac , then IV ketorolac PCA . Up to two rescue doses of morphine ( 5 mg per dose , subcutaneously ) were given in either group when pain during deep inhalation exceeded 5/10 on VAS . Ten patients from Group 1 required rescue doses of morphine compared to 22 patients from Group 2 ( P < 0.0011 ) . Two and 16 patients from Groups 1 and 2 , respectively , were withdrawn because of inadequate analgesia ( P < 0.01 ) . Mean pain scores were less in Group 1 than in Group 2 at each time , but only significantly so at 15 min ( P < 0.0021 ) , 30 min ( P < 0.0336 ) , and 24 h ( P < 0.0358 ) after starting PCA . Time to acceptance of oral liquids was equivalent in Groups 1 and 2 ( 22 h and 21 h , respectively ) . IV ketorolac PCA , although well tolerated , has limited effectiveness as the sole postoperative analgesic after intraabdominal operations . ( Anesth Analg 1995;80:1150 - 3 A prospect i ve r and omized controlled study was performed to assess the efficacy and safety of patient-controlled analgesia ( PCA ) in patients undergoing thoracotomy . This method was compared with a conventional pain management technique consisting of regularly scheduled i m injections of analgesics . Forty adult patients were r and omly assigned to receive intravenous PCA or i m meperidine treatment over a 48-hr period after surgery . Care was taken to optimize analgesia in patients of both groups . The MeGill Pain Question naire , visual analogue and verbal-numeric scales were administered at regular intervals to measure various components of the patients ’ pain experience , degree of pain relief , adverse side effects and overall treatment efficacy . Functional recovery after surgery was also examined . The results showed good and comparable analgesia with both pain-control methods . However , a greater number of patients receiving i m injections required dosage adjustments than in the PCA group . Patients ’ and nurses ’ evaluations of overall treatment efficacy also favoured PCA treatment . There were no major group differences in the side effect profile . Recovery pattern was also comparable in the two groups except for the length of hospitalisation . There were fewer long-stay patients in the PCA than in the i m group . Meperidine intake was similar in both groups but considerable interpatient variation was seen . In conclusion , PCA is a safe , effective and individualized treatment method for controlling pain after thoracotomy . There appears to be some clinical advantages of PCA over i m dosing regimens for analgesia after thoracotomy . RésuméUne étude prospect i ve dûment contrôlée fut effectuée afin d’évaluer l’efficacité et la sécurité de l’auto-analgésie intraveineuse ( patient-controlled analgesia : PCA ) chez des patients ayant subi une thoractomie . Cette méthode était comparée à un mode conventionnel d’analgésie où des injections intramusculaires ( i m ) d’analgésiques étaient administrées de façon régulière . Quarante patients adultes furent assignés au hasard à l’un ou l’autre groupe de traitement où de la mépéridine était adminsitrée soit en mode PCA , soit en mode i m . L’étude s’est échelonnée sur une période de 48 hr après la chirurgie . L’obtention d’une analgésie optimale a fait l’objet d’une attention particulière et ce , chez les patients des deux groupes . Le question naire MeGill sur la douleur de même que des échelles de type visuel analogique et verbal-numérique furent administrés à intervalles fréquents afin de mesurer différentes composantes de la douleur des patients , le degré de soulagement , les effets secondaires et l’efficacité globale du traitement . Certains paramètres de récupération fonctionnelle ont également été mesurés . Les résultats ont démontré une analgésie adéquate et comparable avec les deux types de traitement . Toutefois , un nombre plus élevé de patients du groupe i m a nécessité des changements de dosage par rapport au groupe PCA . Les mesures d’efficacité globale obtenues en fin de traitement auprès des patients et des infirmières militaient également en faveur du mode PCA . Le profil des effets secondaires ne montrait pas de différence majeure entre les deux groupes . Les paramètres de récupération étaient également comparables sauf pour le séjour hospitalier qui était moindre chez les patients du groupe PCA . La consommation de mépéridine était similaire chez les deux groupes mais les quantités variaient considérablement d’un patient à l’autre . En conclusion , le PCA apparaît être une méthode efficace et sécuritaire pour soulager la douleur post-thoracotomie ; elle foumit un traitement individualisé et avantageux par rapport au mode traditionnel d’injections i m This study was conducted in order to investigate the advantages and limitations of four analgesic modalities : a ) epidural morphine ; b ) intravenous morphine ; c ) patient controlled intravenous morphine ( patient-controlled analgesia ) ; and d ) non-steroidal anti-inflammatory drugs . Eighty patients undergoing major abdominal surgical procedures were prospect ively and r and omly treated with one of the above-mentioned analgesic methods . Evaluation of pain perception was done using the visual analogue pain score and the simple descriptive scale 4 hours after the procedure , in the early morning on postoperative day 1 and in the afternoon on postoperative days 1 , 2 and 3 . The need for supplementary analgesia and the onset of complications , if any , were also evaluated for each patient . Patient-controlled intravenous morphine yielded the best analgesic effect over the entire period . Epidural morphine was more effective in the very early postoperative period compared to modalities ( b ) and ( d ) . Non-steroidal anti-inflammatory drugs , on the other h and , were more effective on the later postoperative days . None of the patients in group C needed supplementary analgesia , as against 20 % in group A , 55 % in group B and 40 % in group D. Patients with hypochondriasis scores > 70 or depression scores > 70 required supplementation of analgesia more often . Morphine proved to be the drug of choice . Drug titration may be modulated in relation to the psychological characteristics of the patient . The best drug titration modality , in fact , is patient-controlled analgesia In children , patient controlled analgesia ( PCA ) and continuous infusion ( CI ) of morphine are well established methods of relieving postoperative pain . This study was design ed to assess the efficacy of PCA plus background infusion ( BI ) ( 15 microg x kg(-1 ) x h(-1 ) and bolus doses of 15 microg x kg(-1 ) with a lock-out interval of 10 min ) with CI ( 20 to 40 microg x kg(-1 ) x h(-1 ) ) in terms of analgesia , morphine needs and side-effects . A stratified r and omized controlled trial was carried out . 47 children aged 5 - 18 years undergoing major elective lower/upper abdominal or spinal surgery were allocated . The magnitude of surgery was assessed by the Severity of Surgical Stress scoring ( SSS ) system . Pain was assessed by self-report every three h. Side-effects compatible with morphine as well as morphine consumption were recorded . Morphine consumption was significantly increased in the PCA group compared with the CI group . Moreover , morphine consumption was associated with SSS , independent of the technique of administration . There were no significant differences between groups in pain scores or in the incidence of side-effects OBJECTIVE : To assess whether intrathecal ( IT ) analgesia facilitates early extubation and provides superior pain control after cardiac surgery compared with patient-controlled analgesia ( PCA ) or nurse-administered SC injections . METHODS : Sixty-two patients undergoing elective cardiac surgery participated in this prospect i ve , r and omized , partly-blinded study . Perioperative care was st and ardized , and patients were assigned to receive IT morphine ( ITM group ) followed by PCA , IT placebo ( ITP group ) followed by PCA , or SC injections of morphine every 4 hours as needed ( SC group ) . Rating scales and question naires were used to assess clinical outcomes . RESULTS : ITM did not favor earlier extubation , and there was even a tendency for longer extubation × in the ITM group compared with the ITP and SC groups . Pain scores , adverse effects , postoperative recovery , and patient satisfaction were also comparable in the 3 groups . CONCLUSIONS : Considering that the administration of IT morphine is more costly and can be riskier than conventional analgesic regimens , we conclude that its use is not indicated in patients undergoing cardiac surgery if early extubation is planned Objectives We design ed a clinical study to determine : a ) the safety and efficacy of patient-controlled analgesia ( PCA ) therapy in children and adolescents undergoing major-operations , b ) if the use of a concurrent opioid infusion improved the efficacy of conventional PCA therapy , and c ) if nurse control of the PCA device was a useful alternative in the intensive care unit ( ICU ) setting . Design Subjects were r and omly assigned to receive morphine sulfate for postoperative pain relief via intermittent PCA boluses on dem and or PCA plus a continuous infusion ( PCA + CI ) . Children ( n = 12 ) who were unable to use the PCA device because of inadequate developmental level or upper extremity weakness were assigned to a nurse-controlled analgesia ( NCA ) group . Setting In the ICU of a university-based pediatric teaching hospital . Patients Fifty-four children and adolescents underwent elective scoliosis surgery . Interventions The PCA devices were connected to the patient 's i.v . catheter immediately after surgery . Morphine sulfate was administered on dem and by either the patient or an ICU nurse for pain relief during the first 72 h after the operation . Main Outcome Measures Pain scores were recorded simultaneously by both the nurse and the patient using st and ardized visual analog scales . Opioid analgesic usage , side effects , and therapeutic interventions were recorded by the ICU nurse . Results There were no differences between the PCA and PCA + CI groups with regard to morphine use , pain relief , side effects , or patient satisfaction . Nurses consistently underestimated their patient 's level of pain , and children in the NCA groups received less morphine per kilogram than those who self-administered their own analgesic medication . Conclusions Both PCA and NCA were safe and efficient methods of analgesic administration in the pediatric ICU setting . However , use of a concurrent opioid infusion with PCA therapy did not provide any clinical ly significant advantages over intermittent bolus doses of the analgesic medication after scoliosis surgery . For patients unable to use a conventional PCA device , NCA is an acceptable alternative for the management of acute pain in the ICU setting The aim of this study was to investigate post-operative pain intensity , analgesic consumption and the incidence of chronic pain in women after different types of breast cancer surgery . Patients were r and omized to either patient-controlled analgesia or nurse-administered analgesia . Opioid-consumption was registered for 24 h. A division of the patient- material into four subgroups was performed : ( 1 ) mastectomy ; ( 2 ) mastectomy and axillary lymph node dissection ; ( 3 ) mastectomy and reconstruction ; and ( 4 ) mastectomy , reconstruction and axillary lymph node dissection . Visual analogue scale was used to measure pain intensity . Four years after surgery , a question naire regarding persistent pain was completed . Patients undergoing reconstruction scored higher pain levels than the others . Patient-controlled analgesia provided better pain relief but also considerably higher consumption of opioids by the women who underwent breast reconstruction . The incidence of remaining pain was 25 % after 3 - 4 years . Immediate breast reconstruction causes severe post-operative pain that can respond poorly to opioids . Chronic pain after breast cancer surgery is common and should be further analysed aim ing at better prevention and treatment options The present study contrasted the pharmaco-economics and analgesic efficacy of intramuscular ( i.m . ) opioid treatment with a parenteral disposable patient-controlled analgesia ( PCA ) system in two groups of 20 female patients ( ASA I-II , aged 35 - 69 years ) scheduled for abdominal hysterectomy . The PCA group received a continuous infusion of 1.5 mg h-1 piritramide , a mu-opioid receptor agonist , with incremental doses of 1.5 mg ( lock-out interval = 15 min ) . The i.m . group received 0.3 mg kg-1 piritramide i.m . when requested by the patient with a minimum interval of 5 h. Pain intensity , sedation and the functional recovery of the patients were followed for 72 h post-operatively . The sum of pain intensity differences ( SPID ) was used as a measure of analgesic efficiency . Equipment and drug costs , and the dem and on nursing time were recorded over 3 days post-operatively . The costs of PCA and i.m . therapies per patient were used to calculate the cost-benefit ( cost of treatment vs. nursing time ) and cost-effectiveness ( cost of treatment vs. SPID ) analyses . Both treatments initially provided comparable analgesia , but PCA was more efficient after 16 h and significantly reduced nursing time for pain treatment ( PCA = 61 + /- 4 min , i.m . = 88 + /- 5 min ; P < 0.001 ) . Functional recovery was not different for either treatment . Cost analysis indicated a better cost-benefit ratio for the i.m . treatment ( 0.35 vs. 1.1 for PCA treatment ) , but a similar cost-effectiveness for both treatments ( PCA = 1.9 Belgian Francs ( BEF ) unit-1 SPID ; i.m . = 1.7 BEF unit-1 SPID ) A r and omized , controlled clinical trial was conducted on 72 patients undergoing elective cardiac surgery to compare patient-controlled analgesia ( PCA ) to nurse-titrated infusion of morphine . Pain and nausea scores were assessed at 5 , 20 , 32 and 44 hours after cardiopulmonary bypass . Serum cortisol estimations were performed at 24 and 48 hours , and morphine consumption was measured at 0 - 24 and 24 - 48 hours . There was no difference between pain scores ( P=0.72 ) , nausea scores ( P=0.52 ) , serum cortisol at 24 and 48 hours ( P=0.32 and P=0.34 ) , and morphine consumption at 0 - 24 and 24 - 48 hours ( P=0.16 and P=0.12 ) . There was also no difference in the time to tracheal extubation ( P=0.79 ) and discharge from ICU ( P=0.64 ) . There was a significant association between pain and serum cortisol at 48 hours ( P=0.023 ) . This study also found a tenfold difference in the amount of morphine used ( range = 11 to 108 mg ) , with no significant association with patient age or sex . We could find no significant benefit from the routine use of PCA in cardiac surgical patients In a prospect i ve study of 30 total hip or knee joint arthroplasty patients , the use of the patient-controlled analgesia ( PCA ) pump was evaluated for patient acceptance and relief of pain . In 30 patients , ( average age , 72.5 years ) excellent analgesia was obtained with the PCA machine without the side effects of conventional intramuscular dosing . PCA was enthusiastically received by nurses , physicians , and patients , and it has become the method of choice in the author 's hospital Purpose Primary objective was to assess whether oral analgesia with oxycodone offers superior pain relief after cesareans than patient controlled analgesia ( PCA ) . Secondary outcomes were additional pain medication , time to first mobilization , therapeutic side effects , postoperative restrictions , overall satisfaction and costs . Material s and methods R and omized controlled trial at a University Hospital conduct between July 2009 and November 2009 . Of the 1,112 patients , 257 met the inclusion criteria and 239 agreed to participate . Patients were r and omly assigned to either receive intravenous piritramide PCA ( 2 mg piritramide/ml 0.9 % saline ) or oral oxycodone ( 20 mg ) . Pain was assessed on a visual analog pain scale ( VAS ) at 2 , 12 , 24 , 32 , 40 , 48 and 72 h after cesarean . Results No differences in VAS scores were observed within the general study population . Pain scores of oxycodone versus PCA were comparable at 24 h. Patients r and omized to PCA demonstrated increased dem and for rescue medication 48 h after cesarean ( p = 0.057 ) . In the PCA group , patients with previous cesarean had increased operative times , a trend towards increased VAS scores after 48 h ( p = 0.081 ) and increased VAS scores in comparison to patients who did not have cesarean before ( p = 0.044 ) . For this subgroup , no difference was seen in the oxycodone patients ( p = 0.883 ) . Conclusion General satisfaction with both treatment regimes was high . The results support the potential use of oral pain regimes and emphasis the importance of a multimodal approach to treat post-cesarean pain . Oral oxycodone is a not expensive , convenient and comparable analgesic to PCA devices with opioids after cesarean . Trial registration at clinical trials.gov identifier : NCT 01115101 Despite relatively widespread use of various forms of patient controlled analgesia ( PCA ) , there remain conflicting results in the literature as to the efficacy of PCA . This study was conducted to assess the efficacy and postoperative outcomes of intravenous PCA compared to intramuscular ( IM ) injections in 73 patients who received major abdominal surgery . These patients were r and omly selected and r and omly assigned preoperatively to receiving IM or PCA modes of analgesia postoperatively . The following factors were compared : amount of pain ; amount of analgesia use ; degree of patient satisfaction with pain control both while on parenteral analgesia and after switching to oral ; length of time to first ambulation ; and length of stay in hospital . Results of the study did not demonstrate a statistically significant difference in any of these , using a P-value of 0.01 . The PCA patients took an average of 4.5 hours longer than the IM patients to ambulate postoperatively and the IM patients received at least three times as much antiemetic ( P = 0.001 ) . Locus of control was not found to be a major factor in satisfaction or pain levels . Subsequent meta-analyses have also failed to yield significant differences between IM and PCA groups except in patient satisfaction . It is recommended that expansion of PCA programmes with abdominal surgery patients be considered only in cases where there is fiscal advantage or where patient satisfaction can be a driving force Our aim was to quantify the analgesic efficiency of the patient-controlled analgesia technique ( PCA ) , using ketorolac , in children aged 6–14 undergoing a surgical intervention . We carried out a double-blind test with two r and omly selected groups : the PCA group comprising patients su bmi tted to intravenous PCA , with “ bolus on dem and ” and the St and ard group , with conventional analgesia dispensed with ketorolac I.V. ( 0.5 mg/kg/6 hours ) . Evaluation of pain experienced was performed using the Hannallah behavioural scale and quantification of the summing of pain intensity . Analgesic efficiency was determined by the pain intensity difference ( PID ) score . Evaluation of pain experienced during hour 1 reveals a marked reduction with time for each group ; no inter-group differences were found . At hour 6 there were neither intra-group nor inter-group differences . The accumulated pain score revealed a significant reduction in hour 6 , with no differences between the two groups . Evaluation of the analgesic effect revealed no differences , either intra-group or intergroup , during the experimental period . The sum of the PIDs revealed significant differences in the st and ard group between the values for hours 1 and 6 . Under the experimental conditions described , both techniques were equally effective for pain treatment , but the efficiency was higher for the PCA group . ResumenSe cuantifica la eficacia analgésica de la técnica de analgesia controlada por el paciente ( ACP ) , utiliz and o ketorolaco , en niños de 6 a 14 años intervenidos quirúrgicamente . Se efectúa un ensayo doble ciego con dos grupos aleatorios : grupo ACP de pacientes sometidos a ACP intravenosa de “ bolos a dem and a ” y grupo pautado de analgesia convencional pautada con ketorolaco I.V.(0,5 mg/kg/6 horas ) . La evaluación del dolor se realiza mediante la escala conductual de Hannallah y la cuantificación del sumatorio de la intensidad del dolor . La eficacia analgésica se determina mediante los valores de diferencia en la intensidad del dolor ( PID ) . La valoración del dolor durante la hora 1 muestra una clara disminución con el tiempo dentro de cada grupo , no existiendo diferencias intergrupales . A la hora 6 no hay diferencias ni intra ni intergrupales . La suma acumulativa de la puntuación del dolor presenta una disminución significativa en la hora 6 , no apareciendo diferencias entre ambos grupos . La valoración del efecto analgésico no presenta diferencias ni intra ni intergrupales en el periodo experimental considerado . La sumatoria de los PID muestra diferencias significativas en el grupo pautado entre los valores de la hora 0 y 6 . En las condiciones experimentales descritas , ambas técnicas son igualmente eficaces para el tratamiento del dolor , pero la eficiencia es mayor en el grupo ACP & NA ; Two pumps , ‘ PA ’ and ‘ PB , ’ with different drug delivery characteristics were available at the time of this study for patient‐controlled analgesia ( PCA ) . PB purportedly produces a ‘ placebo effect ’ by emitting an audible signal whenever the patient depresses the trigger button . PA emits an audible signal only when the drug is successfully administered into the patient 's intravenous line . In a prospect i ve , r and omized Latin squares cross‐over study , the 2 pumps and conventional therapy were compared for efficacy and cost . Patients in both pump groups used less drug and perceived less pain than those on conventional therapy . However , statistically less anxiety and greater pain relief and patient and nursing satisfaction were reported with PA only . Daily cost including drug , pharmacy and nursing time , pump rental was 33 % , PA , versus 23 % , PB , more than conventional therapy . Purchase and amortization of the pumps decreases the cost . We conclude that PCA provides superior pain management at minimal additional cost A r and omized , prospect i ve trial of patient-controlled analgesia ( PCA ) , that is , a method of analgesia administration involving a computer-driven pump activated by patients to receive small doses within defined limits was performed in 82 children and adolescents after major orthopedic surgery to compare ( 1 ) intramuscularly administered morphine , ( 2 ) PCA morphine and ( 3 ) PCA morphine with a low-dose continuous morphine infusion ( PCA-plus ) . Patients receiving PCA and PCA-plus had lower pain scores and greater satisfaction than patients receiving intramuscularly administered morphine . The three groups used equal amounts of morphine and most measures of recovery were identical in the groups . In particular , PCA and PCA-plus did not increase the incidence of opioid-related complications , and patients receiving PCA-plus were less se date d than patients receiving intramuscular therapy . We conclude that PCA and PCA-plus are safe and effective methods of pain relief in children and adolescents after orthopedic surgery , are better accepted than intramuscular injections , and do not increase perioperative morbidity Background Many studies have shown in the efficacy of patient‐controlled analgesia ( PCA ) . However , it is not clear whether PCA has clinical or economic benefits in addition to efficient analgesia . The current study was design ed to evaluate these issues by comparing PCA with regularly administered intramuscular injections of opioids after hysterectomy . Methods This prospect i ve study included 126 patients who underwent abdominal hysterectomy and were r and omly assigned to receive PCA or regularly timed intramuscular injections of morphine during a period of 48 h. Doses were adjusted to provide satisfactory analgesia in both treatment groups . Pain at rest and with movement , functional recovery , drug side effects , and patient satisfactory were measured using rating scales and question naires . The costs of PCA and intramuscular therapy were calculated based on personnel time and drug and material requirements . Results Comparable analgesia was observed with the two treatment methods , with no significant differences in the incidence of side effects or patient satisfaction . The medication dosage had to be adjusted significantly more frequently in the intramuscular group than in the PCA patients . The PCA did not favor a faster recuperation time compared with intramuscular therapy in terms of times of ambulation , resumption of liquid and solid diet , passage of bowel gas , or hospital discharge . The results of the economic evaluation , which used a cost‐minimization model and sensitivity analyses , showed that PCA was more costly than regular intramuscular injections despite the fact that no costs for the pump were included in the analyses . Cost differences in nursing time favoring PCA were offset by drug and material costs associated with this type of treatment . Conclusions Compared with regularly scheduled intramuscular dosing , PCA is more costly and does not have clinical advantages for pain management after hysterectomy . Because of the comparable outcomes , the general use of PCA in similar patients should be question ed BACKGROUND : Opioids are st and ard treatment for postoperative pain . In this study , we compared the safety and efficacy of intranasal ( IN ) morphine to IV and oral morphine and placebo . METHODS : Two-hundred-twenty-five patients with moderate-to-severe pain after third molar extraction were r and omized to receive a single dose of IN morphine 7.5 mg or 15 mg , IV morphine 7.5 mg , oral morphine 60 mg or placebo . Pain intensity was assessed using visual analog and categorical scales , and pain relief using a categorical scale . Outcomes included total pain relief , pain intensity difference , summed pain intensity difference , time to analgesic onset , time to requesting rescue medication , and patients ’ global evaluation of their treatment . Safety assessment s included adverse event recording and nasal examinations . RESULTS : Across the various efficacy outcomes , both IN morphine doses were statistically similar to the positive comparators ( IV and oral morphine ) , and all four morphine treatments were statistically superior to placebo . Overall , IN morphine 15 mg presented an efficacy profile similar to IV morphine 7.5 mg ; both treatments demonstrated rapid onset of efficacy , generally persistent throughout the 6-h assessment period . The lower dose of IN morphine , 7.5 mg , was statistically similar to the other active treatments at 2 h and 6 h and similar to placebo at 4 h. Study medications were generally well tolerated , with no withdrawals due to adverse events or other safety concerns , and no serious adverse events reported . The most frequently reported adverse events were typical systemic opioid effects . CONCLUSIONS : IN morphine offers a noninvasive alternative to IV morphine for postoperative analgesia OBJECTIVE To determine whether patient-controlled analgesia or scheduled intravenous analgesia provides superior pain relief and satisfaction with pain control after vaginal reconstructive surgery . STUDY DESIGN Fifty-nine women scheduled for vaginal reconstructive surgery were enrolled in this r and omized trial . Operative procedures and postoperative orders were st and ardized . Visual analog scales for pain and satisfaction with pain control were recorded during the hospital stay and 2 weeks after surgery . RESULTS Patients receiving patient-controlled analgesia had less pain on postoperative day 1 , 25 mm vs 39 mm , on visual analog scales ( P = .007 ) . Although this group used twice as much hydromorphone ( 3.57 mg vs 1.48 mg , P < .001 ) , there was no difference in side effects , length of hospital stay , or complications . For the sample overall , larger amounts of narcotic used correlated with higher pain scores ( r = 0.364 , P = .009 ) and worse satisfaction scores ( r = -0.348 , P = .012 ) . CONCLUSION In patients undergoing vaginal surgery , patient-controlled analgesia offers superior pain relief on postoperative day 1 when compared with scheduled , nurse-administered hydromorphone It is often asserted that older patients are more sensitive to opioid analgesics than younger patients but experimental evidence for this assertion remains sparse . Two studies were conducted investigating the relationship between age and opioid analgesic use in the patient‐controlled analgesia environment . In study I , the relationship was analysed subsequent to our publication of a study investigating patients ' responses to opioid use with patient‐controlled analgesia . Fifty‐five postoperative patients , stratified into ‘ older ’ and ‘ younger ’ patients by median age , received morphine or pethidine or fentanyl patient‐controlled analgesia . A strong inverse relationship was found between age and fentanyl and morphine use but not between age and pethidine use . Study II was a retrospective study of the medical records of 199 patient‐controlled analgesia patients who had received morphine or pethidine patient‐controlled analgesia ; there were insufficient patients who had used fentanyl for a reasonable sample . There was a difference in morphine use with the younger patients using significantly more morphine than the older patients ( > 60 years ) . Findings were less clear for patients receiving pethidine but there was an inverse correlation between age and pethidine use as well . Overall , the findings of these two studies supported the common clinical belief that older patients require less opioids than younger patients Forty patients recovering from upper abdominal surgery were allocated r and omly to receive i.m . morphine 0.15 mg kg-1 as required or patient-controlled analgesia ( PCA ) , with i.v . morphine 1 mg and a 5-min lock out time . Arterial oxygen saturation ( SpO2 ) was measured continuously the night before and for 24 h immediately after surgery . A significantly greater proportion of patients in the PCA group ( nine of 19 ) rated their analgesia as excellent compared with the i.m . group ( two of 20 ) ( P < 0.05 ) . There was no significant difference in the incidence of postoperative hypoxaemia in the two treatment groups . Severe postoperative hypoxaemia ( SpO2 < 85 % for more than 6 min h-1 ) was seen in three patients receiving i.m . analgesia and one patient in the PCA group Abstract We compared the use of patient-controlled analgesia ( PCA ) morphine and p.r.n . intravenous morphine in an intensive care unit setting . Thirty-eight patients scheduled for admission to the Surgical Intensive Care Unit ( SICU ) were prospect ively r and omized to either a PCA group or a p.r.n . intravenous morphine group . Assessment s included pain and sedation scores , respiratory rates , pulse oximetry , and morphine utilization . PCA was found to be comparable in safety and efficacy to nurse-administered morphine in the intensive care environment . An unexpected finding was the higher initial morphine utilization seen in the patients utilizing PCA Patient-controlled analgesia ( PCA ) with intravenous pethidine was compared with nurse-controlled pethidine infusions for pain relief in 200 patients after major abdominal or thoracic surgery . Pain , level of sedation , nausea and presence of other adverse effects , in addition to cumulative pethidine requirement , were measured for the first 24 hours after surgery . Both groups were similar for age , weight and type of surgery . There was no significant difference between the quality of analgesia achieved in both groups . The frequency and severity of adverse effects was also similar . The cumulative pethidine dose administered to both groups was identical . It is concluded that nurse-controlled opioid infusions are as effective as PCA and may be used as an alternative to PCA where this is either unavailable or unsuitable OBJECTIVE To observe the effect of parecoxib on morphine dosage in patient-controlled analgesia ( PCA ) following thoracoscope-assisted thoracotomy . METHODS A consecutive series of 100 patients undergoing thoracoscope-assisted thoracotomy were r and omized into 5 groups and received PCA with morphine doses at 0 , 5 , 10 , 15 , and 20 mg given in 200 ml saline ( groups P(1 ) , P(2 ) , P(3 ) , P(4 ) , and P(5 ) , respectively ) . Parecoxib ( 40 mg ) was given in all the patients immediately before the operation , and the mixture ( 4 - 5 ml ) of lidocaine and ropivacaine was administered into the 3 intercostal spaces upper and lower to the incision before chest closure . PCA was administered for each patient . The visual analogue scale ( VAS ) at rest and coughing and the respiratory functional parameters were recorded at 1 , 2 , 4 , 8 , 12 , 24 , 36 , and 48 h after the start of PCA , and the actual and effective button-pressing times ( D(1)/D(2 ) ) in PCA were also recorded . RESULTS No patients showed signs of respiratory inhibition within 24 h after the operation , and the resting VAS was comparable between the groups within the initial 6 postoperative hours . At 8 to 24 h postoperatively , the VAS scores at rest and coughing were significantly higher in P(1 ) group than in the other groups ( P<0.05 ) , and no significant differences were found between the groups at 36 to 48 h. D(1)/D(2 ) in groups P(1 ) and P(2 ) were significantly different from those in the other 3 groups at 4 - 24 h , but no such difference was found between groups P(3 ) , P(4 ) , and P(5 ) . CONCLUSION The application of parecoxib may reduce the dosage of morphine in PCA following thoracoscope-assisted thoracotomy and results in good analgesic effect without affecting the patients respiratory function and sputum elimination We conclude that the intravenous PCA method is a cost-effective technique . Although the PCA device is expensive , the cost-effectiveness analysis should give explicit figures for physicians and the hospital administrators to decide whether they should use the PCA instead of the conventional method The purpose of this study was to assess , in the early postoperative period of cardiac surgery , the efficacy of patient-controlled analgesia ( PCA ) versus nurse-administered intravenous morphine followed by oral acetaminophen with or without codeine . Patients undergoing coronary bypass and /or valvular surgery were recruited . All were under 75 years of age and were in stable angina with no ischaemic attacks within the last three months . Visual analog scores ( VAS ) were used for pain assessment . Pulmonary function tests were done preoperatively and measured every six hours after surgery until discharge from the intensive care unit . Patients allocated to the PCA group received morphine intravenously by a PCA Plus Micro Delivery Device for at least 48 hours . Patients entered into the nurse-administered intravenous morphine group received intravenous morphine followed by oral acetaminophen with or without codeine in 24 to 36 hours according to the clinical assessment of the critical care nurse . The data showed that the quality of pain control and pulmonary function were comparable in both groups . The equipotent morphine dosage requirements were also not statistically different . It was concluded that there was no significant advantage in using PCA routinely in the early postoperative period after cardiac surgery . Furthermore , repetition of PCA instructions was often required during the study period Previous studies have shown that patient-controlled analgesia ( PCA ) provides effective pain control in the postoperative patient . To determine the impact of PCA technology on the overall hospital course , we design ed a r and omized controlled study comparing patients receiving analgesia using PCA infusion ( Abbott Lifecare , Abbott Laboratories ; Chicago , IL ) with patients receiving analgesia by traditional intramuscular or intravenous methods . All patients had undergone elective cholecystectomy . Sixty-nine patients completed the study , 35 received traditional postoperative analgesia , and 34 received analgesia using the PCA infuser . Comparison of both groups demonstrated no significant difference in postoperative bowel activity with both groups receiving liquids on the first postoperative day . There was no significant difference between the two groups with respect to postoperative length of stay ( 3.4 days for PCA vs 3.6 days for traditional ) . Patients demonstrated a wide range of analgesic requirement in the first 24 hours but the average of the total analgesic required was higher in the PCA group ( average , 29.5 mg ) than the traditional group ( 22.8 mg ) . Urinary complications occurred more commonly in the group of patients receiving traditional analgesia than in the group of patients receiving analgesia with the PCA device . When compared with patients receiving analgesia by traditional methods , patients receiving the PCA infusion required more analgesia with fewer urinary complications and similar postoperative length of stay Thirty‐six patients undergoing lower abdominal surgery were included in a prospect i ve r and omized controlled study to compare the effects of patient‐controlled analgesia ( PCA ) and a st and ard intramuscular/intravenous treatment ( conventional analgesia , CA ) of postoperative pain . Morphine was used in both groups . There were no significant differences between the two analgesic regimens in respect of linear analogue pain scores , verbal pain‐relief scores , amount of morphine used or side‐effects . No treatment‐induced alterations in vital values were experienced We report on 13 patients undergoing flank incisions in whom the postoperative pain was managed with a patient-controlled analgesia device . An initial group of 7 patients was used to determine the optimal injection dose for each patient and to examine variability in narcotic requirement during the postoperative course . A progressive decrease in narcotic need was noted during the postoperative course with patient-controlled analgesia , result ing in excellent patient acceptance , no postoperative complications and no drug-seeking behavior . A second group of 10 patients was r and omized prospect ively to receive either patient-controlled analgesia or a st and ard regimen of intramuscular morphine sulfate . Based on nursing observations , an analgesia and sedation scale was developed that compared the 2 groups . Analysis of a question naire evaluating subjective perception of postoperative pain revealed significantly less pain , less sedation and greater activity among patients r and omized to patient-controlled analgesia ( 95 per cent confidence limit ) The dose requirements and side effects of morphine were compared with those of diamorphine administered by patient‐controlled analgesia in 40 patients following elective total hip replacement . Patients were allocated r and omly to receive in a double‐blind manner either morphine or diamorphine for postoperative pain relief . There were no significant differences between the two groups with regard to postoperative sedation , nausea , well‐being , pain relief and requirements for antiemetic drugs . The dose requirement for diamorphine was approximately 50 % of that for morphine OBJECTIVE To determine whether treatment with patient-controlled analgesia ( PCA ) alone or in combination with nonsteroidal anti-inflammatory drugs can prevent postoperative pulmonary complications after cardiac surgery , when compared with conventional nurse-controlled analgesia . DESIGN R and omized controlled trial . SETTING University Medical Center . PATIENTS A total of 120 patients undergoing elective coronary artery bypass grafting . INTERVENTIONS After extubation of the trachea , 120 patients were r and omly allocated to three different methods of postoperative pain relief for 72 hrs . In group 1 , patients received PCA with a bolus of 1.5 mg piritramide combined with a 10-min lockout interval . Group 2 patients were treated with a combination of PCA and administration of nonsteroidal anti-inflammatory drugs prescribed three times per day . Patients of group 3 received conventional nurse-controlled analgesia . Postoperative assessment included daily visual analog pain scoring ( VAS ) and chest radiographs . All chest radiographs were grade d for the extent of atelectasis by a radiologist blinded as to treatment using a scale from 0 to 9 for each of the three lung fields of the right and left lungs . MEASUREMENTS AND MAIN RESULTS Chest radiograph atelectasis scores and VAS values were similar among the three groups on the first and second days . On the third day , the chest radiograph atelectasis scores of the left lower and the right middle lung field were significantly better in the groups treated with PCA alone ( 4.7 + /- 3.0 ; 0.3 + /- 1.0 ) and in combination with nonsteroidal anti-inflammatory drugs ( 3.9 + /- 1.1 ; 0.4 + /- 1.2 ) than in the control group ( 5.5 + /- 3.1 ; 0.8 + /- 1.8 ) . Furthermore , on the third day , the VAS values for maximum pain were higher in the control group ( 42.6 + /- 19.7 ) compared with the VAS values in the two groups with PCA ( 32.2 + /- 17.9 and 34.5 + /- 21.0 ) . CONCLUSIONS PCA significantly decreases postoperative pulmonary atelectasis in patients after coronary artery bypass grafting when compared with nurse-controlled analgesia . In addition , patients treated with PCA experienced a higher quality of analgesia . We therefore conclude that treatment with PCA may reduce respiratory complications after coronary artery bypass grafting Use of patient-controlled analgesia ( PCA ) was compared with nurse-administered intermittent intramuscular ( NM ) Injections of morphine in older adults during their postoperative recovery . Data analyses indicated that the PCA and IM groups did not dyfer in pain intensity , pain distress , and satisfaction . The PCA group had significantly less sleep disturbance from pain than the IM group . Neither group was considered to have acceptable pain management UNLABELLED Patient-controlled analgesia ( PCA ) is a well-proven procedure for individual pain relief in the post-operative period . Despite its superior approach regarding pharmacokinetic and pharmacodynamic considerations , PCA equipment is not available to many in the clinical practice . The goal of this study was to compare the efficacy and safety of PCA with continuous infusion ( CI ) , an easily feasible method , using tramadol ( T ) as a central ly acting opioid with minor side effects on circulation and ventilation . METHODS The study was conducted on 20 ASA I or II patients aged 20 - 60 years undergoing gynecological operations under st and ardized general anesthesia . They were r and omly allocated to two groups receiving i.v . T for postoperative pain relief via Lifecare PCA 4200 Infuser . Group 1 ( G1 , PCA , n = 10 ) : loading dose 3 mg/kg T , dem and dose 30 mg T , lock-out time 5 min , concurrent infusion 5 mg/h T ; group 2 ( G2 , CI , n = 10 ) : loading dose 3 mg/kg T , continuous infusion 0.35 mg/kg per h T. If the analgesia was inadequate , additional doses of 50 mg T were available in G2 . During a mean trial period of 20 h , the heart rate , blood pressure , respiratory rate and blood gas analysis were documented . The plasma levels of T and beta-endorphins were determined . The quality of analgesia was assessed by using a verbal and a visual analogue scale . RESULTS The mean applied doses of T were 339 + /- 100 mg and 364 + /- 46 mg ( G1 and G2 , respectively ) after 6 h and 565 + /- 243 mg and 707 + /- 139 mg ( G1 and G2 , respectively ) in total ( NS ) . Interindividual differences were substantial in G1 . Five patients in G2 required an additional dose of 50 mg T. Pain scores decreased rapidly in both groups . The pain relief achieved was comparable and excellent after 6 h. The next morning , G2 reported significantly better analgesia in accordance with the higher availability of T as CI during the sleeping period . Mean plasma T levels were 994 + /- 440 ng/ml and 1170 + /- 357 ng/ml ( G1 and G2 , respectively ) . No correlation was found between T-levels and pain scores . The plasma levels of beta-endorphins were substantially elevated after the operation . They returned to normal during T-administration in both groups . No correlation was found between plasma levels of beta-endorphins and pain scores or T-consumption . Hemodynamic changes were minor and without clinical significance . PaO2 and paCO2 remained within small deviations from the physiological range . The respiratory rate , which was initially increased , dropped slightly in both groups . A high incidence of nausea and vomiting was observed , starting in the early phase of the loading dose . CONCLUSIONS T is well suitable for postoperative pain relief after major gynecological surgery using both PCA and CI . PCA ensures adjustment of the medication to the individual dem and , whereas CI provides better analgesia after sleeping periods . We recommend antiemetic prophylaxis before treatment with Morphine sulphate was used for the control of pain following major abdominal surgery for a period of three days either as patient-controlled or continuous infusion . The two groups of patients were comparable with regard to patient and operation details , duration of infusion , pain scores and complications . The only significant difference was a reduced dose requirement of morphine in the patient-controlled analgesia group ( P < 0.005 ) . Some possible explanations for this finding are given . It is suggested that a properly supervised continuous infusion of morphine is as good as patient-controlled administration . There was a negative correlation between the age of the patient and the dose of morphine used INTRODUCTION The present prospect i ve study compared the clinical outcomes between a multimodal analgesia group and a patient-controlled analgesia ( PCA ) group for postoperative pain control in upper extremities surgery . HYPOTHESIS Multimodal analgesia including pre-emptive analgesic can provide similar or superior analgesic effects and a lower incidence of adverse reactions than PCA following upper extremity surgery . PATIENTS AND METHODS Sixty-one patients undergoing upper extremity surgery were r and omized to 2 perioperative analgesic groups ( multimodal analgesia and PCA ) . We compared the clinical outcomes : use of additional pain rescue , opioid-related complication rate , and patient 's satisfaction between the 2 groups . RESULTS No significant differences on the resting and exercise pain scores between the two groups . Also , there were no differences regarding additional pain rescue during postoperative day ( POD ) 1 , 2 and achievement of rehabilitation protocol in both groups . However , use of additional pain rescue in PCA group was increased significantly after PCA removal . Moreover , there was significant difference in the incidence of opioid-related complications on operation day and at POD 1 . At discharge , multimodal analgesia group showed significantly greater satisfaction than PCA group . DISCUSSION Perioperative pain management following upper extremity surgery through the multimodal analgesia could be an acceptable alternative method that can provide good results The authors report the results of two clinical studies on postoperative pain relief with PCA . In the first clinical study 44 patients , undergoing gynecologic surgery , were assigned at r and om to two groups . The first was treated by PCA ( infusor Baxter ) with morphine i.v . ( basal bolus 0.05 mg/kg , loading doses 1 mg every 6 - 15 ' ) , the second with 10 mg morphine i.m . at the end of surgery and then on dem and with a lock-out of 6h at least . In the 2nd clinical study , 40 elder patients su bmi tted to orthopedic surgery , were assigned at r and om to two groups treated with PCA ( morphine i.v . , basal bolus 0.07 mg/kg , bolus PCA 0.007 mg/kg lock-out 15 ' ) and with continuous infusion ( i.c . ) ( basal bolus 0.07 mg/kg , i.c . 0.02 mg/kg/h ) . Our data were analyzed with Student 's " t " unpaired test and showed lower doses of the drug in the groups PCA ( 1st study PCA 25.98 mg/48h , i.m . 45.45 mg/48h , 2nd study PCA 0.155 mg/kg/12h , i.c . 0.311 mg/kg/12h ) and lower rate of side effects in the same groups . Side effects were well controlled using symptomatic drugs . We proposed to our patients , at the end of observation , a question naire about general conditions , sleep , pain evaluation using a descriptive scale and retrospective evaluation . Patients and nurses agree PCA . Nursing staff expressed a positive opinion and patients said they benefitted from PCA . As reported , PCA appears from our results , valid and safe in postoperative pain relief OBJECTIVE The objective of the study was to determine whether any of 3 routes of opioid administration ( patient-controlled analgesia [ PCA ] , scheduled intermittent intravenous [ i.v . ] , or scheduled intermittent subcutaneous [ s.q . ] ) provides superior pain relief and satisfaction among patients undergoing abdominal gynecologic surgery . STUDY DESIGN Patients were r and omized to intravenous hydromorphone by PCA , i.v . hydromorphone via scheduled nurse-administered doses , or s.q . hydromorphone via scheduled nurse-administered doses . Self-reported pain and satisfaction were recorded over 48 hours following arrival at the nursing unit . Linear mixed effects modeling was used to compare outcomes among the groups . RESULTS Neither pain scores nor satisfaction differed by group . PCA patients had higher total opioid use ( P < .0001 ) and a higher rate of pruritus ( P = .04 ) . CONCLUSION Given these findings as well as those in previous literature , no specific method of postoperative analgesia appears to be superior OBJECTIVE To compare three analgesic regimens in patients undergoing colon resection : patient-controlled morphine sulfate analgesia ( PCA ) , intramuscular ( IM ) morphine , and IM ketorolac tromethamine . DESIGN Prospect i ve r and omized case series . SETTING Rural , private teaching hospital . PATIENTS All patients ( 307 ) scheduled to undergo a major colon resection between January 1 , 1992 , and December 31 , 1993 , were eligible to participate . Of these , 10 ( 3 % ) were missed in the screening process , 132 ( 43 % ) declined participation , 73 ( 24 % ) were excluded , and 92 ( 30 % ) were enrolled and r and omly assigned to a treatment group . INTERVENTIONS Ninety-two patients were enrolled in the study . Two patients never received the medication to which they were assigned , owing to administrative error ; their data was not analyzed . Of the remaining patients , 31 were r and omized to the PCA morphine group , 31 were r and omized to the IM morphine group , and 28 were r and omized to the IM ketorolac group . The r and omly assigned drug was first administered in the post-anesthesia care unit . On arrival on the postoperative ward , the patient was asked to rate his or her pain using both a numerical rating scale and a visual analog scale at 30 minutes ; 1 , 2 , 3 , 4 , and 6 hours after arrival on the ward ; and every 4 hours throughout the first 5 postoperative days . The Mini-Mental State Examination ( MMSE ) was administered the day before surgery and then daily for the first 5 postoperative days . The first day the patient passed flatus after surgery was also recorded . MAIN OUTCOME MEASURES The end points analyzed were adverse effects , duration of postoperative ileus , degree of pain control , length of hospitalization , and development of postoperative confusion as measured on serial MMSEs . RESULTS Only two patients , both in the PCA group , reported adverse effects ; neither required a change in analgesia group . Significantly more patients assigned to IM ketorolac broke protocol and required alternative analgesia than did patients in the morphine groups ( 32 % ketorolac vs 16 % IM morphine and 0 % PCA ) . The ketorolac group had a significantly shorter duration of ileus than either morphine group ( P<.0l ) . The ketorolac group also had significantly lower pain scores ( P<.04 ) and less postoperative confusion than the morphine groups ( P<.03 ) , although these results are limited by missing values . The ketorolac group had a significantly shorter length of stay than either morphine group ( P<.01 ) , while there was no significant difference between the morphine groups ( P=.75 ) . CONCLUSIONS While it appears that ketorolac provides a better postoperative course than either IM or PCA morphine in terms of pain control , postoperative confusion , length of stay , and duration of ileus , 18 % of our patients assigned to ketorolac required additional analgesia , and there was a strong patient preference for PCA . Most patients should probably be managed with PCA narcotics , but the addition of ketorolac might reduce narcotic dose and result ant adverse effects . Those patients particularly prone to adverse effects should receive primarily ketorolac PURPOSE The purpose of this prospect i ve study was to compare the effectiveness of patient-controlled intravenous ( i.v . ) opioid analgesic administration ( PCA ) with fixed schedule and dosage oral/rectal administration of naproxen , and opioid analgesics intramuscularly/orally as needed ( i.m./p.o . prn ) for postoperative analgesia over a period of 48 to 56 hours after surgery . PATIENTS AND METHODS There were 75 orthognathic patients aged 25.73 + /- 8.01 years , subdivided into three study groups of 25 : codeine group ( 8 males , 17 females ) ; naproxen group ( 5 males , 20 females ) and PCA group ( 8 male , 17 females ) . The degree of analgesia was assessed every 4 hours from 8:00 AM to 8:00 PM hours on days 1 and 2 postsurgery using a visual analog scale ( VAS ) . Mean daily and mean overall VAS scores were treated as parametric data and were analyzed accordingly . Mean daily VAS scores also were categorized as comfort days when mean scores were less than 3.0 cm , and as discomfort days when mean scores were equal to or greater than 3.0 cm . ANOVA were used to analyze patient demographics , pain scores , surgical time , fentanyl used during general anaesthesia , analgesic morphine equivalents , and vital signs . Chi-square tests were used to analyze sex , comfort ( discomfort ) days , and nausea and vomiting . Mean VAS ratings were analyzed using independent t-tests . RESULTS The three groups were matched in demographics , surgical time , fentanyl used , and sex . The PCA group used less than half the amount of morphine equivalent as the codeine group ( P = .0001 ) . Both the naproxen and the PCA groups were significantly more comfortable than the codeine group during day 1 and day 2 postsurgery . The codeine group had significantly more episodes of nausea than either the naproxen or the PCA groups . CONCLUSION In patients undergoing orthognathic surgery , the naproxen and PCA regimens provided better analgesia than the codeine regimen Patients who were scheduled for an elective joint replacement or spinal procedure were r and omly assigned prospect ively to one of two groups for the management of postoperative pain : ninety-one patients ( Group I ) controlled the administration of a narcotic analgesic themselves and ninety-three patients ( Group II ) received intramuscular injections of a narcotic analgesic , as needed . The patients who controlled the analgesic used a smaller amount of the analgesic on the first postoperative day , but the over-all amount was not significantly different between the two groups . The group that received intramuscular injections reported less pain overall , according to one of three pain- assessment scales , and had more relief of pain over-all and on the first postoperative day , according to another scale . The patients who had had a total joint replacement and who controlled the analgesia walked farther on the first postoperative day than those who received intramuscular injections . There were no significant differences between the two groups with regard to the rate of complications , the arterial oxygen saturation levels during the first twenty-four hours after the operation , or the length of stay in the hospital . The nursing staff preferred the patient-administered method of analgesia , as it necessitated equal or less nursing time to assemble , initiate , and maintain than traditional intramuscular injections . The average cost per patient was $ 58.58 for the patient-administered analgesia and $ 22.45 for the intramuscular injections . ( ABSTRACT TRUNCATED AT 250 WORDS Background : patient-controlled analgesia PCA is a rapidly spreading approach to the management of post-operative pain . The suitability of this method for the morbidly obese patient undergoing bariatric surgery has not yet been determined . Methods : in the present study we r and omly compared two groups of patients undergoing silastic ring vertical gastroplasty . One group received PCA ( 12 patients ) and the other ( 11 patients ) received intermittent doses of pethidine intramuscularly . Results : the cumulative morphine use during the first post-operative day was 52.71 ± 1.83 mg by the PCA group and an equivalent of 24.55 ± 3.42 mg morphine by the IM pethidine group ( p = 0.0002 ) . The analgesic and sedative effects by the PCA were found to be superior . There were no significant differences between the groups in the incidence of side-effects or complications , except a higher , unexplained incidence of wound infection in the PCA group . Conclusion : use of PCA in patients undergoing bariatric surgery has obvious advantages and appears to be a safe procedure OBJECTIVE To compare st and ard nurse-based pain therapy with a patient-controlled analgesia ( PCA ) regimen . DESIGN Prospect i ve , r and omized study . SETTING Single-institutional , clinical investigation in an urban , university-affiliated hospital . PARTICIPANTS Sixty patients undergoing elective first-time cardiac surgery were included . INTERVENTIONS In 30 patients , a st and ard analgesic regimen was used , and in 30 patients , a PCA regimen was used . The perioperative and postoperative management was similar for all patients . MEASUREMENTS AND MAIN RESULTS Degree of sedation , satisfaction , and pain ( by visual analog scale [ VAS ] ) was assessed within the first 3 postoperative days . Vital capacity ( VC ) and forced expiratory volume in 1 second ( FEV1 ) were measured using a portable spirometry system . Cortisol and troponin T ( TnT ) plasma levels were also measured . The expectation of pain was similar in both groups , and the postoperative pain score was significantly lower in the PCA than in the st and ard group throughout the study period . Significantly more piritramid was used in the PCA ( total , 75.6 + /- 33.4 mg ) than in the st and ard group ( total , 20.1 + /- 31.9 mg ) . VC and FEV1 were significantly lower in the st and ard group compared with the PCA patients . Cortisol and TnT plasma levels were similar in both groups . Frequency of side effects were similar for both groups . CONCLUSION Because of the beneficial effects with regard to degree of pain and satisfaction , pain management using PCA systems can be recommended for cardiac surgery patients . It appears to be superior to st and ard nurse-based pain therapy One hundred and twenty-six patients undergoing upper and lower abdominal surgery were studied after operation to compare the analgesic effects of i.m . morphine , sublingual buprenorphine and self-administered i.v . pethidine by Cardiff Palliator . There were no significant differences between analgesic regimens in respect of subjective linear analogue pain scores or static and dynamic lung volumes assessed at 24 and 48 h after operation and 5 days after operation in patients who underwent upper abdominal surgery . Sublingual buprenorphine produced more nausea and sedation than the other two treatments , but the differences were not clinical ly important . However , it offered considerable advantages in terms of ease of administration In the current study , 55 patients undergoing elective cholecystectomy were r and omly allocated to receive postoperative analgesia ( morphine sulfate ) administered through either patient-controlled intravenous ( PCA ) or st and ard intramuscular ( IM ) routes . There were no significant differences in length of hospitalization or required dose of morphine sulfate . Patients r and omized to PCA reported significantly improved subjective relief from pain and a smaller percentage of time in pain during each of the first two postoperative days . In addition , they reported less sedation and less interference with both postoperative breathing and pulmonary recovery than patients who received IM morphine . Theoretically , PCA regimens can deliver narcotic analgesia at a higher and more varied rate ( with fewer side effects ) compared with st and ard IM narcotic delivery , which is more limited by considerations of clinical doses . In PCA dosing , patients should experience less time in pain and sedation . The results of the current study support this premise OBJECT Opioid administration following major intracranial surgery is often limited by a presumed lack of need and a concern that opioids will adversely affect postoperative outcome and interfere with the neurological examination . Nevertheless , evidence is accumulating that these patients suffer moderate to severe postoperative pain and that this pain is often undertreated . The authors hypothesized that intravenous patient-controlled analgesia ( PCA ) would safely and more effectively treat postoperative supratentorial craniotomy pain than conventional as needed ( PRN ) therapy . METHODS Following a st and ardized course of general anesthesia , adult patients who underwent elective supratentorial intracranial surgery were r and omized in the neurosciences intensive care unit to receive either PRN intravenous fentanyl 25 - 50 microg every 30 minutes or PCA intravenous fentanyl 0.5 microg/kg every 15 minutes ( maximum 4 doses/hour ) . The authors measured pain ( self-reported scale score [ 0 - 10 ] ) , sedation ( Ramsay Sedation Scale score ) , Glasgow Coma Scale score , fentanyl use , and major adverse events ( excessive sedation , respiratory depression , pruritus , nausea , or vomiting ) hourly . RESULTS Sixty-four patients with a mean age of 48 years ( range 22 - 77 years ) were r and omized to intravenous PCA ( 29 patients ) or PRN fentanyl ( 35 patients ) groups . There were no statistically significant demographic differences between the 2 groups . Patients receiving intravenous PCA had significantly lower pain scores than those receiving intravenous PRN fentanyl ( 2.53 + /- 1.96 vs 3.62 + /- 2.11 [ p = 0.039 ] ) and received significantly more fentanyl than the PRN group ( 44.1 + /- 34.5 vs 23.6 + /- 23.7 microg/hour [ p = 0.007 ] ) . There were no differences between the 2 groups regarding the number of patients with adverse events . CONCLUSIONS Intravenous PCA more effectively treats the pain of supratentorial intracranial surgery than PRN fentanyl , and patients in the former group did not experience any untoward events related to the self-administration of opioids |
13,656 | 24,585,451 | Trial sequential analyses supported the results in patients with genotypes 1 and 4 , but not in patients with genotypes 2 and 3 .
There is lack of evidence on patient-important outcomes and paucity of evidence on adverse events .
Moderate quality evidence suggests that peginterferon alpha-2a is associated with a higher sustained virological response in serum than with peginterferon alpha-2b .
The clinical consequences of peginterferon alpha-2a versus peginterferon alpha-2b are unknown , and we can not translate an effect on sustained virological response into comparable clinical effects because sustained virological response is still an unvali date d surrogate outcome for patient-important outcomes .
The lack of evidence on patient-important outcomes and the paucity of evidence on adverse events means that we are unable to draw any conclusions about the effects of one peginterferon over the other | BACKGROUND A combination of weekly pegylated interferon ( peginterferon ) alpha and daily ribavirin still represents st and ard treatment of chronic hepatitis C infection in the majority of patients .
However , it is not established which of the two licensed peginterferon products , peginterferon alpha-2a or peginterferon alpha-2b , is the most effective and has a better safety profile . | CONTEXT Previous studies indicate that industry-sponsored trials tend to draw proindustry conclusions . OBJECTIVE To explore whether the association between funding and conclusions in r and omized drug trials reflects treatment effects or adverse events . DESIGN Observational study of 370 r and omized drug trials included in meta-analyses from Cochrane review s selected from the Cochrane Library , May 2001 . From a r and om sample of 167 Cochrane review s , 25 contained eligible meta-analyses ( assessed a binary outcome ; pooled at least 5 full-paper trials of which at least 1 reported adequate and 1 reported inadequate allocation concealment ) . The primary binary outcome from each meta- analysis was considered the primary outcome for all trials included in each meta- analysis . The association between funding and conclusions was analyzed by logistic regression with adjustment for treatment effect , adverse events , and additional confounding factors ( method ological quality , control intervention , sample size , publication year , and place of publication ) . MAIN OUTCOME MEASURE Conclusions in trials , classified into whether the experimental drug was recommended as the treatment of choice or not . RESULTS The experimental drug was recommended as treatment of choice in 16 % of trials funded by nonprofit organizations , 30 % of trials not reporting funding , 35 % of trials funded by both nonprofit and for-profit organizations , and 51 % of trials funded by for-profit organizations ( P<.001 ; chi2 test ) . Logistic regression analyses indicated that funding , treatment effect , and double blinding were the only significant predictors of conclusions . Adjusted analyses showed that trials funded by for-profit organizations were significantly more likely to recommend the experimental drug as treatment of choice ( odds ratio , 5.3 ; 95 % confidence interval , 2.0 - 14.4 ) compared with trials funded by nonprofit organizations . This association did not appear to reflect treatment effect or adverse events . CONCLUSIONS Conclusions in trials funded by for-profit organizations may be more positive due to biased interpretation of trial results . Readers should carefully evaluate whether conclusions in r and omized trials are supported by data Abstract Objectives : The purpose of this r and omized open-label study was to assess the efficacy of treatment with pegylated interferon-α-2a versus pegylated interferon-α-2b , both plus ribavirin , in inducing early and sustained virological response ( EVR and SVR ) in chronic hepatitis C non-responders . Patients and methods : A total of 108 patients with chronic hepatitis C who were non-responders to previous combined therapy ( st and ard interferon-α plus ribavirin for ≥3 months ) were enrolled and equally r and omized into two groups in this intention-to-treat analysis . The patients exhibited similar baseline features . One group received subcutaneous pegylated interferon-α-2a 180 μg once weekly , while the other was treated with subcutaneous pegylated interferon-α-2b 1.5 μg/ kg once weekly . Ribavirin 15 mg/kg/day was included in both protocol s. Treatment duration for EVR was 12 weeks . Patients who demonstrated non-detectable hepatitis C virus ( HCV ) RNA or a ≥2 log10 reduction in viral load at week 12 continued therapy up to 48 weeks , with assessment s every 3 months during a follow-up of 24 weeks . Results : All patients in both groups completed the EVR study , then seven patients receiving pegylated interferon-α-2a and seven patients receiving pegylated interferon-α2b discontinued treatment as a result of severe adverse effects . After 12 weeks of treatment , viral load reduction was > 2 log10 with both pegylated interferon-α-2a ( −2.53 ) and pegylated interferon-α-2b ( −2.48 ) with no significant difference . At the end of week 48 , HCV RNA was undetectable in 14 of 54 patients ( 25.9 % ) receiving pegylated interferon-α-2a and in 15 of 54 patients ( 27.7 % ) receiving pegylated interferon-α-2b . When terminating follow-up , an SVR was observed in 11 of 54 patients ( 20.4 % ) who received pegylated interferon-α-2a and 10 of 54 patients ( 18.4 % ) receiving pegylated interferon-α-2b . The incidence and severity of adverse events was similar in both groups . Conclusions : Our results seem to show that in chronic hepatitis C patients who are non-responsive to previous therapy , EVR to the two pegylated interferons did not significantly differ with a similar therapeutic efficacy defined as SVR AIM The therapy of chronic hepatitis C genotype 4 ( HCV-4 ) has not been optimized yet . This r and omized , prospect i ve , parallel-group clinical trial compared the efficacy and safety of pegylated interferon α-2a ( PEG-IFN α-2a ) plus ribavirin and PEG-IFN α-2b plus ribavirin and assessed the health-related quality of life ( HRQOL ) in patients with chronic HCV-4 . METHODS Eligible patients with proven chronic HCV-4 were r and omized to receive either a weekly dose of PEG-IFN α-2a ( 180 μg ) or PEG-IFN α-2b ( 1.5 μg/kg ) and a daily dose of ribavirin ( 1000 - 1200 mg ) for 48 weeks with 24 weeks post-treatment follow-up . The primary end point was sustained virological response ( SVR ) defined by undetectable HCV RNA 24 weeks after treatment . The Short form-36 Health Survey version 2 ( SF-36v2 ) and the Chronic Liver Disease question naires ( CLDQ ) were assessed before , during and after therapy . RESULTS The overall SVR rate of the entire cohort was 59.9 % . The SVR rates were significantly higher in patients treated with PEG-IFN α-2a and ribavirin ( Group A ; n=109 ) compared with those treated with PEG-IFN α-2b and ribavirin ( Group B ; n=108 , 70.6 vs. 54.6 % , respectively ; P=0.017 ) . The relapse rates were 5.1 % for PEG-IFN α-2a and 15.7 % for PEG-IFN α-2b ( P=0.0019 ) . The SF-36v2 and CLDQ were low during therapy and improved significantly after therapy successful therapy . CONCLUSION Pegylated interferon α-2a plus ribavirin was significantly more effective than PEG-IFN α-2b and ribavirin therapy in the treatment of chronic HCV-4 patients . The tolerability and adverse events were comparable between the two regimens . The HRQOL improved significantly after successful PEG-IFN α-2a plus ribavirin therapy UNLABELLED Although two pegylated interferons ( Peg-IFN ) are available to treat chronic hepatitis C virus ( HCV ) infection , no head-to-head comparative studies have been published . We aim to compare the efficacy and safety of PEG IFN alfa-2b ( PEG 2b ) versus PEG IFN alfa-2a ( PEG 2a ) , plus ribavirin ( RBV ) . A prospect i ve , r and omized , multi-center , open-label clinical trial including 182 human immunodeficiency virus (HIV)-hepatitis C virus ( HCV ) patients naïve for HCV therapy was performed . Patients were assigned to PEG 2b ( 80 - 150 mug/week ; n = 96 ) or PEG 2a ( 180 mug/week ; n = 86 ) , plus RBV ( 800 - 1200 mg/day ) for 48 weeks . The primary endpoint was sustained virological response ( SVR : negative HCV-RNA 24 weeks after completion of treatment ) . At baseline , both groups were well balanced : 73 % male ; 63 % HCV genotype 1 or [ corrected ] 4 ; 29 % had fibrosis index of 3 or greater . The overall SVR was 44 % ( 42 % PEG 2b versus 46 % PEG 2a , P = 0.65 ) . Among genotypes 1 or [ corrected ] 4 , SVRs were 28 % versus 32 % ( P = 0.67 ) and 62 % versus 71 % ( P = 0.6 ) in genotypes 2 or [ corrected ] 3 for PEG 2b and PEG 2a , respectively . Early virological response ( EVR ; > or=2 log reduction from baseline or negative HCV-RNA at week 12 ) was 70 % in the PEG 2b group and 80 % in the PEG 2a group ( P = 0.13 ) , reaching a positive predictive value of SVR of 64 % and a negative predictive value of 100 % in both arms . Side effects were present in 96 % of patients but led to treatment discontinuation in 10 % of patients ( 8 % on PEG 2b and 13 % on PEG 2a , P = 0.47 ) . CONCLUSION In patients with HIV , HCV therapy with PEG 2b or PEG 2a plus RBV had no significant differences in efficacy and safety BACKGROUND / AIMS To compare the pharmacokinetics , pharmacodynamics , and antiviral activity of peginterferon alfa-2b and peginterferon alfa-2a in patients with chronic hepatitis C virus genotype 1 . METHODS Thirty-six patients were r and omised to peginterferon alfa-2b ( 1.5 microg/kg/week ) or peginterferon alfa-2a ( 180 microg/week ) for 4 weeks , then in combination with ribavirin ( 13 mg/kg/day ) for a further 4 weeks . The pharmacokinetic profile of both peginterferons , mRNA expression of a selected group of interferon-induced gene transcripts , and serum HCV-RNA levels were assessed . RESULTS Patients receiving peginterferon alfa-2b had significantly greater up-regulation of interferon-alfa response genes compared with those receiving peginterferon alfa-2a . Correspondingly , patients treated with peginterferon alfa-2b also had a significantly greater log10 maximum and log10 time-weighted average decrease in serum HCV-RNA . A greater proportion of peginterferon alfa-2b patients achieved a > or = 2.0 log10 reduction in serum HCV-RNA levels by week 8 ( 72 % vs 44 % of peginterferon alfa-2a patients , P = 0.09 ) . There was an approximately 16-fold greater exposure to peginterferon in the serum of patients treated with peginterferon alfa-2a . CONCLUSIONS These findings suggest that the biological activity , measured by early interferon-induced gene transcripts and early antiviral responsiveness , may have been greater in patients treated with peginterferon alfa-2b despite their lower exposure to the drug compared with patients treated with peginterferon alfa-2a BACKGROUND & AIMS Ribavirin ( RBV ) combined with either pegylated interferon ( PegIFN ) alpha2a or PegIFNalpha2b is the st and ard of care for chronic hepatitis C virus ( HCV ) infection . Due to the lack of head-to-head studies , the 2 PegIFNs have not been directly compared . The endpoints of our study were safety and antiviral efficacy of the 2 regimens . METHODS Treatment-naïve patients with chronic hepatitis C were r and omly ( 1:1 ) assigned after stratification for HCV genotype to receive either 1.5 mcg/Kg/week PegIFNalpha2b plus RBV 800 - 1200 mg/day or 180 mcg/week PegIFNalpha2a plus RBV 800 - 1200 mg/day for 24 or 48 weeks according to HCV genotype . The study was powered to detect a difference of at least 10 % in safety and efficacy of the 2 regimens . RESULTS The 212 patients on PegIFNalpha2a and the 219 patients on PegIFNalpha2b had similar baseline characteristics , including cirrhosis ( 20 % vs 18 % , respectively ) . By intention to treat , the 2 groups showed similar rates of treatment-related serious adverse events ( 1 % vs 1 % , respectively ) and drop out rates for adverse effects ( 7 % vs 6 % , respectively ) . Overall , sustained virologic response ( SVR ) rate was higher in PegIFNalpha2a than in PegIFNalpha2b patients ( 66 % vs 54 % , respectively , P = .02 ) , being 48 % vs 32 % in the 222 HCV-1 and -4 patients ( P = .04 ) , and 96 % vs 82 % , respectively , in the 143 HCV-2 patients ( P = .01 ) . PegIFNalpha2a independently predicted SVR in the logistic regression analysis ( odds ratio , 1.88 ; 95 % confidence interval : 1.20 - 2.96 ) . CONCLUSIONS Although the 2 regimens showed a similar safety profile , the PegIFNalpha2a-based treatment yielded significantly more SVR than PegIFNalpha2b OBJECTIVES To analyze sources search ed in Cochrane review s , to determine the proportion of trials included in review s that are indexed in major data bases , and to compare the quality of these trials with those from other sources . METHODS All new systematic review s in the Cochrane Library , Issue1 2001 , that were restricted to r and omized controlled trials ( RCTs ) or quasi- RCTs were selected . The sources search ed in the review s were recorded , and the trials included were checked to see whether they were indexed in four major data bases . Trials not indexed were checked to determine how they could be identified . The quality of trials found in major data bases was compared with those found from other sources . RESULTS The range in the number of data bases search ed per review ranged between one and twenty-seven . The proportion of the trials in the four data bases were Cochrane Controlled Trials Register = 78.5 % , MEDLINE = 68.8 % , Embase = 65.0 % , and Science/Social Sciences Citation Index = 60.7 % . Search ing another twenty-six data bases after Cochrane Controlled Trials Register ( CCTR ) , MEDLINE , and Embase only found 2.4 % additional trials . There was no significant difference between trials found in the CCTR , MEDLINE , and Embase compared with other trials , with respect to adequate allocation concealment or sample size . CONCLUSIONS There was a large variation between review s in the exhaustiveness of the literature search es . CCTR was the single best source of RCTs . Additional data base search ing retrieved only a small percentage of extra trials . Contacting authors and manufacturers to find unpublished trials appeared to be a more effective method of obtaining the additional better quality trials BACKGROUND Pegylated interferons ( Peg-IFNs ) represent , in association with Ribavirin , the first line of treatment in chronic C viral hepatitis . The AIM of our paper was to compare the efficacy of Peg-IFN alpha 2a ( Pegasys ) and Peg-IFN alpha 2b ( PegIntron ) in a group of patients from the Department of Gastroenterology in Timisoara . MATERIAL AND METHOD 116 patients with chronic C viral hepatitis were treated . The patients were r and omized in chronological order ( 1:1 ) , so that 58 patients were treated with Peg-IFN alpha 2a 180 microg/kg/week + Ribavirin ( group 1 ) and 58 were treated with Peg-IFN alpha 2b 1.5 microg/kg/week + Ribavirin ( group 2 ) . Ribavirin was administered in the recommended doses , according to weight . The mean age was : group 1 -- 49.3 years , group 2 -- 50.9 years ( p=0.37 ) . Group 1 consisted of 37 women and 21 men and group 2 of 44 women 14 men ( p=0.22 ) . In group 1 , 48 patients were naïve ( N1 ) , 7 were relapsers after previous treatment ( RL1 ) and 3 non-responders to previous treatment ( NR1 ) . In group 2 , 33 patients were naive ( N2 ) , 18 relapsers ( RL2 ) and 7 non-responders ( NR2 ) . After 12 weeks of treatment we evaluated the early virological response ( EVR ) , defined as a drop in the viral load with 2 logs compared to the baseline viremia . RESULTS The following EVR rates were found : in group 1 ( Pegasys ) - 82.2 % ( 48/58 ) ; in group 2 ( PegIntron ) -- 67.2 % ( 39/58 ) ( p=0.08 ) . There were also no significant statistical differences between the response rates in the subgroups : naïve patients [ 89.6 % vs. 75.2 % , p = 0.61 ] , relapsers [ 57.1 % vs. 66.6 % , p = 0.67 ] and non responders [ 33.3 % vs. 28.6 % , p = 1 ] . CONCLUSION Our head to head comparative study showed that there are no statistically significant differences in the EVR between the patients treated with Peg-IFN alpha 2a and Peg-IFN alpha 2b BACKGROUND A sustained virological response ( SVR ) rate of 41 % has been achieved with interferon alfa-2b plus ribavirin therapy of chronic hepatitis C. In this r and omised trial , peginterferon alfa-2b plus ribavirin was compared with interferon alfa-2b plus ribavirin . METHODS 1530 patients with chronic hepatitis C were assigned interferon alfa-2b ( 3 MU subcutaneously three times per week ) plus ribavirin 1000 - 1200 mg/day orally , peginterferon alfa-2b 1.5 microg/kg each week plus 800 mg/day ribavirin , or peginterferon alfa-2b 1.5 microg/kg per week for 4 weeks then 0.5 microg/kg per week plus ribavirin 1000 - 1200 mg/day for 48 weeks . The primary endpoint was the SVR rate ( undetectable hepatitis C virus [ HCV ] RNA in serum at 24-week follow-up ) . Analyses were based on patients who received at least one dose of study medication . FINDINGS The SVR rate was significantly higher ( p=0.01 for both comparisons ) in the higher-dose peginterferon group ( 274/511 [ 54 % ] ) than in the lower-dose peginterferon ( 244/514 [ 47 % ] ) or interferon ( 235/505 [ 47 % ] ) groups . Among patients with HCV genotype 1 infection , the corresponding SVR rates were 42 % ( 145/348 ) , 34 % ( 118/349 ) , and 33 % ( 114/343 ) . The rate for patients with genotype 2 and 3 infections was about 80 % for all treatment groups . Secondary analyses identified bodyweight as an important predictor of SVR , prompting comparison of the interferon regimens after adjusting ribavirin for bodyweight ( mg/kg ) . Side-effect profiles were similar between the treatment groups . INTERPRETATION In patients with chronic hepatitis C , the most effective therapy is the combination of peginterferon alfa-2b 1.5 microg/kg per week plus ribavirin . The benefit is mostly achieved in patients with HCV genotype 1 infections CONTEXT Controversy and uncertainty ensue when the results of clinical research on the effectiveness of interventions are subsequently contradicted . Controversies are most prominent when high-impact research is involved . OBJECTIVES To underst and how frequently highly cited studies are contradicted or find effects that are stronger than in other similar studies and to discern whether specific characteristics are associated with such refutation over time . DESIGN All original clinical research studies published in 3 major general clinical journals or high-impact-factor specialty journals in 1990 - 2003 and cited more than 1000 times in the literature were examined . MAIN OUTCOME MEASURE The results of highly cited articles were compared against subsequent studies of comparable or larger sample size and similar or better controlled design s. The same analysis was also performed comparatively for matched studies that were not so highly cited . RESULTS Of 49 highly cited original clinical research studies , 45 cl aim ed that the intervention was effective . Of these , 7 ( 16 % ) were contradicted by subsequent studies , 7 others ( 16 % ) had found effects that were stronger than those of subsequent studies , 20 ( 44 % ) were replicated , and 11 ( 24 % ) remained largely unchallenged . Five of 6 highly-cited nonr and omized studies had been contradicted or had found stronger effects vs 9 of 39 r and omized controlled trials ( P = .008 ) . Among r and omized trials , studies with contradicted or stronger effects were smaller ( P = .009 ) than replicated or unchallenged studies although there was no statistically significant difference in their early or overall citation impact . Matched control studies did not have a significantly different share of refuted results than highly cited studies , but they included more studies with " negative " results . CONCLUSIONS Contradiction and initially stronger effects are not unusual in highly cited research of clinical interventions and their outcomes . The extent to which high citations may provoke contradictions and vice versa needs more study . Controversies are most common with highly cited nonr and omized studies , but even the most highly cited r and omized trials may be challenged and refuted over time , especially small ones Genetic heterogeneity is a hallmark of the hepatitis C virus , as a result largely of the infidelity of viral RNA-dependent RNA polymerase . R and om nucleotide substitutions are introduced at a very high rate . The existence of genotypes was confirmed by statistical and mathematical techniques , and the relation of the genotypes to each other has been determined . There are six major genotypes , each with multiple subtypes . Isolates of the same genotype have an average sequence homology of 95 % , but different genotypes have sequence similarity of approximately 65 % on average . The nucleotide sequence in portions of the hepatitis C viral genome , including the 5 ' noncoding region , part of the core gene , and other nonstructural proteins , is highly conserved . Genotype analysis typically utilizes these highly conserved regions . There are many techniques for determining viral genotype , and in general , concordance between techniques is good . Methods most commonly used for assigning hepatitis C virus ( HCV ) genotypes in clinical practice include restriction fragment length polymorphism analysis and the reverse hybridization line probe assay ( LiPA ; Innogenetics , Ghent , Belgium ) . The worldwide distribution of HCV genotypes has been determined ; some genotypes are highly characteristic of certain areas . The most common subtypes , 1 and 2 , are less genetically diverse than the others and are more widely distributed . The impact of genotype on disease course is controversial , but recent data suggest that there is a genotype-dependent differential response to therapy . Quasispecies refers to evolution of a highly related but genetically heterogeneous population of HCV isolates . The pathobiological and clinical implication s of HCV quasispecies are poorly understood Methods for combining data from several studies exist and appear to be quite useful . None satisfactorily addresses the question of what studies should be combined . This issue is the most serious method ological limitation . Even studies with statistically significant interaction might still be combined if the effect were in the same direction . Thus , substantial scientific input is required as to what criteria must be met by each potential study . Much can be learned from combining or pooling data but it must be done cautiously . Pooling exercises do not replace well design ed prospect i ve clinical trials . Efforts for establishing basic design criteria to allow for multicentre and multicountry trials to be more easily combined might be useful . BACKGROUND Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus ( HCV ) infection . We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin , interferon alfa-2b plus ribavirin , and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C. METHODS A total of 1121 patients were r and omly assigned to treatment and received at least one dose of study medication , consisting of 180 microg of peginterferon alfa-2a once weekly plus daily ribavirin ( 1000 or 1200 mg , depending on body weight ) , weekly peginterferon alfa-2a plus daily placebo , or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks . RESULTS A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response ( defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy ) than of patients who received interferon alfa-2b plus ribavirin ( 56 percent vs. 44 percent , P<0.001 ) or peginterferon alfa-2a alone ( 56 percent vs. 29 percent , P<0.001 ) . The proportions of patients with HCV genotype 1 who had sustained virologic responses were 46 percent , 36 percent , and 21 percent , respectively , for the three regimens . Among patients with HCV genotype 1 and high base-line levels of HCV RNA , the proportions of those with sustained virologic responses were 41 percent , 33 percent , and 13 percent , respectively . The overall safety profiles of the three treatment regimens were similar ; the incidence of influenza-like symptoms and depression was lower in the groups receiving peginterferon alfa-2a than in the group receiving interferon alfa-2b plus ribavirin . CONCLUSIONS In patients with chronic hepatitis C , once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained virologic response , as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone One reason for dosing a drug by body weight is to reduce interpatient variability in clinical response . This study evaluated the relationship between body weight and drug exposure for peginterferon alpha-2a and peginterferon alpha-2b used in combination with ribavirin for treating patients with chronic hepatitis C. These two products are dosed differently : peginterferon alpha-2a is flat-dosed at 180 microg regardless of body weight , whereas peginterferon alpha-2b is dosed by body weight at 0.5 - 1.5 microg/kg . Bodyweight dosing of peginterferon alpha-2b is purported to overcome the adverse effect of increased body weight on sustained virological response . To test this hypothesis , we measured the area-under-the-curve ( AUC ) for both drugs as part of a previously reported pharmacokinetics study . In total , 22 interferon-naive patients with chronic hepatitis C were treated for 12 weeks . Patients were r and omly assigned in a 1:1 ratio to receive once-weekly peginterferon alpha-2a 180 microg ( n=10 ) or peginterferon alpha-2b 1.0 microg/kg ( n=12 ) . Ribavirin was dosed by body weight at 1000 mg/day ( < or = 75 kg ) or 1200 mg/day ( > 75 kg ) . We found no correlation between body weight and AUC for either peginterferon alpha-2a or peginterferon alpha-2b . Considerable interpatient variability in AUC occurred for peginterferon alpha-2a [ coefficient of variation ( CV ) : 37.5 % ] and , despite dosing by body weight , for peginterferon alpha-2b ( CV : 36.8 % ) . Thus , there appears to be no rationale for a body-weight dosing regimen for peginterferon alpha-2a , and such dosing does not achieve more consistent AUC measurements in patients receiving peginterferon alpha-2b We have screened for the incidence of vascular ophthalmological side effects ( VOSE ) in chronic hepatitis C ( CHC ) patients undergoing pegylated interferon ( peg-IFN ) plus ribavirin ( RBV ) therapy and sought evidence for angiogenesis activation . Thirty-four CHC patients were prospect ively evaluated ( 18 patients with 180 microg/week of peg-IFN-alpha2a plus 800mg/day of RBV and 16 with 1.5 microg/kg/week of peg-IFN-alpha2b plus 800 - 1,200mg/day of RBV ) . Complete ophthalmological evaluation and serum vascular endothelial growth factor ( VEGF ) levels were assessed before and at the end of therapy . Thirteen patients ( 38.2 % ) developed VOSE , eight ( 23.5 % ) featured subconjunctival haemorrhage , and five ( 14.7 % ) had evidence of retinopathy - all were unrelated to age , sex , genotype , the type of antiviral schedule used and response to therapy . At the end of treatment , the VOSE group had significantly higher serum VEGF levels than the group of patients without detectable side effects ( median 281 [ range 106 - 386 ] vs 117 [ 83 - 225 ] pg/ml , P=0.05 ) . These differences increased when VEGF values were corrected by platelet count . In the VOSE group , baseline VEGF and VEGF/platelet values were also significantly higher ( 164 [ 55 - 260 ] vs 64 [ 21 - 172 ] pg/ml , P=0.046 ; and 0.920 [ 0.217 - 1.543 ] vs 0.320 [ 0.100 - 0.661 ] pg/10(6 ) platelets , P=0.024 , respectively ] . In a multivariate model VEGF/platelet values at end of treatment and hepatic fibrosis stage were the only predictors of VOSE development . In 3 out of 13 patients visual acuity was affected and 2 had residual lesions in the follow-up . In this exploratory study , antiviral therapy of CHC frequently induces VOSE , apparently through an activation of angiogenesis Background Pegylated interferon ( PegIFN ) plus ribavirin is the st and ard therapy for patients with chronic hepatitis C genotype 1 . Although several r and omized clinical trials have compared PegIFNα-2a with PegIFNα-2b , these 2 regimens have not been directly compared in Asian patients . We , therefore , compared the safety and antiviral efficacy of these agents in Japanese patients . Methods A total of 201 PegIFN-naïve , chronic hepatitis C patients were r and omly assigned to once-weekly PegIFNα-2a ( 180 μg ) or PegIFNα-2b ( 60–150 μg ) plus ribavirin . We compared the sustained virological response ( SVR ) rates between the 2 regimens and analyzed their effects in relation to baseline characteristics , including single nucleotide polymorphisms ( SNPs ) near the interleukin-28B ( IL28B ) gene ( rs8099917 ) . Results PegIFNα-2a was associated with a higher SVR rate than PegIFNα-2b ( 65.3 vs. 51.0 % , P = 0.039 ) . PegIFNα-2a and SNPs near IL28B independently predicted SVR ( odds ratio 2.36 ; 95 % confidence interval [ CI ] 1.19–15.50 , and odds ratio 7.31 ; 95 % CI 3.45–4.68 , respectively ) in logistic regression analysis . PegIFNα-2a was more effective than PegIFNα-2b ( 81.8 vs. 62.7 % , P = 0.014 ) in IL28B TT genotype patients , despite similarly low SVR rates in patients with TG or GG genotypes ( 36.4 vs. 35.9 % ) . Patients weighing < 60 kg , women , and patients aged > 60 years had significantly higher SVR rates with PegIFNα-2a than with PegIFNα-2b ( 63.9 , 61.3 , and 67.3 % vs. 43.8 , 43.3 , and 39.2 % , respectively ) . Conclusions PegIFNα-2a plus ribavirin result ed in higher SVR rates than PegIFNα-2b plus ribavirin in Japanese patients . PegIFNα-2a-based treatment should therefore be the preferred choice for women , older or low-weight patients , and those with the IL28B TT genotype BACKGROUND AND AIM We assessed whether the two regimens of pegylated alpha-interferon-2b ( PEG-IFN-alpha2b ) plus ribavirin and pegylated alpha-interferon-2a ( PEG-IFN-alpha2a ) plus ribavirin showed differences in terms of sustained virological response , withdrawal due to side-effects and dose adjustment requirements in the treatment of naive chronic hepatitis C virus ( HCV ) patients . METHODS A prospect i ve non-r and omized , open-label comparison was made of naive HCV-infected patients undergoing st and ard 24- or 48-week treatment with two PEG-IFN combined with weight-based dosing regimen of ribavirin ( PEG-IFN-alpha2a/ribavirin , n = 91 ; PEG-IFN-alpha2b/ribavirin , n = 92 ) . RESULTS Sustained virological response was similar in PEG-IFN-alpha2a and PEG-IFN-alpha2b ( 65.9 % vs 62 % , P = 0.64 ) , without differences according to genotype . In 117 patients with HCV genotype 1 , the corresponding rates were 50.8 % versus 46.6 % ( P = 0.713 ) . Rapid virological response at 4 weeks , early virological response at 12 weeks and transient virological response were also similar . In the multivariate analysis , HCV genotype ( odds ratio [ OR ] = 0.076 , 95 % confidence interval [ CI ] 0.029 - 0.198 , P = 0.000 ) and presence of steatosis in the liver biopsy ( OR = 2.799 , 95 % CI 1.362 - 5.755 , P = 0.005 ) were significantly associated with response to antiviral therapy . The rate of withdrawals due to treatment-related adverse events was 13.2 % in the group of PEG-IFN-alpha2a and 10.9 % in the group of PEG-IFN-alpha2b . Dose modification of PEG-IFN was necessary in eight patients given PEG-IFN-alpha2a and in seven given PEG-IFN-alpha2b . CONCLUSION The two PEG-IFN plus ribavirin have comparable anti-HCV activity as shown by similar percentages of patients with sustained virological response BACKGROUND The efficacy and tolerability of Peg-Interferon alpha-2a ( Peg-IFNalpha-2a ) versus Peg-Interferon alpha-2b ( Peg-IFNalpha-2b ) were compared in a patient cohort with hepatitis C virus (HCV)-related active chronic hepatitis , unresponsive to previous antiviral treatment with st and ard IFN ( 6 MU three times/week ) plus ribavirin ( 10.6 mg/kg/day ) for a period of at least 3 months . PATIENTS AND METHODS A total of 143 patients were enrolled and r and omized into two treatment groups ( A-B ) . Group A ( 71 patients ) received one vial of Peg-IFNalpha-2a weekly ( 180 microg ) subcutaneously whereas Group B ( 72 patients ) received 1.5 microg/kg of Peg-IFNalpha-2b weekly subcutaneously . Interferon was combined with ribavirin ( 15 mg/kg/day ) in both groups and all patients who demonstrated nondetectable HCV-RNA or a > or=2(log ) reduction in viral load at week 12 , were treated for 48 weeks , with a 24-week follow up . RESULTS Group A ( 10/71 ) and Group B ( 8/72 ) patients discontinued treatment due to severe side effects . At the end of therapy , HCV-RNA was undetectable in 17/71 ( 23.9 % ) Group A and in 19/72 ( 26.4 % ) of Group B patients . When terminating follow up , a sustained virological response was observed in 14/71 in Group A ( 19.7 % ) and 13/72 in Group B ( 18.0 % ) . CONCLUSIONS Within the limits of the relatively small sample size , Peg-IFNalpha-2a and Peg-IFNalpha-2b demonstrated nonstatistically significant differences in effectiveness in patients nonresponsive to previous antiviral treatment UNLABELLED The overall mortality of patients infected with hepatitis C virus ( HCV ) has not been fully eluci date d. This study analyzed mortality in subjects positive for antibody to HCV ( anti-HCV ) in a community-based , prospect i ve cohort study conducted in an HCV hyperendemic area of Japan . During a 10-year period beginning in 1995 , 1125 anti-HCV-seropositive residents of Town C were enrolled into the study and were followed for mortality through 2005 . Cause of death was assessed by death certificates . Subjects with detectable HCV core antigen ( HCVcAg ) or HCV RNA were considered as having hepatitis C viremia and were classified as HCV carriers ; subjects who were negative for both HCVcAg and HCV RNA ( i.e. , viremia-negative ) were considered as having had a prior HCV infection and were classified as HCV noncarriers . Among the anti-HCV-positive subjects included in the analysis , 758 ( 67.4 % ) were HCV carriers , and 367 were noncarriers . A total of 231 deaths occurred in these subjects over a mean follow-up of 8.2 years : 176 deaths in the HCV carrier group and 55 in the noncarrier group . The overall mortality rate was higher in HCV carriers than in noncarriers , adjusted for age and sex ( hazard ratio , 1.53 ; 95 % confidence interval , 1.13 - 2.07 ) . Although liver-related deaths occurred more frequently among the HCV carriers ( hazard ratio , 5.94 ; 95 % confidence interval , 2.58 - 13.7 ) , the rates of other causes of death did not differ between HCV carriers and noncarriers . Among HCV carriers , a higher level of HCVcAg ( > or=100 pg/mL ) and persistently elevated alanine aminotransferase levels were important predictors of liver-related mortality . CONCLUSION The presence of viremia increases the rate of mortality , primarily due to liver-related death , among anti-HCV-seropositive persons in Japan To compare incidence , risk factors and morphologic pattern of hepatocellular carcinoma ( HCC ) development in hepatitis B virus ( HBV ) and hepatitis C virus ( HCV ) related cirrhosis , 401 patients were followed prospect ively by periodic ultrasound examination for 14 - 189 months ( mean : 84.8+/-36.7 ) . During follow-up , 77 ( 19.2 % ) patients developed HCC , with 5 and 10 year cumulative incidence of 10 and 27.5 % , respectively . The risk of HCC was significantly higher in HBV and HCV co-infected patients ( P=0.014 ) compared to those with single HBsAg or anti-HCV ( antibodies to hepatitis C virus ) positivity . In anti-HCV positive cases the annual risk of HCC increased from 2 % in the first 5 year period to 4 % in the third 5 year period , while it decreased from 2 to 0 % in the same time periods in the HBsAg positive group . By Cox 's regression , age above 59 years ( P=0.001 ) , male sex ( P=0.09 ) , longer duration ( P=0.04 ) and more advanced stage ( P=0.01 ) of cirrhosis , lower platelets count ( P=0.001 ) and higher ALT levels were significant risk factors for HCC in anti-HCV positive patients , while only high alpha-fetoprotein ( AFP ) levels during follow-up ( P=0.04 ) was a significant risk factor for HCC in HBsAg positive cases . The pattern of HCC was nodular in 63 ( 81.8 % ) patients and infiltrating in 14 ( 18.2 % ) , and the former type was associated with older age ( P=0.0001 ) , longer duration ( P=0.002 ) and more advanced stage ( P=0.0001 ) of cirrhosis but not with the viral etiology of disease . In contrast , development of infiltrating HCC was unrelated to age and disease duration and stage , and was associated with male sex ( P=0.01 ) , HBV infection ( P=0.06 ) and HBV and HCV co-infection ( P=0.0001 ) . Our results indicate different incidence profile , risk factors and patterns of morphogenesis of HCC development in HBV and HCV associated cirrhosis , suggesting different mechanisms of carcinogenesis St and ard therapy for chronic hepatitis C ( HCV ) is pegylated interferon in combination with ribavirin . There is limited experience with either drug in dialysis [ end stage renal disease ( ESRD ) ] . Six haemodialysis patients , four with HCV genotype 1 , one with genotype 4 and one genotype 2 were treated with pegylated interferon-alfa-2b ( n = 4 ) and pegylated interferon-alfa-2a ( n = 2 ) for 24 - 48 weeks according to genotype with a dose of 50 or 135 mug/week respectively . All patients were given reduced ribavirin doses , initially 200 - 400 mg/day . Ribavirin trough plasma concentrations were measured with a HPLC method previously developed for earlier treatment studies , aim ing at a target concentration of 10 - 15 micromol/L. Interferon related side-effects were common , in one patient peg-alfa-2b was permanently reduced to 50 mug every 9 - 10 days with improvement in tolerance . Average ribavirin dose was 170 - 300 mg/day . Ribavirin-induced anaemia was treated with high doses of erythropoietin and low doses of iron . Blood-transfusions were not needed . All patients became HCV-RNA-PCR negative during treatment which was completed or nearly completed in four patients . One patient terminated therapy prematurely due to pronounced interferon related side-effects and another died of myocardial infa rct ion probably not related to therapy . Three patients have remained HCV-RNA negative with extended follow-up , two of whom have had a successful kidney transplant . Pegylated interferons are likely to become a valuable addition for HCV therapy in ESRD and are possible to combine with ribavirin . However the pharmacokinetics and tolerability of both peg-alfa-2a and 2b need to be studied more closely in prospect i ve studies before definite dosing recommendations can be made Patients infected with hepatitis C virus ( HCV ) genotype 1 and with serum HCV RNA concentrations over 800 000 IU/mL have relatively low rates of virologic response to pegylated interferons . The 2 forms of pegylated interferon have different pharmacokinetic profiles , and pilot studies comparing them have yielded varying results . We compared the virologic response to 12 weeks of treatment with peginterferon alpha-2a plus ribavirin vs peginterferon alpha-2b plus ribavirin in 380 patients who were infected with HCV genotype 1 and had high viral loads . We observed no between-group differences in viral load reduction over time and no differences in the percentage of patients treated with peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin who achieved early virologic response ( EVR ) , defined as > /=2-log reduction in HCV RNA concentration or undetectable HCV RNA at 12 weeks ( 66%vs 63 % ) . Serum levels of interferon were more frequently below the level of quantitation in patients treated with peginterferon alpha-2b plus ribavirin ( 58 - 68 % ) than in those treated with peginterferon alpha-2a plus ribavirin ( 1 - 2 % ) . Patients treated with peginterferon alpha-2b plus ribavirin had higher rates of discontinuation for safety reasons ( 6%vs 1 % ) . In conclusion , a substantial percentage of patients infected with HCV genotype 1 and high viral load can achieve EVR when treated with peginterferon and ribavirin . The 2 pegylated interferons showed comparable anti-HCV activity during the first 12 weeks of treatment when combined with the same doses of ribavirin ( 1000 - 1200 mg/day ) , but discontinuations for safety reasons were higher in the patients treated with peginterferon alpha-2b plus ribavirin The two available pegylated interferon formulations , peginterferon alpha-2a and peginterferon alpha-2b , have different pharmacokinetic profiles ; as a result they may have differing abilities to suppress the hepatitis C virus . A recently reported study by Formann and colleagues assessing early viral kinetics among 20 patients receiving peginterferon alpha-2b either once or twice weekly suggests that once-weekly administration of peginterferon alpha-2b is not sufficient for continuous exposure to interferon over 160 h. Twice-weekly administration is recommended to avoid increases in viral load as interferon levels decline prior to the end of the one-week dosing period . The objective of this study was to compare viral dynamics and pharmacokinetics between peginterferon alpha-2a and peginterferon alpha-2b in interferon-naive chronic hepatitis C patients . Patients were r and omized to receive peginterferon alpha-2a 180 microg ( n=10 ) or peginterferon alpha-2b 1.0 microg/kg ( n=12 ) once weekly . Serum peginterferon concentrations were measured at baseline , 24 , 48 , 120 and 168h . Hepatitis C virus ( HCV ) RNA was measured at baseline , 24 , 48 , 120 and 168 h during week 1 and then at 4 and 12 weeks . Peginterferon alpha-2b achieved maximal serum levels at 24 h , and then decreased rapidly . Of the 12 patients who received peginterferon alpha-2b , no drug was detectable in seven ( 58 % ) patients at 120 h and in 11 ( 92 % ) at 168 h. In contrast , peginterferon alpha-2a concentrations increased continuously over time , reaching maximal serum levels from 48 to 168 h. Drug was detectable in all 10 patients at 168 h. At weeks 1 and 4 no significant difference was observed in mean HCV RNA between the groups . However , at week 12 , mean HCV RNA was significantly lower in the peginterferon alpha-2a group versus the peginterferon alpha-2b group ( 2.8126 vs 3.8726 ; P<0.01 ) . The differences in mean HCV RNA values at 12 weeks may be related to the different absorption and distribution profiles of the two drugs . In conclusion , once-weekly administration of peginterferon alpha-2b ( 1.0 microg/kg/wk ) may be insufficient for continuous interferon exposure ; twice-weekly administration may help avoid increases in viral replication as interferon levels decline . Larger-scale studies assessing both viral kinetics and sustained virological responses are needed to confirm these observations BACKGROUND Treatment guidelines recommend the use of peginterferon alfa-2b or peginterferon alfa-2a in combination with ribavirin for chronic hepatitis C virus ( HCV ) infection . However , these regimens have not been adequately compared . METHODS At 118 sites , patients who had HCV genotype 1 infection and who had not previously been treated were r and omly assigned to undergo 48 weeks of treatment with one of three regimens : peginterferon alfa-2b at a st and ard dose of 1.5 microg per kilogram of body weight per week or a low dose of 1.0 microg per kilogram per week , plus ribavirin at a dose of 800 to 1400 mg per day , or peginterferon alfa-2a at a dose of 180 microg per week plus ribavirin at a dose of 1000 to 1200 mg per day . We compared the rate of sustained virologic response and the safety and adverse-event profiles between the peginterferon alfa-2b regimens and between the st and ard-dose peginterferon alfa-2b regimen and the peginterferon alfa-2a regimen . RESULTS Among 3070 patients , rates of sustained virologic response were similar among the regimens : 39.8 % with st and ard-dose peginterferon alfa-2b , 38.0 % with low-dose peginterferon alfa-2b , and 40.9 % with peginterferon alfa-2a ( P=0.20 for st and ard-dose vs. low-dose peginterferon alfa-2b ; P=0.57 for st and ard-dose peginterferon alfa-2b vs. peginterferon alfa-2a ) . Estimated differences in response rates were 1.8 % ( 95 % confidence interval [ CI ] , -2.3 to 6.0 ) between st and ard-dose and low-dose peginterferon alfa-2b and -1.1 % ( 95 % CI , -5.3 to 3.0 ) between st and ard-dose peginterferon alfa-2b and peginterferon alfa-2a . Relapse rates were 23.5 % ( 95 % CI , 19.9 to 27.2 ) for st and ard-dose peginterferon alfa-2b , 20.0 % ( 95 % CI , 16.4 to 23.6 ) for low-dose peginterferon alfa-2b , and 31.5 % ( 95 % CI , 27.9 to 35.2 ) for peginterferon alfa-2a . The safety profile was similar among the three groups ; serious adverse events were observed in 8.6 to 11.7 % of patients . Among the patients with undetectable HCV RNA levels at treatment weeks 4 and 12 , a sustained virologic response was achieved in 86.2 % and 78.7 % , respectively . CONCLUSIONS In patients infected with HCV genotype 1 , the rates of sustained virologic response and tolerability did not differ significantly between the two available peginterferon-ribavirin regimens or between the two doses of peginterferon alfa-2b . ( Clinical Trials.gov number , NCT00081770 . UNLABELLED Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response ( SVR ) have a lower risk of hepatic decompensation and hepatocellular carcinoma ( HCC ) . In this prospect i ve analysis , we compared the rate of death from any cause or liver transplantation , and of liver-related morbidity and mortality , after antiviral therapy among patients who achieved SVR , virologic nonresponders ( NR ) , and those with initial viral clearance but subsequent breakthrough or relapse ( BT/R ) in the HALT-C ( Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis ) Trial . Laboratory and /or clinical outcome data were available for 140 of the 180 patients who achieved SVR . Patients with nonresponse ( NR ; n = 309 ) or who experienced breakthrough or relapse ( BT/R ; n = 77 ) were evaluated every 3 months for 3.5 years and then every 6 months thereafter . Outcomes included death , liver-related death , liver transplantation , decompensated liver disease , and HCC . Median follow-up for the SVR , BT/R , and NR groups of patients was 86 , 85 , and 79 months , respectively . At 7.5 years , the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group ( 2.2 % and 2.7 % , respectively ) was significantly lower than that of the NR group ( 21.3 % and 27.2 % , P < 0.001 for both ) but not the BT/R group ( 4.4 % and 8.7 % ) . The adjusted hazard ratio ( HR ) for time to death/liver transplantation ( HR = 0.17 , 95 % confidence interval [ CI ] = 0.06 - 0.46 ) or development of liver-related morbidity/mortality ( HR = 0.15 , 95 % CI = 0.06 - 0.38 ) or HCC ( HR = 0.19 , 95 % CI = 0.04 - 0.80 ) was significant for SVR compared to NR . Laboratory tests related to liver disease severity improved following SVR . CONCLUSION Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation , and in liver-related morbidity/mortality , although they remain at risk for HCC BACKGROUND Treatment with pegylated interferon ( peginterferon ) and ribavirin for 48 weeks is more effective than conventional interferon and ribavirin in patients with chronic hepatitis C. OBJECTIVE To assess the efficacy and safety of 24 or 48 weeks of treatment with peginterferon-alpha2a plus a low or st and ard dose of ribavirin . DESIGN R and omized , double-blind trial . SETTING 99 international centers . PATIENTS 1311 patients with chronic hepatitis C. INTERVENTION Peginterferon-alpha2a , 180 microg/wk , for 24 or 48 weeks plus a low-dose ( 800 mg/d ) or st and ard weight-based dose ( 1000 or 1200 mg/d ) of ribavirin . MEASUREMENT Sustained virologic response : undetectable HCV RNA concentration at the end of treatment and during 12 to 24 weeks of follow-up . RESULTS Overall and in patients infected with HCV genotype 1 , 48 weeks of treatment was statistically superior to 24 weeks and st and ard-dose ribavirin was statistically superior to low-dose ribavirin . In patients with HCV genotype 1 , absolute differences in sustained virologic response rates between 48 and 24 weeks of treatment were 11.2 % ( 95 % CI , 3.6 % to 18.9 % ) and 11.9 % ( CI , 4.7 % to 18.9 % ) , respectively , between st and ard- and low-dose ribavirin . Sustained virologic response rates for peginterferon-alpha2a and st and ard-dose ribavirin for 48 weeks were 63 % ( CI , 59 % to 68 % ) overall and 52 % ( CI , 46 % to 58 % ) in patients with HCV genotype 1 . In patients with HCV genotypes 2 or 3 , the sustained virologic response rates in the 4 treatment groups were not statistically significantly different . CONCLUSION Treatment with peginterferon-alpha2a and ribavirin may be individualized by genotype . Patients with HCV genotype 1 require treatment for 48 weeks and a st and ard dose of ribavirin ; those with HCV genotypes 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks BACKGROUND & AIMS Patients with chronic hepatitis C virus ( HCV ) infection are frequently treated with a combination of pegylated interferon ( peginterferon ) and ribavirin . This study compared the efficacy and safety of peginterferon alfa-2a and peginterferon alfa-2b , each in combination with ribavirin . METHODS A total of 320 consecutive , treatment-naive , HCV RNA-positive patients with chronic hepatitis were r and omly assigned to once-weekly peginterferon alfa-2a ( 180 microg , group A ) or peginterferon alfa-2b ( 1.5 microg/kg , group B ) plus ribavirin 1000 mg/day ( body weight < 75 kg ) or 1200 mg/day ( body weight > or=75 kg ) for 48 weeks ( genotype 1 or 4 ) or 24 weeks ( genotype 2 or 3 ) . The primary end point was sustained virological response ( SVR ) by intention-to-treat . RESULTS More patients in group A than group B achieved an SVR ( 110/160 [ 68.8 % ] vs 87/160 [ 54.4 % ] ; P = .008 ) . Higher SVR rates were obtained in group A than group B among patients with genotype 1/4 ( 51/93 [ 54.8 % ] vs 37/93 [ 39.8 % ] ; P = .04 ) , with genotype 2/3 ( 59/67 [ 88.1 % ] vs 50/67 [ 74.6 % ] ; P = .046 ) , without cirrhosis ( 96/127 [ 75.6 % ] vs 75/134 [ 55.9 % ] ; P = .005 ) , and with baseline levels HCV RNA > 500,000 IU/mL ( 58/84 [ 69 % ] vs 43/93 [ 46.2 % ] ; P = .002 ) . SVR rates in groups A and B were not statistically different among patients with baseline HCV RNA < or=500,000 IU/mL ( 52/76 [ 68.4 % ] vs 44/67 [ 65.7 % ] ; P = .727 ) or in patients with cirrhosis ( 14/33 [ 42.4 % ] vs 12/26 [ 46.1 % ] ; P = .774 ) . CONCLUSIONS In patients with chronic HCV infection , peginterferon alfa-2a plus ribavirin produced a significantly higher SVR rate than peginterferon alfa-2b plus ribavirin BACKGROUND & AIMS Recent studies have shown that 12 weeks of treatment with telaprevir , administered every 8 hours ( q8h ) , combined with pegylated interferon ( peginterferon ) alfa-2a plus ribavirin significantly increased the rate of hepatitis C virus ( HCV ) eradication ( sustained virologic response [ SVR ] ) in patients infected with HCV genotype 1 compared with approved therapy . We investigated the efficacy , safety , tolerability , and pharmacokinetics of telaprevir given q8h or every 12 hours ( q12 h ) in combination with peginterferon alfa-2a or alfa-2b . METHODS Treatment-naive patients ( n = 161 ) infected with HCV genotype 1 were r and omly assigned to groups that were given open-label telaprevir ( 750 mg q8 h or 1125 mg q12 h ) in combination with st and ard doses of peginterferon alfa-2a ( 180 μg/wk ) and ribavirin ( 1000 - 1200 mg/day ) or peginterferon alfa-2b ( 1.5 μg·kg(-1)·wk(-1 ) ) and ribavirin ( 800 - 1200 mg/day ) . Patients received triple therapy for 12 weeks , followed by 12 or 36 additional weeks of treatment with peginterferon alfa and ribavirin , based on virologic response . RESULTS Baseline characteristics were similar for all groups . SVR rates were 81.0 % to 85.0 % among groups ; most patients received 24 weeks of therapy ( 68.0 % ) . There were no significant differences in SVR rates ( intent-to-treat analysis ) among groups ( P ≥ .787 ) , between the pooled q8 h and q12 h groups ( P = .997 ) , or between the pooled peginterferon alfa-2a/ribavirin and peginterferon alfa-2b/ribavirin groups ( P = .906 ) . The safety profile was similar among all groups . CONCLUSIONS A high proportion ( > 80 % ) of patients achieved an SVR regardless of the telaprevir dosing frequency ( q8 h or q12 h ) or type of peginterferon alfa used ( alfa-2a or alfa-2b ) National Institutes of Health ( NIH ) consensus and stateof-the-science statements are prepared by independent panels of health professionals and public representatives on the basis of 1 ) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality ( AHRQ ) ; 2 ) presentations by investigators working in areas relevant to the conference questions during a 2-day public session ; 3 ) questions and statements from conference attendees during open discussion periods that are part of the public session ; and 4 ) closed deliberations by the panel during the remainder of the second day and morning of the third . This statement is an independent report of the panel and is not a policy statement of the National Institutes of Health or the U.S. government . The statement reflects the panel ’s assessment of medical knowledge available at the time the statement was written . Thus , it provides a “ snapshot in time ” of the state of knowledge on the conference topic . When reading the statement , keep in mind that new knowledge is inevitably accumulating through medical research . Hepatitis B is a major cause of liver disease worldwide , ranking as a substantial cause of cirrhosis and hepatocellular carcinoma . The development and use of a vaccine for hepatitis B virus ( HBV ) has result ed in a substantial decline in the number of new cases of acute hepatitis B among children , adolescents , and adults in the United States . However , this success has not yet been duplicated worldwide , and both acute and chronic HBV infection continue to represent important global health problems . Seven treatments are currently approved for adult patients with chronic HBV infection in the United States : interferon- , pegylated interferon- , lamivudine , adefovir dipivoxil , entecavir , telbivudine , and tenofovir disoproxil fumarate . Interferon- and lamivudine have been approved for children with HBV infection . Although available r and omized , controlled trials ( RCTs ) show encouraging short-term results — demonstrating the favorable effect of these agents on such intermediate markers of disease as HBV DNA level , liver enzyme tests , and liver histology— limited rigorous evidence exists demonstrating the effect of these therapies on important long-term clinical outcomes , such as the development of hepatocellular carcinoma or a reduction in deaths . Questions therefore remain about which groups of patients benefit from therapy and at which point in the course of disease this therapy should be initiated Overwhelming evidence shows the quality of reporting of r and omised controlled trials ( RCTs ) is not optimal . Without transparent reporting , readers can not judge the reliability and validity of trial findings nor extract information for systematic review s. Recent method ological analyses indicate that inadequate reporting and design are associated with biased estimates of treatment effects . Such systematic error is seriously damaging to RCTs , which are considered the gold st and ard for evaluating interventions because of their ability to minimise or avoid bias . A group of scientists and editors developed the CONSORT ( Consoli date d St and ards of Reporting Trials ) statement to improve the quality of reporting of RCTs . It was first published in 1996 and up date d in 2001 . The statement consists of a checklist and flow diagram that authors can use for reporting an RCT . Many leading medical journals and major international editorial groups have endorsed the CONSORT statement . The statement facilitates critical appraisal and interpretation of RCTs . During the 2001 CONSORT revision , it became clear that explanation and elaboration of the principles underlying the CONSORT statement would help investigators and others to write or appraise trial reports . A CONSORT explanation and elaboration article was published in 2001 alongside the 2001 version of the CONSORT statement . After an expert meeting in January 2007 , the CONSORT statement has been further revised and is published as the CONSORT 2010 Statement . This up date improves the wording and clarity of the previous checklist and incorporates recommendations related to topics that have only recently received recognition , such as selective outcome reporting bias . This explanatory and elaboration document-intended to enhance the use , underst and ing , and dissemination of the CONSORT statement-has also been extensively revised . It presents the meaning and rationale for each new and up date d checklist item providing examples of good reporting and , where possible , references to relevant empirical studies . Several examples of flow diagrams are included . The CONSORT 2010 Statement , this revised explanatory and elaboration document , and the associated website ( www.consort-statement.org ) should be helpful re sources to improve reporting of r and omised trials Under-enrolment of women to r and omized clinical trials , including chronic hepatitis C , has long been recognized . The aim of this study was to identify factors predictive of sustained virological response ( SVR ) to PEG IFN/Ribavirin antiviral therapy in relation to gender and reproductive status of female patients involved . Seven hundred and forty-six treatment-naïve patients ( 431 men , 315 women ) treated with Peg-IFNα-2a ( 180 μg/week ) or Peg-IFNα-2b ( 1.5 μg/kg/week ) plus ribavirin ( 800 - 1400 mg/day ) for 24 or 48 weeks were studied between 2006 and 2010 . Differences in SVR rate , overall and by gender were assessed after adjustment and propensity score matching . SVR was obtained in 44.2 % of Peg-IFNα-2a-treated patients and in 51.2 % of Peg-IFNα-2b-treated patients ( intention-to-treat ; P = 0.139 ) . Age , fibrosis stage and genotype 2 and 3 were independently associated with SVR by multivariate analysis . Analysing by gender , the difference in SVR between PEG-IFNα types was not significant in men but highly significant in women ( Peg-IFNα-2a:39.1%vs Peg-IFNα-2b:54.4 % , P = 0.007 ) . This was attributable to a higher SVR rate with Peg-IFNα-2b in the difficult postmenopausal population ( 26.9 % Peg-IFNα-2a vs 46.0 % Peg-IFNα-2b , P = 0.040 ) . In women , absence of menopause , genotype 2 hepatitis C virus infection and use of Peg-IFNα-2b were independently associated with SVR . In conclusion , predictive factors for SVR are different in men and women . Factors differing between genders are menopause , severe steatosis and peg-interferon used . The higher SVR rate with Peg-IFNα-2b in menopausal women is likely attributable to more favourable pharmacokinetics that allows Peg-IFNα-2b to reach visceral fat and oppose the increased cytokine production and enhanced inflammatory status in menopause UNLABELLED Chronic hepatitis C virus infection can cause chronic liver disease , cirrhosis and liver cancer . The Hepatitis C Antiviral Long-term Treatment against Cirrhosis ( HALT-C ) Trial was a prospect i ve , r and omized controlled study of long-term , low-dose peginterferon therapy in patients with advanced chronic hepatitis C who failed to respond to a previous course of optimal antiviral therapy . The aim of this follow-up analysis is to describe the frequency and causes of death among this cohort of patients . Deaths occurring during and after the HALT-C Trial were review ed by a committee of investigators to determine the cause of death and to categorize each death as liver- or nonliver-related and as related or not to complications of peginterferon . Rates of liver transplantation were also assessed . Over a median of 5.7 years , 122 deaths occurred among 1,050 r and omized patients ( 12 % ) , of which 76 were considered liver-related ( 62 % ) and 46 nonliver-related ( 38 % ) ; 74 patients ( 7 % ) underwent liver transplantation . At 7 years the cumulative mortality rate was higher in the treatment compared to the control group ( 20 % versus 15 % , P = 0.049 ) ; the primary difference in mortality was in patients in the fibrosis compared to the cirrhosis stratum ( 14 % versus 7 % , P = 0.01 ) ; comparable differences were observed when liver transplantation was included . Excess mortality , emerging after 3 years of treatment , was related largely to nonliver-related death ; liver-related mortality was similar in the treatment and control groups . No specific cause of death accounted for the excess mortality and only one death was suspected to be a direct complication of peginterferon . CONCLUSION Long-term maintenance peginterferon in patients with advanced chronic hepatitis C is associated with an excess overall mortality , which was primarily due to nonliver-related causes among patients with bridging fibrosis Published evidence suggests that aspects of trial design lead to biased intervention effect estimates , but findings from different studies are inconsistent . This study combined data from 7 meta-epidemiologic studies and removed overlaps to derive a final data set of 234 unique meta-analyses containing 1973 trials . Outcome measures were classified as " mortality , " " other objective , " " or subjective , " and Bayesian hierarchical models were used to estimate associations of trial characteristics with average bias and between-trial heterogeneity . Intervention effect estimates seemed to be exaggerated in trials with inadequate or unclear ( vs. adequate ) r and om-sequence generation ( ratio of odds ratios , 0.89 [ 95 % credible interval { CrI } , 0.82 to 0.96 ] ) and with inadequate or unclear ( vs. adequate ) allocation concealment ( ratio of odds ratios , 0.93 [ CrI , 0.87 to 0.99 ] ) . Lack of or unclear double-blinding ( vs. double-blinding ) was associated with an average of 13 % exaggeration of intervention effects ( ratio of odds ratios , 0.87 [ CrI , 0.79 to 0.96 ] ) , and between-trial heterogeneity was increased for such studies ( SD increase in heterogeneity , 0.14 [ CrI , 0.02 to 0.30 ] ) . For each characteristic , average bias and increases in between-trial heterogeneity were driven primarily by trials with subjective outcomes , with little evidence of bias in trials with objective and mortality outcomes . This study is limited by incomplete trial reporting , and findings may be confounded by other study design characteristics . Bias associated with study design characteristics may lead to exaggeration of intervention effect estimates and increases in between-trial heterogeneity in trials reporting subjectively assessed outcomes |
13,657 | 18,621,950 | The collaboration among government scientists , university research ers and community partners emerged as a new model of CBPR partnerships that effectively integrates research and action . | INTRODUCTION Integrating research and action represents a goal and key principles of community-based participatory research ( CBPR ) , but there has been little effort to synthesis e the literature to evaluate whether such integration is occurring .
OBJECTIVES ( 1 ) To examine the extent to which CBPR integrates action to effect community-level change and ( 2 ) to ascertain factors that facilitate such integration . | Social epidemiology is the study of relations between social factors and health status in population s. Although recent decades have witnessed a rapid development of this research program in scope and sophistication , causal inference has proven to be a persistent dilemma due to the natural assignment of exposure level based on unmeasured attributes of individuals , which may lead to substantial confounding . Some optimism has been expressed about r and omized social interventions as a solution to this long-st and ing inferential problem . We review the causal inference problem in social epidemiology , and the potential for causal inference in r and omized social interventions . Using the example of a currently on-going intervention that r and omly assigns families to non-poverty housing , we review the limitations to causal inference even under experimental conditions and explain which causal effects become identifiable . We note the benefit of using the r and omized trial as a conceptual model , even for design and interpretation of observational studies in social epidemiology BACKGROUND Community Action Against Asthma ( CAAA ) is a community-based participatory research ( CBPR ) project that assesses the effects of outdoor and indoor air quality on exacerbation of asthma in children , and tests household- and neighborhood-level interventions to reduce exposure to environmental asthma triggers . Representatives of community-based organizations , academia , an integrated health system , and the local health department work in partnership on CAAA 's Steering Committee ( SC ) to design and implement the project . OBJECTIVE To conduct a process evaluation of the CAAA community-academic partnership . DESIGN In-depth interviews containing open-ended questions were conducted with SC members . Analysis included established methods for qualitative data , including focused coding and constant comparison methods . SETTING Community setting in Detroit , Michigan . PARTICIPANTS Twenty-three members of the CAAA SC . MEASUREMENTS Common themes identified by SC members relating to the partnership 's ability to achieve project goals and the successes and challenges facing the partnership itself . MAIN RESULTS Identified partnership accomplishments included : successful implementation of a complex project , identification of children with previously undiagnosed asthma , and diverse participation and community influence in SC decisions . Challenges included ensuring all partners ' influence in decision-making , the need to adjust to " a different way of doing things " in CBPR , constraints and costs of doing CBPR felt by all partners , ongoing need for communication and maintaining trust , and balancing the needs of science and the community through intervention . CONCLUSIONS CBPR can enhance and facilitate basic research , but care must be given to trust issues , governance issues , organizational culture , and costs of participation for all organizations involved Objectives Childhood asthma is a growing public health concern in low-income urban communities . Indoor exposure to asthma triggers has emerged as an important cause of asthma exacerbations . We describe indoor environmental conditions related to asthma triggers among a low-income urban population in Seattle/King County , Washington , as well as caregiver knowledge and re sources related to control of these triggers . Methods Data are obtained from in-person , structured , closed-end interviews with the caretakers of children aged 4–12 years with persistent asthma living in households with incomes less than 200 % of poverty . Additional information is collected during a home inspection . The children and their caregivers are participants in the ongoing Seattle-King County Healthy Homes Project , a r and omized controlled trial of an intervention to empower low-income families to reduce exposure to indoor asthma triggers . We report findings on the conditions of the homes prior to this intervention among the first 112 enrolled households . Results A smoker was present in 37.5 % of homes . Mold was visible in 26.8 % of homes , water damage was present in 18.6 % of homes , and damp conditions occurred in 64.8 % of households , while 39.6 % of caregivers were aware that excessive moisture can increase exposures to allergens . Dust-trapping reservoirs were common ; 76.8 % of children 's bedrooms had carpeting . Cockroach infestation in the past 3 months was reported by 23.4 % of caregivers , while 57.1 % were unaware of the association of roaches and asthma . Only 19.8 % of the children had allergy-control mattress covers . Conclusions Many low-income urban children with asthma in King County live in indoor environments that place them at substantial risk of ongoing exposure to asthma triggers . Subst and ard housing and lack of re sources often underlie these exposures . Initiatives involving health educators , outreach workers , medical providers , health care insurers , housing agencies , and elected officials are needed to reduce these exposures R and omized controlled trials ( RCTs ) are essential for evaluating the efficacy of clinical interventions , where the causal chain between the agent and the outcome is relatively short and simple and where results may be safely extrapolated to other setting s. However , causal chains in public health interventions are complex , making RCT results subject to effect modification in different population s. Both the internal and external validity of RCT findings can be greatly enhanced by observational studies using adequacy or plausibility design s. For evaluating large-scale interventions , studies with plausibility design s are often the only feasible option and may provide valid evidence of impact . There is an urgent need to develop evaluation st and ards and protocol s for use in circumstances where RCTs are not appropriate OBJECTIVES We assessed the effectiveness of a community health worker intervention focused on reducing exposure to indoor asthma triggers . METHODS We conducted a r and omized controlled trial with 1-year follow-up among 274 low-income households containing a child aged 4 - 12 years who had asthma . Community health workers provided in-home environmental assessment s , education , support for behavior change , and re sources . Participants were assigned to either a high-intensity group receiving 7 visits and a full set of re sources or a low-intensity group receiving a single visit and limited re sources . RESULTS The high-intensity group improved significantly more than the low-intensity group in its pediatric asthma caregiver quality -of-life score ( P=.005 ) and asthma-related urgent health services use ( P=.026 ) . Asthma symptom days declined more in the high-intensity group , although the across-group difference did not reach statistical significance ( P=.138 ) . Participant actions to reduce triggers generally increased in the high-intensity group . The projected 4-year net savings per participant among the high-intensity group relative to the low-intensity group were 189 - 721 dollars . CONCLUSIONS Community health workers reduced asthma symptom days and urgent health services use while improving caregiver quality -of-life score . Improvement was greater with a higher-intensity intervention Pediatric asthma is a growing public health issue , disproportionately affecting low-income people and people of color . Exposure to indoor asthma triggers plays an important role in the development and exacerbation of asthma . We describe the implementation of the Seattle-King County Healthy Homes Project , a r and omized , controlled trial of an outreach/education intervention to improve asthma-related health status by reducing exposure to allergens and irritants in the home . We r and omly assigned 274 low-income children with asthma ages 4 - 12 to either a high- or a low-intensity group . In the high-intensity group , community health workers called Community Home Environmental Specialists ( CHES ) conducted initial home environmental assessment s , provided individualized action plans , and made additional visits over a 12-month period to provide education and social support , encouragement of participant actions , provision of material s to reduce exposures ( including bedding encasements ) , assistance with roach and rodent eradication , and advocacy for improved housing conditions . Members of the low-intensity group received the initial assessment , home action plan , limited education during the assessment visit , and bedding encasements . We describe the recruitment and training of CHES and challenges they faced and explain the assessment and exposure reduction protocol s addressing dust mites , mold , tobacco smoke , pets , cockroaches , rodents , dust , moisture , and toxic or hazardous chemicals . We also discuss the gap between the practice s recommended in the literature and what is feasible in the home . We accomplished home interventions and participants found the project very useful . The project was limited in resolving structural housing quality issues that contributed to exposure to indoor triggers The goal of this investigation was to use a community-based participatory research approach to develop , pilot test , and administer an asthma screening question naire to identify children with asthma and asthma symptoms in a community setting . This study was conducted as the recruitment effort for Community Action Against Asthma , a r and omized trial of a household intervention to reduce exposure to environmental triggers of asthma and was not design ed as a classic prevalence study . An asthma screening question naire was mailed and /or h and delivered to parents of 9,627 children , aged 5 to 11 years , in two geographic areas of Detroit , Michigan , with predominantly African American and Hispanic population s. Additional question naires were distributed via community networking . Measurements included parent report of their child 's frequency of respiratory symptoms , presence of physician diagnosis of asthma , and frequency of doctor-prescribed asthma medication usage . Among the 3,067 completed question naires , 1,570 ( 51.2 % of returned surveys , 16.3 % of eligible population ) were consistent with asthma of any severity and 398 ( 12.9 % of returned surveys , 4.1 % of eligible population ) met criteria , for moderate-to-severe asthma . Among those meeting criteria for moderate-to-severe asthma , over 30 % had not been diagnosed by a physician , over one half were not taking daily asthma medication , and one quarter had not taken any physician-prescribed asthma medication in the past year . Screening surveys conducted within the context of a community-based participatory research partnership can identify large numbers of children with undiagnosed and /or undertreated moderate-to-severe asthma . These children are likely to benefit from interventions to reduce morbidity and improve quality of life The environment is suspected to play an important role in the prevalence and severity of asthma in inner-city children . This paper describes the implementation and baseline data of an inner-city community-based participatory research clinical trial design ed to test the effectiveness of a pollutant and allergen control strategy on children 's asthma morbidity . Participants were 100 elementary-school-aged children with asthma , graduates of a school-based asthma education program in East Baltimore . The intervention for half of the r and omly assigned families consisted of environmental control education , allergen-proof encasements , pest extermination , and a HEPA air cleaner at the beginning of the study . Controls received the same at the end of the study . Participants visited a clinic for question naires , allergy skin testing , spirometry , and blood sample at baseline and 12 months . Home environments , NO(2 ) , O(3 ) , airborne particulates , and allergens were evaluated at baseline and at 6 and 12 months . Asthma morbidity and adherence was assessed quarterly . Collaboration with the community proved very beneficial in creating a study design and procedures acceptable to an inner-city community |
13,658 | 28,103,573 | Our findings suggest that metformin intake is associated with improved survival outcomes in terms of OS and CS in CRC patients with diabetes , particular for OS in stage II and stage III patients . | Several observational studies have shown that metformin can modify the risk and survival of colorectal cancer ( CRC ) in patients with diabetes mellitus , although the magnitude of this relationship has not been determined . | OBJECTIVE The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase ( AMPK ) . Activation of AMPK can suppress tumor formation and inhibit cell growth in addition to lowering blood glucose levels . We tested the hypothesis that metformin reduces the risk of cancer in people with type 2 diabetes . RESEARCH DESIGN AND METHODS In an observational cohort study using record-linkage data bases and based in Tayside , Scotl and , U.K. , we identified people with type 2 diabetes who were new users of metformin in 1994–2003 . We also identified a set of diabetic comparators , individually matched to the metformin users by year of diabetes diagnosis , who had never used metformin . In a survival analysis we calculated hazard ratios for diagnosis of cancer , adjusted for baseline characteristics of the two groups using Cox regression . RESULTS Cancer was diagnosed among 7.3 % of 4,085 metformin users compared with 11.6 % of 4,085 comparators , with median times to cancer of 3.5 and 2.6 years , respectively ( P < 0.001 ) . The unadjusted hazard ratio ( 95 % CI ) for cancer was 0.46 ( 0.40–0.53 ) . After adjusting for sex , age , BMI , A1C , deprivation , smoking , and other drug use , there was still a significantly reduced risk of cancer associated with metformin : 0.63 ( 0.53–0.75 ) . CONCLUSIONS These results suggest that metformin use may be associated with a reduced risk of cancer . A r and omized trial is needed to assess whether metformin is protective in a population at high risk for cancer OBJECTIVE The Treatment Options for type 2 Diabetes in Adolescents and Youth ( TODAY ) trial demonstrated that combination therapy with metformin plus rosiglitazone provided superior durability of glycemic control compared with metformin alone , with significantly lower treatment failure rates ( 38.6 vs. 51.7 % ) , and metformin plus lifestyle was intermediate . Herein we describe the temporal changes in measures of β-cell function and insulin sensitivity over a 4-year period among the three treatments . RESEARCH DESIGN AND METHODS TODAY participants ( 699 ) were tested periodically with an oral glucose tolerance test to determine insulin sensitivity ( 1/fasting insulin [ 1/IF ] ) , insulinogenic index ( △ I30/ △ G30 ) or C-peptide index ( △ C30/ △ G30 ) , and β-cell function relative to insulin sensitivity ( oral disposition index [ oDI ] ) . RESULTS During the first 6 months , metformin plus rosiglitazone exhibited a significantly greater improvement in insulin sensitivity and oDI versus metformin alone and versus metformin plus lifestyle ; these improvements were sustained over 48 months of TODAY . Irrespective of treatment , those who failed to maintain glycemic control had significantly lower β-cell function ( ∼50 % ) , higher fasting glucose concentration , and higher HbA1c at r and omization compared with those who did not fail . CONCLUSIONS The beneficial change in insulin sensitivity and the result ant lower burden on β-cell function achieved in the first 6 months with metformin plus rosiglitazone appear to be responsible for its superior glycemic durability over metformin alone and metformin plus lifestyle . However , initial β-cell reserve and HbA1c at r and omization are independent predictors of glycemic durability . Therefore , efforts to preserve β-cell function before significant loss occurs and to reduce HbA1c may be beneficial in the treatment of youth with type 2 diabetes Locally advanced rectal cancer is commonly treated with chemoradiation prior to total mesorectal excision ( TME ) . Studies suggest that metformin may be an effective chemopreventive agent in this disease as well as a possible adjunct to current therapy . In this study , we examined the effect of metformin use on pathologic complete response ( pCR ) rates and outcomes in rectal cancer . The charts of 482 patients with locally advanced rectal adenocarcinoma treated from 1996 to 2009 with chemoradiation and TME were review ed . Median radiation dose was 50.4 Gy ( range 19.8–63 ) . Nearly , all patients were treated with concurrent 5‐fluorouracil‐based chemotherapy ( 98 % ) followed by adjuvant chemotherapy ( 81.3 % ) . Patients were categorized as nondiabetic ( 422 ) , diabetic not taking metformin ( 40 ) , or diabetic taking metformin ( 20 ) . No significant differences between groups were found in clinical tumor classification , nodal classification , tumor distance from the anal verge or circumferential extent , pretreatment carcinoembryonic antigen level , or pathologic differentiation . pCR rates were 16.6 % for nondiabetics , 7.5 % for diabetics not using metformin , and 35 % for diabetics taking metformin , with metformin users having significantly higher pCR rates than either nondiabetics ( P = 0.03 ) or diabetics not using metformin ( P = 0.007 ) . Metformin use was significantly associated with pCR rate on univariate ( P = 0.05 ) and multivariate ( P = 0.01 ) analyses . Furthermore , patients taking metformin had significantly increased disease‐free ( P = 0.013 ) and overall survival ( P = 0.008 ) compared with other diabetic patients . Metformin use is associated with significantly higher pCR rates as well as improved survival . These promising data warrant further prospect i ve study BACKGROUND Recent studies have suggested an effect of metformin on mortality for patients with both diabetes and colorectal cancer ( crc ) . However , the literature is contradictory , with both positive and negative effects being identified . We set out to determine the effect of metformin with respect to prognosis in crc patients . METHODS After a retrospective chart review of crc patients treated at the Cancer Centre of Southeastern Ontario , Kaplan-Meier analyses and Cox proportional hazards regression models were used to compare overall survival ( os ) in patients with and without diabetes . RESULTS We identified 1304 crc patients treated at the centre . No significant differences between the diabetic and nondiabetic groups were observed with respect to tumour pathology , extent of metastatic disease , time or toxicity of chemotherapy , and the os rate ( 1-year os : 85.6 % vs. 86.4 % , p = 0.695 ; 2-year os : 73.6 % vs. 77.0 % , p = 0.265 ) . In subgroup analysis , diabetic patients taking metformin survived significantly longer than their counterparts taking other diabetes treatments ( os for the metformin group : 91 % at 1 year ; 80.5 % at 2 years ; os for the group taking other treatments , including diet control : 80.6 % at 1 year , 67.4 % at 2 years ) . Multivariate analysis suggests that patients with diabetes taking treatments other than metformin experience worse survival ( p = 0.025 ) . CONCLUSIONS Our results suggest that crc patients with diabetes , excluding those taking metformin , might have a worse crc prognosis . Taking metformin appears to have a positive association with prognosis . The protective nature of metformin needs further evaluation in prospect i ve analyses |
13,659 | 20,819,243 | The AUROC analyses indicate that WHtR may be a more useful global clinical screening tool than WC , with a weighted mean boundary value of 0·5 , supporting the simple public health message ' keep your waist circumference to less than half your height ' | null | null |
13,660 | 24,269,526 | The literature suggests several unique immunomodulatory and neuroplastic profiles for PA subtypes ( i.e. resistance , aerobic and mind-body ) in depression and ARCD .
In depression , levels of various cytokines at baseline may predict treatment response to subtypes of PA and pharmacological agents .
The pro-neuroplastic effects of resistance and aerobic PA in ARCD may differ due to variances in neurotrophin profiles . | Physical activity ( PA ) is emerging as a safe and effective tool in the prevention and treatment of psychiatric disorders .
PA subtypes include aerobic , resistance , flexibility , neuromotor ( involving balance , agility and co-ordination ) , mind-body ( e.g. tai chi , qi gong and yoga ) and mixed type trainings .
Evidence from clinical trials suggests that PA subtypes can have positive clinical effects , however the effects on the symptomatology may vary according to the PA subtype .
It therefore st and s to reason that various PA subtypes may modulate the immune system and neuroplastic processes differently .
This systematic review aims to assess the immunomodulatory and neuroplastic profiles of various PA subtypes , particularly in unipolar depression and age-related cognitive decline ( ARCD ) . | Background : Social anxiety disorder ( SAD ) is characterized by distorted self-views . The goal of this study was to examine whether mindfulness-based stress reduction ( MBSR ) alters behavioral and brain measures of negative and positive self-views . Methods : Fifty-six adult patients with generalized SAD were r and omly assigned to MBSR or a comparison aerobic exercise ( AE ) program . A self-referential encoding task was administered at baseline and post-intervention to examine changes in behavioral and neural responses in the self-referential brain network during functional magnetic resonance imaging . Patients were cued to decide whether positive and negative social trait adjectives were self-descriptive or in upper case font . Results : Behaviorally , compared to AE , MBSR produced greater decreases in negative self-views , and equivalent increases in positive self-views . Neurally , during negative self versus case , compared to AE , MBSR led to increased brain responses in the posterior cingulate cortex ( PCC ) . There were no differential changes for positive self versus case . Secondary analyses showed that changes in endorsement of negative and positive self-views were associated with decreased social anxiety symptom severity for MBSR , but not AE . Additionally , MBSR-related increases in dorsomedial prefrontal cortex ( DMPFC ) activity during negative self-view versus case were associated with decreased social anxiety related disability and increased mindfulness . Analysis of neural temporal dynamics revealed MBSR-related changes in the timing of neural responses in the DMPFC and PCC for negative self-view versus case . Conclusion : These findings suggest that MBSR attenuates maladaptive habitual self-views by facilitating automatic ( i.e. , uninstructed ) recruitment of cognitive and attention regulation neural networks . This highlights potentially important links between self-referential and cognitive-attention regulation systems and suggests that MBSR may enhance more adaptive social self-referential processes in patients with SAD BACKGROUND Mindfulness-based stress reduction ( MBSR ) programs have consistently been shown to enhance the psychosocial well-being of participants . Given the well-established association between psychosocial factors and immunologic functioning , it has been hypothesized that enhanced psychosocial well-being among MBSR participants would be associated with corresponding changes in markers of immune activity . OBJECTIVES The objectives of this study were to examine changes in psychosocial and immunologic measures in a heterogeneous patient sample following participation in a MBSR program . DESIGN A single-group , pretest/post-test design was utilized . SETTING The intervention was conducted at an academic health center . SUBJECTS This pilot study involved 24 participants ( aged 28 - 72 years ) . Inclusion criteria were as follows : > or = 18 years of age , English-speaking , and no known autoimmune disorder . INTERVENTION The intervention was an 8-week MBSR program . OUTCOME MEASURES Distress and quality of life ( QOL ) measures included the Brief Symptom Inventory-18 and the Medical Outcomes Survey Short-Form Health Survey , respectively . Immunologic measures included natural killer ( NK ) cell cytolytic activity and C-reactive protein ( CRP ) . RESULTS Patients completed psychosocial assessment s and provided a blood sample at baseline ( pre-MBSR ) and within 2 weeks post-MBSR . Significant improvements in anxiety and overall distress as well as across multiple domains of QOL were observed from baseline to post-MBSR . Reductions in anxiety and overall distress were associated with reductions in CRP . Patients who reported improvement in overall mental well-being also showed increased NK cytolytic activity from pre- to post-MBSR , whereas patients who reported no improvement in mental well-being showed no change in NK cytolytic activity . CONCLUSIONS Positive improvement in psychologic well-being following MBSR was associated with increased NK cytolytic activity and decreased levels of CRP BACKGROUND Nearly two-thirds of elderly patients treated for depression fail to achieve symptomatic remission and functional recovery with first-line pharmacotherapy . In this study , we ask whether a mind-body exercise , Tai Chi Chih ( TCC ) , added to escitalopram will augment the treatment of geriatric depression design ed to achieve symptomatic remission and improvements in health functioning and cognitive performance . METHODS : One hundred twelve older adults with major depression age 60 years and older were recruited and treated with escitalopram for approximately 4 weeks . Seventy-three partial responders to escitalopram continued to receive escitalopram daily and were r and omly assigned to 10 weeks of adjunct use of either 1 ) TCC for 2 hours per week or 2 ) health education ( HE ) for 2 hours per week . All participants underwent evaluations of depression , anxiety , resilience , health-related quality of life , cognition , and inflammation at baseline and during 14-week follow-up . RESULTS Subjects in the escitalopram and TCC condition were more likely to show greater reduction of depressive symptoms and to achieve a depression remission as compared with those receiving escitalopram and HE . Subjects in the escitalopram and TCC condition also showed significantly greater improvements in 36-Item Short Form Health Survey physical functioning and cognitive tests and a decline in the inflammatory marker , C-reactive protein , compared with the control group . CONCLUSION : Complementary use of a mind-body exercise , such as TCC , may provide additional improvements of clinical outcomes in the pharmacologic treatment of geriatric depression BACKGROUND Cognitive decline among seniors is a pressing health care issue . Specific exercise training may combat cognitive decline . We compared the effect of once-weekly and twice-weekly resistance training with that of twice-weekly balance and tone exercise training on the performance of executive cognitive functions in senior women . METHODS In this single-blinded r and omized trial , 155 community-dwelling women aged 65 to 75 years living in Vancouver were r and omly allocated to once-weekly ( n = 54 ) or twice-weekly ( n = 52 ) resistance training or twice-weekly balance and tone training ( control group ) ( n = 49 ) . The primary outcome measure was performance on the Stroop test , an executive cognitive test of selective attention and conflict resolution . Secondary outcomes of executive cognitive functions included set shifting as measured by the Trail Making Tests ( parts A and B ) and working memory as assessed by verbal digit span forward and backward tests . Gait speed , muscular function , and whole-brain volume were also secondary outcome measures . RESULTS Both resistance training groups significantly improved their performance on the Stroop test compared with those in the balance and tone group ( P < or = .03 ) . Task performance improved by 12.6 % and 10.9 % in the once-weekly and twice-weekly resistance training groups , respectively ; it deteriorated by 0.5 % in the balance and tone group . Enhanced selective attention and conflict resolution was significantly associated with increased gait speed . Both resistance training groups demonstrated reductions in whole-brain volume compared with the balance and tone group at the end of the study ( P < or = .03 ) . CONCLUSION Twelve months of once-weekly or twice-weekly resistance training benefited the executive cognitive function of selective attention and conflict resolution among senior women . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00426881 Exercise is an efficacious treatment for major depressive disorder ( MDD ) and has independently been shown to have anti-inflammatory effects in non-depressed subjects . Patients with MDD have elevated inflammatory cytokines but it is not known if exercise affects inflammation in MDD patients and whether these changes are clinical ly relevant . In the TReatment with Exercise Augmentation for Depression ( TREAD ) study , participants who were partial responders to a selective serotonin reuptake inhibitor were r and omized to receive one of two doses of exercise : 16 kilocalories per kilogram of body weight per week ( KKW ) , or 4 KKW for 12 weeks . Blood sample s were collected before initiation and again at the end of the 12-week exercise intervention . Serum was analyzed using a multiplexed ELISA for interferon-γ ( IFN-γ ) , interleukin-1β ( IL-1β ) , interleukin-6 ( IL-6 ) and tumor necrosis factor-α ( TNF-α ) . Higher baseline levels of TNF-α were associated with greater decrease in depression symptoms over the 12-week exercise period ( P<0.0001 ) . In addition , a significant positive correlation between change in IL-1β and change in depression symptom scores was observed ( P=0.04 ) . There were no significant changes in mean level of any cytokine following the 12-week intervention , and no significant relationship between exercise dose and change in mean cytokine level . Results suggest that high TNF-α may differentially predict better outcomes with exercise treatment as opposed to antidepressant medications for which high TNF-α is linked to poor response . Our results also confirm findings from studies of antidepressant medications that tie decreasing IL-1β to positive depression treatment outcomes Background Mild cognitive impairment ( MCI ) represents a critical window to intervene against dementia . Exercise training is a promising intervention strategy , but the efficiency ( i.e. , relationship of costs and consequences ) of such types of training remains unknown . Thus , we estimated the incremental cost-effectiveness of resistance training or aerobic training compared with balance and tone exercises in terms of changes in executive cognitive function among senior women with probable MCI . Methods Economic evaluation conducted concurrently with a six-month three arm r and omized controlled trial including eighty-six community dwelling women aged 70 to 80 years living in Vancouver , Canada . Participants received twice-weekly resistance training ( n = 28 ) , twice weekly aerobic training ( n = 30 ) or twice-weekly balance and tone ( control group ) classes ( n = 28 ) for 6 months . The primary outcome measure of the Exercise for Cognition and Everyday Living ( EXCEL ) study assessed executive cognitive function , a test of selective attention and conflict resolution ( i.e. , Stroop Test ) . We collected healthcare re source utilization costs over six months . Results Based on the bootstrapped estimates from our base case analysis , we found that both the aerobic training and resistance training interventions were less costly than twice weekly balance and tone classes . Compared with the balance and tone group , the resistance-training group had significantly improved performance on the Stroop Test ( p = 0.04 ) . Conclusions Resistance training and aerobic training result in health care cost saving and are more effective than balance and tone classes after only 6 months of intervention . Resistance training is a promising strategy to alter the trajectory of cognitive decline in seniors with MCI . Trial Registration Clinical Trials.gov NCT00958867 Background Depression is one of the most frequently missed diagnoses in elderly people , with obvious negative effects on quality of life . Various studies have shown that long chain omega-3 polyunsaturated fatty acids ( n-3 PUFA ) may be useful in its management . Our objective was to evaluate whether a supplement containing n-3 PUFA improves depressive symptoms in depressed elderly patients , and whether the blood fatty acid pattern is correlated with these changes . Methods The severity of depressive symptoms according to the Geriatric Depression Scale ( GDS ) , blood fatty acid composition and erythrocyte phospholipids were analyzed in 46 depressed females aged 66 - 95y , diagnosed with depression according to DSMIV , within the context of a r and omized , double-blind , placebo-controlled trial . 22 depressed females were included in the intervention group ( 2.5 g/day of n-3 PUFA for 8 weeks ) , and 24 in the placebo group . We also measured immunological parameters ( CD2 , CD3 , CD4 , CD8 , CD16 , CD19 and cytokines ( IL-5 , IL-15 ) . Results The mean GDS score and AA/EPA ratio , in whole blood and RBC membrane phospholipids , were significantly lower after 2 months supplementation with n-3 PUFA . A significant correlation between the amelioration of GDS and the AA/EPA ratio with some immunological parameters , such as CD2 , CD19 , CD4 , CD16 and the ratio CD4/CD8 , was also found . Nevertheless , omega-3 supplementation did not significantly improve the studied immunological functions . Conclusions n-3 PUFA supplementation ameliorates symptoms in elderly depression . The n-3 PUFA status may be monitored by means of the determination of whole blood AA/EPA ratio OBJECTIVE Most patients with major depressive disorder ( MDD ) require second-step treatments to achieve remission . The Treatment with Exercise Augmentation for Depression ( TREAD ) study was design ed to test the efficacy of aerobic exercise as an augmentation treatment for MDD patients who had not remitted with antidepressant treatment . METHOD Eligible participants in this r and omized controlled trial were sedentary individuals ( men and women aged 18 - 70 years ) diagnosed with DSM-IV nonpsychotic MDD who had not remitted with selective serotonin reuptake inhibitor ( SSRI ) treatment . Participants were recruited through physician referrals and advertisements . A total of 126 participants were r and omized to augmentation treatment with either 16 kcal per kg per week ( KKW ) or 4 KKW of exercise expenditure for 12 weeks while SSRI treatment was held constant . Supervised sessions were conducted at The Cooper Institute , Dallas , Texas , with additional home-based sessions as needed to fulfill the weekly exercise prescription . The primary outcome was remission ( as determined by a score ≤ 12 on the Inventory of Depressive Symptomatology , Clinician-Rated ) . The study took place between August 2003 and August 2007 . RESULTS There were significant improvements over time for both groups combined ( F₁,₁₂₁ = 39.9 , P < .0001 ) , without differential group effect ( group effect : F₁,₁₃₄ = 3.2 , P = .07 ; group-by-time effect : F₁,₁₁₉ = 3.8 , P = .06 ) . Adjusted remission rates at week 12 were 28.3 % versus 15.5 % for the 16-KKW and 4-KKW groups , respectively , leading to a number needed to treat ( NNT ) of 7.8 for 16 KKW versus 4 KKW . Men , regardless of family history of mental illness , and women without a family history of mental illness had higher remission rates by week 12 with higher-dose ( women , 39.0 % ; men , 85.4 % ) than with lower-dose exercise ( women , 5.6 % ; men , 0.1 % ) ( women : t₉₅ = 2.1 , P = .04 ; men : t₈₈ = 5.4 , P < .0001 ) ( NNT : women , 3.0 ; men , 1.2 ) . CONCLUSIONS There was a trend for higher remission rates in the higher-dose exercise group ( P < .06 ) , with a clinical ly meaningful NNT of 7.8 in favor of the high exercise dose . Significant differences between groups were found when the moderating effects of gender and family history of mental illness were taken into account and suggest that higher-dose exercise may be better for all men and for women without a family history of mental illness . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00076258 Physical exercises and relaxation have been found to be beneficial for depression . However , there is little evidence on the use of Qigong , a mind-body practice integrating gentle exercise and relaxation , in the management of depression . The aim of this paper is to evaluate the effects of Qigong on depression . The paper examined clinical trials measuring the effect of Qigong on depression within six large-scale medical research data bases ( PubMed , Medline , ProQuest , Science Direct , EMBASE , and PsycInfo ) till October 2011 . Key words “ Qigong , ” “ depression , ” and “ mood ” were used . Ten studies were identified as original r and omized controlled trial ( RCT ) studies investigating the effect of Qigong on depression as primary ( n = 2 ) or secondary outcome ( n = 8) . Four studies reported positive results of the Qigong treatment on depression ; two reported that Qigong effect on depression was as effective as physical exercise . One study reported that Qigong was comparable to a conventional rehabilitation program , but the remaining three studies found no benefits of Qigong on depression . While the evidence suggests the potential effects of Qigong in the treatment of depression , the review of the literature shows inconclusive results . Further research using rigorous study design s is necessary to investigate the effectiveness of Qigong in depression PURPOSE The purpose of this study was to assess the impact of 24 wk of resistance training at two different intensities on cognitive functions in the elderly . METHODS Sixty-two elderly individuals were r and omly assigned to three groups : CONTROL ( N = 23 ) , experimental moderate ( EMODERATE ; N = 19 ) , and experimental high ( EHIGH ; N = 20 ) . The volunteers were assessed on physical , hemodynamic , cognitive , and mood parameters before and after the program . RESULTS On the 1 RM test ( P < 0.001 ) , the two experimental groups performed better than the CONTROL group , but they did not show differences between themselves . The EHIGH group gained more lean mass ( P = 0.05 ) than the CONTROL group and performed better on the following tests : digit span forward ( P < 0.001 ) , Corsi 's block-tapping task backward ( P = 0.001 ) , similarities ( P = 0.03 ) , Rey-Osterrieth complex figure immediate recall ( P = 0.02 ) , Toulouse-Pieron concentration test errors ( P = 0.01 ) , SF-36 ( general health ) ( P = 0.04 ) , POMS ( tension-anxiety , P = 0.04 ; depression-dejection , P = 0.03 ; and total mood disorder , P = 0.03 ) . The EMODERATE group scored higher means than the CONTROL group on digit span forward ( P < 0.001 ) , Corsi 's block-tapping task backward ( P = 0.01 ) , similarities ( P = 0.02 ) , Rey-Osterrieth complex figure immediate recall ( P = 0.02 ) , SF-36 ( general health , P = 0.005 ; vitality , P = 0.006 ) , POMS ( tension-anxiety , P = 0.001 ; depression-dejection , P = 0.006 ; anger-hostility , P = 0.006 ; fatigue-inertia , P = 0.02 ; confusion-bewilderment , P = 0.02 ; and total mood disorder , P = 0.001 ) . We also found that IGF-1 serum levels were higher in the experimental groups ( EMODERATE , P = 0.02 ; EHIGH , P < 0.001 ) . CONCLUSIONS Moderate- and high-intensity resistance exercise programs had equally beneficial effects on cognitive functioning The hippocampus shrinks in late adulthood , leading to impaired memory and increased risk for dementia . Hippocampal and medial temporal lobe volumes are larger in higher-fit adults , and physical activity training increases hippocampal perfusion , but the extent to which aerobic exercise training can modify hippocampal volume in late adulthood remains unknown . Here we show , in a r and omized controlled trial with 120 older adults , that aerobic exercise training increases the size of the anterior hippocampus , leading to improvements in spatial memory . Exercise training increased hippocampal volume by 2 % , effectively reversing age-related loss in volume by 1 to 2 y. We also demonstrate that increased hippocampal volume is associated with greater serum levels of BDNF , a mediator of neurogenesis in the dentate gyrus . Hippocampal volume declined in the control group , but higher preintervention fitness partially attenuated the decline , suggesting that fitness protects against volume loss . Cau date nucleus and thalamus volumes were unaffected by the intervention . These theoretically important findings indicate that aerobic exercise training is effective at reversing hippocampal volume loss in late adulthood , which is accompanied by improved memory function Neuropathological studies have revealed the presence of a broad variety of inflammation-related proteins ( complement factors , acute-phase proteins , pro-inflammatory cytokines ) in Alzheimer 's disease ( AD ) brains . These constituents of innate immunity are involved in several crucial pathogenic events of the underlying pathological cascade in AD , and recent studies have shown that innate immunity is involved in the etiology of late-onset AD . Genome-wide association studies have demonstrated gene loci that are linked to the complement system . Neuropathological and experimental studies indicate that fibrillar amyloid-β ( Aβ ) can activate the innate immunity-related CD14 and Toll-like receptor signaling pathways of glial cells for pro-inflammatory cytokine production . The production capacity of this pathway is under genetic control and offspring with a parental history of late-onset AD have a higher production capacity for pro-inflammatory cytokines . The activation of microglia by fibrillar Aβ deposits in the early pre clinical stages of AD can make the brain susceptible later on for a second immune challenge leading to enhanced production of pro-inflammatory cytokines . An example of a second immune challenge could be systemic inflammation in patients with pre clinical AD . Prospect i ve epidemiological studies show that elevated serum levels of acute phase reactants can be considered as a risk factor for AD . Clinical studies suggest that peripheral inflammation increases the risk of dementia , especially in patients with preexistent cognitive impairment , and accelerates further deterioration in demented patients . The view that peripheral inflammation can increase the risk of dementia in older people provides scope for prevention Mindfulness-based stress reduction ( MBSR ) is thought to reduce emotional reactivity and enhance emotion regulation in patients with social anxiety disorder ( SAD ) . The goal of this study was to examine the neural correlates of deploying attention to regulate responses to negative self-beliefs using functional magnetic resonance imaging . Participants were 56 patients with generalized SAD in a r and omized controlled trial who were assigned to MBSR or a comparison aerobic exercise ( AE ) stress reduction program . Compared to AE , MBSR yielded greater ( i ) reductions in negative emotion when implementing regulation and ( ii ) increases in attention-related parietal cortical regions . Meditation practice was associated with decreases in negative emotion and social anxiety symptom severity , and increases in attention-related parietal cortex neural responses when implementing attention regulation of negative self-beliefs . Changes in attention regulation during MBSR may be an important psychological factor that helps to explain how mindfulness meditation training benefits patients with anxiety disorders We report secondary findings from a r and omized controlled trial on the effects of exercise on memory in older adults with probable MCI . We r and omized 86 women aged 70–80 years with subjective memory complaints into one of three groups : resistance training , aerobic training , or balance and tone ( control ) . All participants exercised twice per week for six months . We measured verbal memory and learning using the Rey Auditory Verbal Learning Test ( RAVLT ) and spatial memory using a computerized test , before and after trial completion . We found that the aerobic training group remembered significantly more items in the loss after interference condition of the RAVLT compared with the control group after six months of training . In addition , both experimental groups showed improved spatial memory performance in the most difficult condition where they were required to memorize the spatial location of three items , compared with the control group . Lastly , we found a significant correlation between spatial memory performance and overall physical capacity after intervention in the aerobic training group . Taken together , our results provide support for the prevailing notion that exercise can positively impact cognitive functioning and may represent an effective strategy to improve memory in those who have begun to experience cognitive decline IMPORTANCE Few rigorous clinical trials have investigated the effectiveness of exercise on the physical functioning of patients with Alzheimer disease ( AD ) . OBJECTIVES To investigate the effects of intense and long-term exercise on the physical functioning and mobility of home-dwelling patients with AD and to explore its effects on the use and costs of health and social services . DESIGN A r and omized controlled trial . SETTING AND PARTICIPANTS A total of 210 home-dwelling patients with AD living with their spousal caregiver . INTERVENTIONS The 3 trial arms included ( 1 ) group-based exercise ( GE ; 4-hour sessions with approximately 1-hour training ) and ( 2 ) tailored home-based exercise ( HE ; 1-hour training ) , both twice a week for 1 year , and ( 3 ) a control group ( CG ) receiving the usual community care . MAIN OUTCOME MEASURES The Functional Independence Measure ( FIM ) , the Short Physical Performance Battery , and information on the use and costs of social and health care services . RESULTS All groups deteriorated in functioning during the year after r and omization , but deterioration was significantly faster in the CG than in the HE or GE group at 6 ( P = .003 ) and 12 ( P = .015 ) months . The FIM changes at 12 months were -7.1 ( 95 % CI , -3.7 to -10.5 ) , -10.3 ( 95 % CI , -6.7 to -13.9 ) , and -14.4 ( 95 % CI , -10.9 to -18.0 ) in the HE group , GE group , and CG , respectively . The HE and GE groups had significantly fewer falls than the CG during the follow-up year . The total costs of health and social services for the HE patient-caregiver dyads ( in US dollars per dyad per year ) were $ 25,112 ( 95 % CI , $ 17,642 to $ 32,581 ) ( P = .13 for comparison with the CG ) , $ 22,066 in the GE group ( $ 15,931 to $ 28,199 ; P = .03 vs CG ) , and $ 34,121 ( $ 24,559 to $ 43,681 ) in the CG . CONCLUSIONS AND RELEVANCE An intensive and long-term exercise program had beneficial effects on the physical functioning of patients with AD without increasing the total costs of health and social services or causing any significant adverse effects . TRIAL REGISTRATION anzctr.org.au Identifier : ACTRN12608000037303 OBJECTIVE To investigate the contribution of biomarkers of glucose homeostasis ( adiponectin , glucose , glycated albumin , and insulin levels ) and inflammation ( high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A(2 ) levels ) to the risk of developing Alzheimer disease ( AD ) and all-cause dementia . DESIGN Prospect i ve cohort study . SETTING Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination ( 1985 - 1988 ) and were followed up prospect ively for the development of AD and all-cause dementia . PARTICIPANTS Eight hundred forty ( 541 women , median age of 76 years ) subjects participated in the study . MAIN OUTCOME MEASURES We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age , education , body mass index , recent change in weight , APOE ε4 allele status , and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD . RESULTS Over a mean follow-up period of 13 years , 159 persons developed dementia ( including 125 with AD ) . After adjustment for other risk factors , only adiponectin in women was associated with an increased risk of all-cause dementia ( hazard ratio [ HR ] , 1.29 ; 95 % confidence interval [ CI ] , 1.00 - 1.66 ; P=.054 ) and AD ( HR , 1.33 ; 95 % CI , 1.00 - 1.76 ; P=.050 ) per 1-SD increase in adiponectin level . Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia ( HR , 1.63 ; 95 % CI , 1.03 - 2.56 ; P=.04 ) and AD ( HR , 1.87 ; 95 % CI , 1.13 - 3.10 ; P=.01 ) as compared with those with values less than the median . CONCLUSION In women , increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD Previous studies have suggested beneficial effects of physical activity on cognition . Here , we asked in an interventional approach if physical activity performed at different intensity levels would differentially affect episodic memory function . Additionally , we tried to identify mechanisms mediating these changes . Sixty-two healthy elderly individuals were assessed for level of physical activity , aerobic fitness , episodic memory score , neurotrophin and catecholamine levels , and received a magnetic resonance image of the brain at baseline and after a six months intervention of medium or low-intensity physical activity or control . Increase in total physical activity was positively associated with increase in memory score over the entire cohort , without significant differences between intensity groups . It was also positively associated with increases in local gray matter volume in prefrontal and cingulate cortex , and BDNF levels ( trend ) . In conclusion , we showed that physical activity conveys the beneficial effects on memory function independently of its intensity , possibly mediated by local gray matter volume and neurotrophic factors . Our findings may carry significant implication s for prevention of cognitive decline in the elderly Purpose Cancer patients often experience diminished cognitive function ( CF ) and quality of life ( QOL ) due to the side effects of treatment and the disease symptoms . This study evaluates the effects of medical Qigong ( MQ ; combination of gentle exercise and meditation ) on CF , QOL , and inflammation in cancer patients . Methods Eighty-one cancer patients recruited between October 2007 and May 2008 were r and omly assigned to two groups : a control group ( n = 44 ) who received the usual health care and an intervention group ( n = 37 ) who participated in a 10-week MQ program . Self-reported CF was measured by the European Organization for Research and Treatment of Cancer ( EORTC-CF ) and the Functional Assessment of Cancer Therapy — Cognitive ( FACT-Cog ) . The Functional Assessment of Cancer Therapy — General ( FACT-G ) was used to measure QOL . C-reactive protein ( CRP ) was assessed as a biomarker of inflammation . Results The MQ group self-reported significantly improved CF ( mean difference ( MD ) = 7.78 , t51 = −2.532 , p = 0.014 ) in the EORTC-CF and all the FACT-Cog subscales [ perceived cognitive impairment ( MD = 4.70 , t43 = −2.254 , p = 0.029 ) , impact of perceived cognitive impairment on QOL ( MD = 1.64 , t45 = −2.377 , p = 0.024 ) , and perceived cognitive abilities ( MD = 3.61 , t45 = −2.229 , p = 0.031 ) ] compared to controls . The MQ group also reported significantly improved QOL ( MD = 12.66 , t45 = −5.715 , p < 0.001 ) and had reduced CRP levels ( MD = −0.72 , t45 = 2.092 , p = 0.042 ) compared to controls . Conclusions Results suggest that MQ benefits cancer patients ’ self-reported CF , QOL , and inflammation . A larger r and omized controlled trial including an objective assessment of CF is planned This study examines and compares the effect of aerobic and resistance exercise on emotional and physical function among older persons with initially high or low depressive symptomatology . Data are from the Fitness , Arthritis and Seniors Trial , a trial among 439 persons 60 years or older with knee osteoarthritis r and omized to health education ( control ) , resistance exercise , or aerobic exercise groups . Depressive symptoms ( assessed by the Center for Epidemiologic Studies --Depression scale ) and physical function ( disability , walking speed , and pain ) were assessed at baseline and after 3 , 9 , and 18 months . Compared with results for the control group , aerobic exercise significantly lowered depressive symptoms over time . No such effect was observed for resistance exercise . The reduction in depressive symptoms with aerobic exercise was found both among the 98 participants with initially high depressive symptomatology and among the 340 participants with initially low depressive symptomatology and was the strongest for the most compliant persons . Aerobic and resistance exercise significantly reduced disability and pain and increased walking speed both , and to an equal extent , in persons with high depressive symptomatology and persons with low depressive symptomatology OBJECTIVES To evaluate the effects of a behavioral intervention , Tai Chi Chih ( TCC ) on circulating markers of inflammation in older adults . DESIGN A prospect i ve , r and omized , controlled trial with allocation to two arms , TCC and health education ( HE ) , 16 weeks of intervention administration , and 9 weeks follow-up . PARTICIPANTS A total of 83 healthy older adults , aged 59 to 86 years . MEASUREMENTS The primary endpoint was circulating levels of interleukin 6 ( IL-6 ) . Secondary outcomes were circulating levels of C-reactive protein , soluble IL-1 receptor antagonist , soluble IL-6 receptor , soluble intercellular adhesion molecule , and IL-18 . Severity of depressive symptoms , sleep quality , and physical activity was also assessed over the treatment trial . RESULTS Among those older adults with high levels of IL-6 at entry , a trend for a treatment group by time interaction was found ( F[1,70 ] = 3.48 , p = 0.07 ) , in which TCC produced a drop of IL-6 levels comparable to those found in TCC and HE subgroups who had low levels of IL-6 at entry ( t72 's = 0.80 , 1.63 , p 's > 0.10 ) , whereas IL-6 in HE remained higher than the TCC and HE subgroups with low entry IL-6 ( t72 = 2.47 , p = 0.02 ; t72 = 1.71 , p = 0.09 ) . Decreases in depressive symptoms in the two treatment groups correlated with decreases of IL-6 ( r = 0.28 , p < 0.05 ) . None of the other cellular markers of inflammation changed in TCC versus HE . CONCLUSION TCC can be considered a useful behavioral intervention to reduce circulating levels of IL-6 in older adults who show elevated levels of this inflammatory marker and are at risk for inflammation-related morbidity It is unclear whether the age-associated reduction in baroreflex sensitivity is modifiable by exercise training . The effects of aerobic exercise training and yoga , a non-aerobic control intervention , on the baroreflex of elderly persons was determined . Baroreflex sensitivity was quantified by the alpha-index , at high frequency ( HF ; 0.15 - 0.35 Hz , reflecting parasympathetic activity ) and mid-frequency ( MF ; 0.05 - 0.15 Hz , reflecting sympathetic activity as well ) , derived from spectral and cross-spectral analysis of spontaneous fluctuations in heart rate and blood pressure . Twenty-six ( 10 women ) sedentary , healthy , normotensive elderly ( mean 68 years , range 62 - 81 years ) subjects were studied . Fourteen ( 4 women ) of the sedentary elderly subjects completed 6 weeks of aerobic training , while the other 12 ( 6 women ) subjects completed 6 weeks of yoga . Heart rate decreased following yoga ( 69 + /- 8 vs. 61 + /- 7 min-1 , P < 0.05 ) but not aerobic training ( 66 + /- 8 vs. 63 + /- 9 min-1 , P = 0.29 ) . VO2 max increased by 11 % following yoga ( P < 0.01 ) and by 24 % following aerobic training ( P < 0.01 ) . No significant change in alpha MF ( 6.5 + /- 3.5 vs. 6.2 + /- 3.0 ms mmHg-1 , P = 0.69 ) or alpha HF ( 8.5 + /- 4.7 vs. 8.9 + /- 3.5 ms mmHg-1 , P = 0.65 ) occurred after aerobic training . Following yoga , alpha HF ( 8.0 + /- 3.6 vs. 11.5 + /- 5.2 ms mmHg-1 , P < 0.01 ) but not alpha MF ( 6.5 + /- 3.0 vs. 7.6 + /- 2.8 ms mmHg-1 , P = 0.29 ) increased . Short- duration aerobic training does not modify the alpha-index at alpha MF or alpha HF in healthy normotensive elderly subjects . alpha HF but not alpha MF increased following yoga , suggesting that these parameters are measuring distinct aspects of the baroreflex that are separately modifiable BACKGROUND Increased levels of inflammatory proteins have been found in the brains and plasma sample s of patients with dementia . Whether the levels of inflammatory proteins in plasma sample s are elevated before clinical onset of dementia is unclear . OBJECTIVE To determine whether high levels of inflammatory proteins in plasma sample s are associated with an increased risk of dementia . DESIGN AND SETTING A case-cohort study within the Rotterdam Study , a population -based prospect i ve cohort study in the Netherl and s. PARTICIPANTS The source population comprises 6713 subjects who , at baseline ( 1990 - 1993 ) , were free of dementia and underwent venipuncture . From these , we selected both a r and om subcohort of 727 subjects and 188 cases who had developed dementia at follow-up . MAIN OUTCOME MEASURES The associations between plasma levels of alpha1-antichymotrypsin , C-reactive protein , interleukin 6 , the soluble forms of intercellular adhesion molecule-1 , and vascular cell adhesion molecule-1 and the risk of dementia were examined using the Cox proportional hazards regression models . RESULTS High levels of alpha1-antichymotrypsin , interleukin 6 , and , to a lesser extent , C-reactive protein were associated with an increased risk of dementia ; rate ratios per st and ard deviation increase were 1.49 ( 95 % confidence interval , 1.23 - 1.81 ) , 1.28 ( 95 % confidence interval , 1.06 - 1.55 ) , and 1.12 ( 95 % confidence interval , 0.99 - 1.25 ) , respectively . Similar associations were observed for Alzheimer disease , whereas rate ratios of vascular dementia were higher for alpha1-antichymotrypsin and C-reactive protein . Soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not associated with dementia . CONCLUSION Plasma levels of inflammatory proteins are increased before clinical onset of dementia , Alzheimer disease , and vascular dementia OBJECTIVE To assess the benefit and harm of exercise training in adults with clinical depression . METHOD The DEMO trial is a r and omized pragmatic trial for patients with unipolar depression conducted from January 2005 through July 2007 . Patients were referred from general practitioners or psychiatrists and were eligible if they fulfilled the International Classification of Diseases , Tenth Revision , criteria for unipolar depression and were aged between 18 and 55 years . Patients ( N = 165 ) were allocated to supervised strength , aerobic , or relaxation training during a 4-month period . The primary outcome measure was the 17-item Hamilton Rating Scale for Depression ( HAM-D(17 ) ) , the secondary outcome measure was the percentage of days absent from work during the last 10 working days , and the tertiary outcome measure was effect on cognitive abilities . RESULTS At 4 months , the strength measured by 1 repetition maximum for chest press increased by a mean ( 95 % CI ) of 4.0 kg ( 0.8 to 7.2 ; p = .014 ) in the strength training group versus the relaxation group , and maximal oxygen uptake increased by 2.7 mL/kg/min ( 1.2 to 4.3 ; p = .001 ) in the aerobic group versus the relaxation group . At 4 months , the mean change in HAM-D(17 ) score was -1.3 ( -3.7 to 1.2 ; p = .3 ) and 0.4 ( -2.0 to 2.9 ; p = .3 ) for the strength and aerobic groups versus the relaxation group . At 12 months , the mean differences in HAM-D(17 ) score were -0.2 ( -2.7 to 2.3 ; p = .8 ) and 0.6 ( -1.9 to 3.1 ; p = .6 ) for the strength and aerobic groups versus the relaxation group . At 12 months , the mean differences in absence from work were -12.1 % ( -21.1 % to -3.1 % ; p = .009 ) and -2.7 % ( -11.7 % to 6.2 % ; p = .5 ) for the strength and aerobic groups versus the relaxation group . No statistically significant effect on cognitive abilities was found . CONCLUSION Our findings do not support a biologically mediated effect of exercise on symptom severity in depressed patients , but they do support a beneficial effect of strength training on work capacity . TRIAL REGISTRATION ( Clinical Trials.gov ) Identifier : NCT00103415 Objective : Lethal sepsis occurs when an excessive inflammatory response evolves that can not be controlled by physiologic anti-inflammatory mechanisms , such as the recently described cholinergic anti-inflammatory pathway . Here we studied whether the cholinergic anti-inflammatory pathway can be activated by pharmacologic cholinesterase inhibition in vivo . Design : Prospect i ve , r and omized laboratory investigation that used an established murine sepsis model . Setting : Research laboratory in a university hospital . Subjects : Female C57BL/6 mice . Interventions : Sepsis in mice was induced by cecal ligation and puncture . Animals were treated immediately with intraperitoneal injections of nicotine ( 400 & mgr;g/kg ) , physostigmine ( 80 & mgr;g/kg ) , neostigmine ( 80 & mgr;g/kg ) , or solvent three times daily for 3 days . Measurements and Main Results : Treatment with physostigmine significantly reduced lethality ( p ≤ .01 ) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine ( p ≤ .05 ) . Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-&kgr;B ( p ≤ .05 ) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-&agr ; , interleukin-1&bgr ; , and interleukin-6 ( p ≤ .001 ) , and pulmonary neutrophil invasion ( p ≤ .05 ) . Animals treated with the peripheral cholinesterase inhibitor neostigmine showed no difference compared with physostigmine-treated animals . Conclusions : Our results demonstrate that cholinesterase inhibitors can be used successfully in the treatment of sepsis in a murine model and may be of interest for clinical use OBJECTIVES This study investigated the ongoing effects of participation in a mindfulness-based stress reduction ( MBSR ) program on quality of life ( QL ) , symptoms of stress , mood and endocrine , immune and autonomic parameters in early stage breast and prostate cancer patients . METHODS Forty-nine patients with breast cancer and 10 with prostate cancer enrolled in an eight-week MBSR program that incorporated relaxation , meditation , gentle yoga and daily home practice . Demographic and health behaviors , QL , mood , stress symptoms , salivary cortisol levels , immune cell counts , intracellular cytokine production , blood pressure ( BP ) and heart rate ( HR ) were assessed pre- and post-intervention , and at 6- and 12-month follow-up . RESULTS Fifty-nine , 51 , 47 and 41 patients were assessed pre- and post-intervention and at 6- and 12-month follow-up , respectively , although not all participants provided data on all outcomes at each time point . Linear mixed modeling showed significant improvements in overall symptoms of stress which were maintained over the follow-up period . Cortisol levels decreased systematic ally over the course of the follow-up . Immune patterns over the year supported a continued reduction in Th1 ( pro-inflammatory ) cytokines . Systolic blood pressure ( SBP ) decreased from pre- to post-intervention and HR was positively associated with self-reported symptoms of stress . CONCLUSIONS MBSR program participation was associated with enhanced quality of life and decreased stress symptoms , altered cortisol and immune patterns consistent with less stress and mood disturbance , and decreased blood pressure . These pilot data represent a preliminary investigation of the longer-term relationships between MBSR program participation and a range of potentially important biomarkers During " nondamaging " exercise , skeletal muscle markedly releases interleukin (IL)-6 , and it has been suggested that one biological role of this phenomenon is to inhibit the production of tumor necrosis factor (TNF)- alpha , which is known to cause pathogenesis such as insulin resistance and atherosclerosis . To test this hypothesis , we performed three experiments in which eight healthy males either rested ( CON ) , rode a bicycle for 3 h ( EX ) , or were infused with recombinant human IL-6 ( rhIL-6 ) for 3 h while they rested . After 2.5 h , the volunteers received a bolus of Escherichia coli lipopolysaccharide endotoxin ( 0.06 ng/kg ) i.v . to induce low- grade inflammation . In CON , plasma TNF-alpha increased significantly in response to endotoxin . In contrast , during EX , which result ed in elevated IL-6 , and rhIL-6 , the endotoxin-induced increase in TNF-alpha was totally attenuated . In conclusion , physical exercise and rhIL-6 infusion at physiological concentrations inhibit endotoxin-induced TNF-alpha production in humans . Hence , these data provide the first experimental evidence that physical activity mediates antiinflammatory activity and suggest that the mechanism include IL-6 , which is produced by and released from exercising muscles This study addresses the paucity of research on the prospect i ve relationship between a range of inflammatory markers and symptoms of depression and anxiety during aging . In the Sydney Memory and Aging Study , the relationships between remitted depression , current and first onset of symptoms of depression or anxiety ( Geriatric Depression Scale and Goldberg Anxiety Scale ( GDS , GAS ) , and markers of systemic inflammation ( C-reactive protein ( CRP ) , interleukins-1β , -6 , -8 , -10 , -12 , plasminogen activator inhibitor-1 ( PAI-1 ) , serum amyloid A , tumor necrosis factor-α , and vascular adhesion molecule-1 ) were investigated . The sample consists of N=1037 non-demented community-dwelling elderly participants aged 70 - 90 years assessed at baseline and after 2-years . All analyses were adjusted for gender , age , years of education , total number of medical disorders diagnosed by a doctor , cardiovascular disorders , endocrine disorders , smoking , body mass index , currently using anti-depressants , NSAIDS or statins and diabetes mellitus . The results show a significant linear relationship between increasing levels of IL-6 and depressive symptoms at baseline only , whereas IL-8 was associated with depressed symptoms at baseline and at 2 years follow-up . In addition , IL-8 was associated with first onset of mild to moderate depressive symptoms over 2 years . Logistic regression analyses showed that PAI-1 ( OR=1.37 , 95 % CI=1.10 - 1.71 , p=0.005 ) was associated with remitted depression . Results for anxiety symptoms were negative . The findings are suggestive of IL-6 and IL-8 being associated with current symptoms and IL-8 being associated with first onset of depressive symptoms , whereas PAI-1 could be regarded as a marker of remitted depression Inflammatory responses are associated with cardiovascular disease and may be associated with dementing disease . We evaluated the long‐term prospect i ve association between dementia and high‐sensitivity C‐reactive protein , a nonspecific marker of inflammation . Data are from the cohort of Japanese American men who were seen in the second examination of the Honolulu Heart Program ( 1968–1970 ) and subsequently were reexamined 25 years later for dementia in the Honolulu‐Asia Aging Study ( 1991–1996 ) . In a r and om sub sample of 1,050 Honolulu‐Asia Aging Study cases and noncases , high‐sensitivity C‐reactive protein concentrations were measured from serum taken at the second examination ; dementia was assessed in a clinical examination that included neuroimaging and neuropsychological testing and was evaluated using international criteria . Compared with men in the lowest quartile ( < 0.34mg/L ) of high‐sensitivity C‐reactive protein , men in the upper three quartiles had a 3‐fold significantly increased risk for all dementias combined , Alzheimer 's disease , and vascular dementia . For vascular dementia , the risk increased with increasing quartile . These relations were independent of cardiovascular risk factors and disease . These data support the view that inflammatory markers may reflect not only peripheral disease , but also cerebral disease mechanisms related to dementia , and that these processes are measurable long before clinical symptoms appear Increased serum levels of inflammatory mediators have been associated with numerous disease states including atherosclerosis , Type II diabetes , hypertension , depression , and overall mortality . We hypothesized that a long-term exercise intervention among older adults would reduce serum inflammatory cytokines , and this reduction would be mediated , in part , by improvements in psychosocial factors and /or by beta-adrenergic receptor mechanisms . Adults age 64 were r and omly assigned to either an aerobic exercise treatment ( CARDIO ) or a flexibility/strength exercise treatment ( FLEX ) 3 days/week , 45 min/day for 10 months . A subgroup of subjects treated with non-selective beta(1)beta(2 ) adrenergic antagonists were included to evaluate the potential role of beta-adrenergic receptor adaptations as mediators of an exercise-induced change in inflammation . The inflammatory mediators [ C-reactive protein ( CRP ) , IL-6 , tumor necrosis factor (TNF)-alpha , and IL-18 ] and the psychosocial factors ( depression , perceived stress , optimism , sense of coherence , and social support ) were measured pre- and post-intervention . The CARDIO treatment result ed in significant reductions in serum CRP , IL-6 , and IL-18 compared to the FLEX treatment ( significant treatment x time interaction , p<.05 ) , whereas TNFalpha declined in both groups ( main effect of time , p=.001 ) . However , several psychosocial factors ( depression , optimism , and sense of coherence ) improved in both groups suggesting that the reduction of CRP , IL-6 , and IL-18 in the CARDIO group was not mediated by improvements in psychosocial scores . With respect to the potential role of beta-adrenergic receptors , both CARDIO subjects treated with beta-adrenergic antagonists and those who were not treated with those medications demonstrated similar reductions in serum CRP , IL-6 , IL-18 , and TNFalpha . In summary , we have observed that an aerobic exercise intervention can significantly reduce serum inflammatory mediators , but beta-adrenergic receptors and psychosocial factors do not appear to be involved |
13,661 | 26,458,540 | Conclusions Our review indicates that SHE rates differ between patients depending on treatment regimen .
However , SHEs are also driven by other factors . | Background Diabetes mellitus ( DM ) leads to multiple complications , including severe hypoglycaemia events ( SHEs ) .
SHEs can impact a patient ’s quality of life and compliance and may directly result in additional costs to the health care system .
The aim of this review was to evaluate the risk of severe hypoglycaemia in patients with type 1 ( T1 ) and 2 ( T2 ) DM as observed in everyday clinical practice for various drug regimens . | Abstract Aim - PREDICTIVE ( Predictable Results and Experience in Diabetes Through Intensification and Control to Target : an International Variability Evaluation ) is a multi-national study design ed to evaluate the safety and efficacy of insulin detemir ( Levemir ® ) in " real world " medical practice . The aim of the study is to report the PREDICTIVE results of the Belgian type 1 diabetic cohort . Methods – Two hundred and thirty-two patients treated with a basal-bolus insulin scheme were considered for analysis . Seventy-eight percent of those patients were previously treated with insulin glargine as a basal insulin , while 22 % received NPH , before switching to Levemir ® . Results - Mean age and duration of diabetes were 45±15 and 18±13 years , respectively ( means±SD ) . HbA1C was 8.3±1.2 % . We observed ( at weeks 12 and 26 after baseline ) a significant reduction in all hypoglycaemic events including major hypoglycaemias after switching to detemir ( p<0.0001 ) . There was no change in HbA1C . Fasting blood glucose decreased from 170±49 to 158±45 mg/dl at week 26 ( p<0.009 ) , while fasting blood glucose variability was reduced from 69±35 to 57±30 mg/dl at week 26 ( p<0.0001 ) . Total insulin doses increased during the trial from 0.74±0.28 to 0.82±0.14 U/kg/day ( p<0.0001 ) . No weight gain was observed during the study . Patient ’s satisfaction increased significantly ( from 6.3±1.5 to 7.2±1.6 at week 26 , p<0.0001 ) . Conclusion - This report from the Belgian cohort of PREDICTIVE extends the safety and efficacy data of insulin detemir in type 1 diabetic patients treated with a basal-bolus insulin scheme AIMS The IMPROVE observational study evaluated the safety profile and effectiveness of biphasic insulin aspart 30/70 ( BIAsp 30 ) in patients with type 2 diabetes in routine practice in 11 countries . METHODS Patients who initiated insulin therapy with , or switched existing insulin therapy to , BIAsp 30 in routine care were eligible for this 26-week , non-interventional observational study . Data on adverse events , hypoglycaemia and glycaemic parameters were obtained from patients ' diaries and medical notes . Question naire-based patient treatment satisfaction was also measured . We report global results and , uniquely for a diabetes observational study , country-specific data . RESULTS A total of 52,419 patients were enrolled from three pre study treatment groups : no pharmaceutical therapy ( n = 8966 , diabetes duration 2.0 years , baseline HbA1c 9.9 % ) , oral antidiabetic drugs ( OADs ) only ( n = 33,797 , diabetes duration 7.4 years , baseline HbA1c 9.2 % ) and insulin + /- OADs ( n = 9568 , diabetes duration 10.4 years , baseline HbA1c 9.3 % ) . At final visit , HbA1c , fasting and postpr and ial blood glucose were significantly reduced from baseline in all subgroups ( no pharmaceutical therapy : -3.1 % , -5.9 and -9.0 mmol/l , respectively ; OADs-only : -2.1 % , -4.1 and -6.1 mmol/l ; insulin + /- OADs : -2.0 % , -3.3 and -5.1 mmol/l ) . Major hypoglycaemia rates decreased in all subgroups ; minor hypoglycaemia increased in the insulin-naïve groups . There was no mean weight gain across subgroups . Across all countries , glycaemic parameters and major hypoglycaemia were reduced ; weight increases were seen in some countries . Treatment satisfaction increased in all subgroups and countries following BIAsp 30 therapy . CONCLUSIONS Initiating insulin with , or switching insulin therapy to , BIAsp 30 in routine care result ed in improved glycaemic control , reduced major hypoglycaemia and greater treatment satisfaction Aims : The international IMPROVE ™ observational study investigated the safety profile and effectiveness of biphasic insulin aspart 30/70 ( BIAsp 30 ) in the routine treatment of patients with type 2 diabetes . We present analyses for the subgroup of patients who switched from basal insulin to BIAsp 30 . Methods : Patients in routine care who started insulin therapy with or switched to BIAsp 30 from existing insulin regimens were eligible for this 26-week study . This analysis includes only patients previously treated with basal insulin . Outcomes including adverse events , hypoglycaemic events and glycaemic profile were recorded from patients ’ notes , recall and diaries . Results : Of the 748 patients included ( age 59.7 ± 11.8 years , diabetes duration 11.4 ± 7.3 years , baseline HbA1c 9.1 ± 1.6 % ) , 497 were previously using human neutral protamine Hagedorn ( NPH ) insulin and 245 analogue basal insulin . Overall , major and minor hypoglycaemia rates decreased from baseline to final visit ( major : 0.171 to 0.011 ; minor : 9.70 to 5.89 events/patient-year ) and were similar between the subgroups . HbA1c and fasting blood glucose were significantly reduced from baseline ( NPH pre study : −1.6 % , −2.4 mmol/l ; analogue basal pre study : −1.8 % , −2.4 mmol/l ) , as was postpr and ial blood glucose , with 33.8 % of patients achieving the HbA1c target < 7 % without hypoglycaemia . Insulin dose increased slightly from pre study ( 0.33 ± 0.21 U/kg ) , baseline ( 0.40 ± 0.20 U/kg ) to final visit ( 0.52 ± 0.26 U/kg ) ; most patients ( 76 % ) followed a twice-daily regimen at final visit . Body weight did not change significantly and treatment satisfaction increased . Conclusions : Patients with type 2 diabetes inadequately controlled on basal insulins may improve their glycaemic control by intensification to BIAsp 30 therapy Background : The First Basal Insulin Evaluation ( FINE ) Asia study is a multinational , prospect i ve , observational study of insulin-naïve Type 2 diabetes mellitus ( T2DM ) patients in Asia , uncontrolled ( A1c ≥ 8 % ) on oral hypoglycemic agents , design ed to evaluate the impact of basal insulin initiation . Methods : Basal insulin was initiated with or without concomitant oral therapy and doses were adjusted individually . All treatment choices , including the decision to initiate insulin , were at the physician 's discretion to reflect real-life practice . Results : Patients ( n= 2679 ) from 11 Asian countries were enrolled ( mean [ ±SD ] duration of diabetes 9.3 ± 6.5 years ; weight 68.1 ± 12.7 kg ; A1c 9.8 ± 1.6 % ) . After 6 months of basal insulin ( NPH insulin , insulin glargine , or insulin detemir ) , A1c decreased to 7.7 ± 1.4 % ; 33.7 % patients reached A1c < 7 % . Fasting blood glucose ( FBG ) decreased from 11.7 ± 3.6 to 7.2 ± 2.5 mmol/L and 36.8 % of patients reached FBG < 6.1 mmol/L. The mean daily insulin dose prescribed increased marginally from 0.18 to 0.23 U/kg per day at baseline to 0.22–0.24 U/kg per day at Month 6 . Mean changes in body weight and reported rates of hypoglycemia were low over the duration of the study . Conclusions : Initiation of insulin therapy is still being delayed by approximately 9 years , result ing in many Asian patients developing severe hyperglycemia . Initiating insulin treatment with basal insulin was effective and safe in Asian T2DM patients in a real-world setting , but insulin needs may differ from those in Western countries BACKGROUND The Initiation of Insulin to reach A1C Target ( INITIATEplus ) trial studied the effect of self-titrating biphasic insulin aspart 70/30 ( BiAsp 30 ) twice daily during 24 weeks in insulin-naïve patients with type 2 diabetes who were poorly controlled by oral medication , and originally r and omized according to frequency of dietary counseling interventions . OBJECTIVE The purpose of this study was to compare the efficacy and tolerability of biphasic insulin aspart 70/30 ( BIAsp 30 , NovoLog Mix 70/30 ) in INITIATEplus patients ≤65 versus > 65 years old , irrespective of dietary counseling frequency , and to test the hypothesis that self-titrating BIAsp 30 in patients > 65 years old could be well-tolerated and effective in this age group . METHODS An exploratory post hoc sub analysis , using st and ard statistical methods , was performed on patients stratified according to age . Data collected from 3492 patients in the intent-to-treat population who were ≤65 years old and 716 patients who were > 65 years old compared glycosylated hemoglobin ( HbA(1c ) ) and plasma glucose changes from baseline . Hypoglycemia rates and adverse event ( AE ) incidence were compared for the tolerability population of 4007 patients ≤65 years old and 805 patients > 65 years old . RESULTS Baseline-adjusted HbA(1c ) changes for patients ≤65 versus > 65 years old were -2.38 % versus -2.73 % ( P < 0.0001 ) , with final HbA(1c ) achieving 7.55 % and 7.06 % , respectively . Thirty-nine percent of patients ≤65 years old achieved HbA(1c ) ≤7 % compared with 51 % of patients > 65 years old . Baseline-adjusted fasting plasma glucose decreases were greater for the > 65 year old population ( 85.2 vs 91.2 mg/dL ; P = 0.004 ; ≤65 vs > 65 years old , respectively ) . Minor hypoglycemia was reported in 9.7 % and 7.7 % of patients ≤65 versus > 65 years old , respectively ( 0.52 vs 0.41 episodes per patient per year [ ppy ] ; P = 0.01 ) . Major hypoglycemia occurred in 1.5 % and 3.1 % of patients ( 0.05 vs 0.14 episodes ppy , ≤65 vs > 65 years old , respectively ; P < 0.0001 ) . Nocturnal major hypoglycemia was reported for 0.4 % and 0.6 % of patients ( P = 0.0028 ) , whereas nocturnal minor hypoglycemia was reported for 3.8 % and 2.6 % ( P = 0.007 ) of patients ≤65 and > 65 years old , respectively . AEs were reported for 24 % and 28 % of patients ≤65 and > 65 years old , respectively , serious AEs were reported for 4 % and 9 % of patients , respectively , and AE-related withdrawals were reported for 1.3 % and 2 % of patients , respectively . CONCLUSIONS Self-titrated biphasic insulin aspart 70/30 was found to be well-tolerated and effective in type 2 diabetes patients > 65 years old , as well as in patients ≤65 years old . HbA(1c ) and fasting plasma glucose decreases were significantly ( P < 0.05 ) higher for patients > 65 years old versus patients ≤65 years old . Tolerability was indicated by major and minor hypoglycemia rates at or below < 0.5 episodes ppy in both age groups . Overall rates of AE and serious AEs were higher among patients > 65 years ; withdrawals related to AEs were 2 % compared with 1.3 % in the younger age group AIM To examine the criteria that may influence physicians ' choice of starting insulin in type 2 diabetes patients in routine practice in Algeria as a sub- analysis of the A₁chieve study . METHODS A₁chieve was a 24-week international , prospect i ve , non-interventional study conducted to evaluate the safety and effectiveness of biphasic insulin aspart 30 ( BIAsp 30 ) , insulin detemir ( IDet ) , or insulin aspart alone or in combination , in real-life clinical setting s. We report an analysis of baseline data from insulin-naive patients initiating basal or premix insulin from the Algeria cohort ( n = 1494 ) . Demographic and anthropometric data , blood glucose control at inclusion , microvascular complications , and pre- study therapy was compared between the two groups . RESULTS A total of 772 insulin-naive patients initiating therapy with IDet or BIAsp 30 were included in this analysis : IDet : 638 ( 83 % ) , BIAsp 30 : 134 ( 17 % ) . Most IDet-group patients initiated once-daily therapy ( n = 636 ; 99.7 % ) ; conversely , most BIAsp 30-group patients started twice-daily therapy ( n = 104 ; 77.6 % ) . Baseline factors influencing regimen choice were microvascular complications ( odds ratio [ 95 % CI ] , yes/no : 0.73 [ 0.55 , 0.98 ] ; p = 0.034 ) and HbA1c at baseline ( % , odds ratio [ 95 % CI ] 0.82 [ 0.72 , 0.94 ] ; p = 0.004 ) . CONCLUSIONS In routine practice , physicians in Algeria are more likely to prescribe basal insulin at initiation of insulin therapy in type 2 diabetes . The prescription of a premix insulin therapy correlated with poor glycaemic control and the incidence of microvascular complications AIM PRESENT ( Physicians ' Routine Evaluation of Safety and Efficacy of NovoMix 30 Therapy ) is the largest , multinational , open-labelled , uncontrolled and completed observational study of the efficacy and safety of biphasic insulin aspart 30 ( BIAsp 30 ) treatment in clinical practice . We present results of 3 months of treatment in Chinese patients with type 2 diabetes mellitus who were inadequately controlled on current treatment . METHODS Patients received BIAsp 30 treatment with or without oral antidiabetic drugs ( OADs ) . Patients were categorized according to their treatment prior to entering the study : drug-naive ( n = 3697 ) , OAD ( n = 4754 ) , insulin ( n = 2392 ) or OAD + insulin ( n = 817 ) . RESULTS At 3 months , significant reductions from baseline were observed in the mean haemoglobin A(1c ) ( HbA(1c ) ) ( -2.24 + /- 1.67 , -2.04 + /- 1.57 , -1.82 + /- 1.49 and -1.86 + /- 1.61 % ) , fasting plasma glucose ( -3.93 + /- 3.12 , -3.51 + /- 2.55 , -2.99 + /- 2.93 and -3.38 + /- 3.16 mmol/l ) and postpr and ial plasma glucose ( -7.09 + /- 4.92 , -6.51 + /- 4.02 , -5.20 + /- 4.31 and -5.50 + /- 4.32 mmol/l ) in the drug-naive , OAD , insulin and insulin + OAD groups respectively ( p < 0.001 ) . The proportions of patients in each group achieving target HbA(1c ) of less than 7 % were higher at 3 months ( 49.5 , 51.8 , 51.0 and 48.3 % ) compared with baseline ( 3.2 , 4.2 , 7.1 and 8.3 % ) . The rates of hypoglycaemic episodes ( events per patient-year ) were lower at the end of the study in all the groups compared with baseline . Hypoglycaemic episodes were mostly minor and diurnal in nature . A total of 151 adverse drug reactions were reported , of which five were serious adverse drug reaction ( SADRs ) . These SADRs were all symptoms of local hypersensitivity . CONCLUSIONS The use of BIAsp 30 monotherapy or in combination with OADs in clinical practice was efficacious and safe in Chinese patients with poorly controlled type 2 diabetes Aims This paper presents the treatment outcomes for patients intiated on biphasic insulin aspart 30 ( BIAsp 30 ) treatment : BIAsp 30-only , BIAsp 30 + sulphonylureas ( SU ) , BIAsp 30 + biguanides ( BI ) , BIAsp 30 + SU + BI , BIAsp 30 + alpha-glucosidase inhibitors ( GI ) , and BIAsp 30 + BI + thiazolidinediones ( TZD ) after failing oral antidiabetic drugs ( OADs ) treatment . Methods This was a multi-national , multi-centre , six-month , prospect i ve , open-labelled , uncontrolled , clinical experience evaluation study , with the exception of a three-month study in one country ( China ) ( “ all exclude China ” and “ China ” ) . Initiation and discontinuation of BIAsp 30 treatment were entirely at the discretion of the attending physicians . Results Mean HbA1c , FPG and PPPG were significantly reduced from baseline at three and six months in all groups ( P < 0.001 ) . In “ all exclude China ” , reductions in mean HbA1c , FPG and PPPG at six months were as follows : BIAsp 30-only group ( −2.12 ± 1.76 % points ; −4.82 ± 3.86 mmol/L ; −6.89 ± 4.74 mmol/L ) , BIAsp 30 + BI group ( −2.24 ± 1.77 % points ; −4.48 ± 3.68 mmol/L ; −6.66 ± 4.55 mmol/L ) , BIAsp 30 + SU group ( −1.95 ± 1.59 % points ; −3.98 ± 3.19 mmol/L ; −6.25 ± 4.45 mmol/L ) and BIAsp 30 + SU + BI group ( −1.78 ± 1.20 % points ; −3.57 ± 2.78 mmol/L ; −5.89 ± 3.98 mmol/L ) . The only serious adverse drug reaction was reported by the BIAsp 30-only group . In the “ China ” group , reductions in mean HbA1c , FPG and PPPG at three months were : BIAsp 30-only group ( −2.16 ± 1.52 % points ; −3.34 ± 2.49 mmol/L ; −6.29 ± 3.92 mmol/L ) , BIAsp 30 + BI group ( −2.44 ± 1.52 % points ; −4.01 ± 2.50 mmol/L ; −7.10 ± 3.96 mmol/L ) , BIAsp 30 + GI group ( −2.33 ± 1.41 % points ; −4.34 ± 2.52 mmol/L ; −7.97 ± 3.99 mmol/L ) and BIAsp 30 + BI + TZD group ( −1.21 ± 1.60 % points ; −3.50 ± 2.29 mmol/L ; −5.97 ± 3.39 mmol/L ) . No serious ADR were reported in China . The most frequent hypoglycaemic episodes were diurnal and minor in nature . Conclusions BIAsp 30 treatment in a clinical setting improved glycaemic control in type 2 diabetes patients failing OADs The prevalence of obesity and diabetes continues to rise in the US . Glucagon-like peptide-1 receptor agonist ( GLP-1RA ) is an effective treatment option for type 2 diabetes mellitus ( T2DM ) that promotes weight loss . Common and effective treatment options added to metformin therapy ( basal insulin , sulfonylureas , and pioglitazone ) contribute to weight gain , which makes the addition of GLP-1RAs advantageous . Exenatide was the first agent in this class and has recently been approved for use in combination with insulin glargine by the US Food and Drug Administration and the European Medicines Agency . Until recently , there was a lack of data examining basal insulin combined with these agents . The main purpose of this article is to review the prospect i ve interventional data on the safety and efficacy of GLP-1RAs ( exenatide , liraglutide , albiglutide , lixisenatide ) combined with basal insulin therapy in nonpregnant adults with T2DM . Data bases search ed were PubMed , Cochrane Central Register of Controlled Trials and the Data base of Systematic Review s ( inception to January 2012 ) . Abstract s presented at relevant diabetes and endocrine meetings from 2009 to 2011 were also review ed , as were reference lists of identified publications . A total of five studies met the criteria and were included in the review . Data from these studies demonstrated that this combination therapy offers advantages for the treatment of diabetes , such as additional lowering of A1c without major risk for hypoglycemia , lower basal insulin requirements , decreased postpr and ial glucose levels ( with or without fasting plasma glucose decreases ) , and weight loss , or at the very least , less weight gain . However , the gastrointestinal side effects and high cost of these agents may limit their use . This review demonstrates that adding a GLP-1RA to an existing basal insulin regimen is a reasonable treatment strategy in nonpregnant adult patients with T2DM Aims : IMPROVE ™ is an open-label , multinational , non-r and omised , 26-week observational study design ed to evaluate the safety and effectiveness of biphasic insulin aspart 30 ( BIAsp 30 ) in routine clinical practice . Here , we report data for patients switching to BIAsp 30 from human premixed insulin . Methods : Patients ( n=3856 ) with type 2 diabetes previously receiving human premixed insulin with or without oral antidiabetic drugs were eligible for inclusion . Demographic data , efficacy end-points ( HbA1c , fasting blood glucose and postpr and ial blood glucose ) and safety end-points ( serious adverse drug reactions , hypoglycaemia and adverse events ) were collected at baseline and final visit . A subgroup analysis of mean dose change was also undertaken . Results : Switching patients to BIAsp 30 result ed in significant improvements in glycaemic control combined with a reduced risk of hypoglycaemia . Patients who reached the HbA1c target ( < 7 % ) had shorter diabetes duration , lower HbA1c at baseline and needed less insulin . Over 30 % of patients were able to reach this target without experiencing hypoglycaemia over the 26-week period . Compared with asymmetric dose switching , unit-for-unit switching result ed in the highest proportion of patients reaching HbA1c target and incurred the least amount of dose titration . Conclusions : A unit-for-unit switch is the most effective as well as the simplest approach when transferring patients from biphasic human insulin 30 to BIAsp 30 The pharmacological advantages of the rapid-acting analog , insulin aspart , over human insulin have contributed to the widespread prescription of the premix , biphasic insulin aspart 30/70 ( BIAsp 30 ) , in type 1 ( T1DM ) and type 2 diabetes ( T2DM ) . This article review s the available literature on the pharmacology , efficacy and safety of BIAsp 30 in T1DM and T2DM from an online search of the PubMed data base . Following injection , BIAsp 30 reaches higher plasma insulin levels more quickly than human premix or basal insulin , giving effective reduction of postpr and ial hyperglycemia . In T1DM patients , r and omized controlled trials ( RCTs ) have shown that HbA1c reduction is similar , but postpr and ial glycemic control is better , with BIAsp 30 than with human insulin regimens . In T2DM patients , lowering of HbA1c and postpr and ial hyperglycemia with BIAsp 30 compare favorably with optimized oral antidiabetes drug treatment , insulin glargine , and , in obese patients , human premix . An increase in minor hypoglycemia with BIAsp 30 relative to basal insulin has been reported in T2DM patients , but major and nocturnal hypoglycemia rates are generally low . Findings from RCTs in T2DM patients are supported by large observational studies . In summary , BIAsp 30 once to three times daily represents a simple and effective tool for the modern management of diabetes AIMS To determine incidence rates of severe hypoglycaemia and compare incidence rates by insulin regimen in a diverse sample of youth with Type 1 diabetes from two sites . METHODS In this observational study , 255 youth ( 51 % female ) aged 9 - 15 years receiving varied insulin regimens provided data prospect ively for a median of 1.2 years . Reported episodes of severe hypoglycaemia , defined as episodes requiring help from another person for oral treatment or episodes result ing in seizure/coma , and current insulin regimens were collected systematic ally . Incidence rates were calculated and compared according to insulin regimen in bivariate and multivariate analyses . RESULTS At first encounter , participants had a median age of 12.2 years ( range 9.0 - 15.0 ) , median diabetes duration of 4.4 years ( range 1.0 - 13.0 ) and mean HbA(1c ) of 67 ± 12 mmol/mol ( 8.3 ± 1.1 % ) . The incidence rate was 37.6/100 patient-years for all severe hypoglycaemia and 9.6/100 patient-years for seizure/coma . The incidence rate for severe hypoglycaemia was 31.8/100 patient-years on continuous subcutaneous insulin infusion ( pump therapy ) , 34.4/100 patient-years on basal-bolus injections and 46.1/100 patient-years on NPH ( NPH vs. pump therapy : P = 0.04 ) . The incidence rate for seizure/coma was 4.5/100 patient-years on pump therapy , 11.1/100 patient-years on basal-bolus injections and 14.4/100 patients -years on NPH ( NPH vs. pump therapy : P = 0.004 ) . In the multivariate analysis , the rate of seizure/coma was significantly higher for those on NPH vs. pump therapy ( rate ratio 2.9 , P = 0.03 ) . CONCLUSIONS Rates of severe hypoglycaemia in youth with Type 1 diabetes remain high . Pump therapy was associated with lower rates of all severe hypoglycaemia and seizure/coma in comparison with NPH AIM To evaluate the safety and effectiveness of biphasic insulin aspart 30 ( BIAsp 30 ) in Filipino patients with type 2 diabetes previously treated with biphasic human insulin 30 ( BHI 30 ) . METHODS Safety and effectiveness outcomes were measured in all patients switching from BHI 30 to BIAsp 30 in the Filipino cohort of the 24-week , multinational , prospect i ve , non-interventional A₁chieve study . RESULTS A total of 111 Filipino patients ( mean age ± SD , 57.4 ± 12.8 years ; BMI , 25.8 ± 5.6 kg/m(2 ) ) with mean diabetes duration of 9.9 ± 7.1 years switched therapy from BHI 30 to BIAsp 30 . The mean pre- study BHI 30 dose was 0.65 ± 0.28 IU/kg and the baseline BIAsp 30 dose was 0.65 ± 0.26 U/kg titrated up to 0.70 ± 0.26 U/kg by Week 24 . No serious adverse drug reactions were reported . Overall hypoglycaemia was reduced from 5.62 to 1.98 events/patient-year . Minor and nocturnal hypoglycaemia decreased and no major hypoglycaemia was reported at Week 24 . Glucose control improved from baseline to Week 24 ( HbA1c , -2.2 ± 2.1 % [ 24 ± 23 mmol/mol ] ; FPG , -72.0 ± 71.8 mg/dL ; PPPG , -145.5 ± 125.4 mg/dL ) . A total of 24 patients achieved HbA1c levels < 7.0 % at Week 24 compared to 6 patients reporting this target at baseline . Quality of life was positively impacted at Week 24 ( change in visual analogue scores , 15.3 ± 16.9 points ) . CONCLUSION Switching from BHI 30 to BIAsp 30 improved glycaemic control without increasing the risk of hypoglycaemia In this open study of clinical practice , 142 paediatric patients with type 1 diabetes mellitus ( > 1 year duration ) , stratified by age , received pr and ial insulin ( regular or lispro ) and either once daily insulin glargine ( GLAR ; n=74 ) , titrated to target fasting blood glucose ( FBG ) levels 4.4 - 7.8 mmol/l , or NPH/semilente insulin ( NPH insulin , administered once , twice or three times daily ; n=68 ) , titrated to target FBG 4.4 - 8.9 mmol/l . Both groups were treated for 20 + /- 10 months . HbA(1c ) significantly increased in GLAR ( 7.3 + /- 1.0 % to 7.6 + /- 1.1 % ; p = 0.003 ) and NPH/semilente insulin ( 7.7 + /- 1.6 % to 8.3 + /- 1.5 % ; p = 0.0001 ) treated patients . The incidence of symptomatic hypoglycaemia was comparable between GLAR versus NPH/semilente insulin at endpoint ( 2.19 vs. 1.94 episodes/week ) ; however , the overall incidence of severe hypoglycaemia was significantly lower with GLAR versus NPH/semilente insulin ( 0.14 vs. 0.73 events/patient-year ; p = 0.002 ) . The daily insulin dose was similar between the treatment groups ; however , perceived quality of life ( QoL ) was better with GLAR . GLAR is associated with equivalent glycaemic control , less severe hypoglycaemia and improved QoL compared with NPH/semilente insulin BACKGROUND A1chieve ( ® ) ( Novo Nordisk A/S , Bagsværd , Denmark ) was a prospect i ve , multicenter , noninterventional study in 66,726 people with type 2 diabetes mellitus ( T2DM ) in 28 countries beginning biphasic insulin aspart 30 ( aspart premix ) , insulin detemir , or insulin aspart in routine clinical care . SUBJECTS AND METHODS A subgroup of 27,594 insulin-naive people began therapy with aspart premix with or without oral agents . Safety and effectiveness data were taken from clinic records at baseline and after 24 weeks . Seven regional country groupings were prespecified . RESULTS Mean final insulin dose ranged from 0.68±0.26 U/kg/day ( Middle East/Gulf ) to 0.38±0.14 U/kg/day ( South Asia ) . The baseline glycated hemoglobin ( HbA1c ) level varied from 10.5±2.0 % ( Latin America ) to 9.2±1.3 % ( South Asia ) , with reductions from -2.9±2.1 % ( Latin America ) to -1.9±1.3 % ( South Asia ) . The proportion of people reaching an HbA1c level of < 7.0 % was highest in China ( 56 % ) and lowest in North Africa ( 22 % ) . Fasting plasma glucose level reductions were from -6.4±5.3 mmol/L ( Latin America ) to -3.6±2.6 mmol/L ( South Asia ) . Most people began aspart premix twice daily , varying from 91 % ( North Africa ) to 70 % ( Latin America ) . Improvement in HbA1c increased with baseline dose frequency ( once daily , -1.5±1.4 % ; twice daily , -2.2±1.6 % ; three times daily , -2.9±2.2 % ) . CONCLUSIONS Insulin-naive people with T2DM beginning aspart premix insulin in routine clinical practice in non-western nations had clinical ly useful improvements in blood glucose control after 24 weeks in all seven regions . Improvements from baseline for glucose control variables were greater than cross-regional differences in those variables at 24 weeks AIMS Assess safety and glycaemic control in patients initiating insulin with , or switching from basal insulin to , biphasic insulin aspart 30/70 ( BIAsp 30 ) in primary care in Finl and . METHODS A non-r and omised , non-interventional , open-label , 26-week study of type 2 diabetes ( T2D ) patients prescribed BIAsp 30 by their physician , who determined starting dose , titration and injection frequency . RESULTS 496 patients provided safety data ( insulin-naïve n=197 ; prior insulin n=299 [ 84.9 % received NPH insulin ] ) . Three patients ( 0.6 % ) reported four SADRs ( three hypoglycaemia , one hypoglycaemia with unconsciousness ) . HbA1c was significantly ( p<0.0001 ) reduced after 26 weeks ' BIAsp 30 therapy ( final dose ) : insulin-naïve -1.4 % ( 44.4 IU ) ; prior insulin -1.1 % ( 77.4 IU ) . HbA1c<7.0 % was achieved by 10 % of insulin-naïve patients at baseline and 51 % at 26-week follow-up . In the prior insulin group , 7 % and 30 % of patients had HbA1c<7.0 % at baseline and 26 weeks , respectively . Minor hypoglycaemia increased significantly from baseline to study end : insulin-naïve 0.66 - 6.45 events/patient/year ( p<0.0001 ) ; prior insulin 5.11 - 8.58 events/patient/year ( p<0.05 ) . Weight increased by 1.0 kg ( insulin-naïve ) and 1.3 kg ( previous insulin ) . CONCLUSION BIAsp 30 , initiated and titrated in T2D patients in primary care in Finl and , showed a good safety profile and significantly improved glycaemic control Introduction Hypoglycemia is a complication in the management of type 2 diabetes , and elderly people are at greater risk of experiencing hypoglycemia events than younger patients . Insulin analogs achieve glycemic control with minimal risk of hypoglycemia and may therefore be a good treatment option for all patients . Methods A1chieve was an international , multicenter , prospect i ve , open-label , non-interventional , 24-week study in people with type 2 diabetes who started/switched to therapy with biphasic insulin aspart 30 , insulin detemir or insulin aspart ( alone/in combination ) in routine clinical practice . This sub- analysis evaluated clinical safety and effectiveness of insulin aspart as part of a basal-bolus regimen ( ±oral glucose-lowering drugs ) in three age-groups ( ≤40 , > 40–65 , and > 65 years ) of insulin-experienced and insulin-naive people with type 2 diabetes . Results In total , 4,032 patients were included in the sub- analysis . After 24 weeks of insulin aspart treatment , significant improvements versus baseline were observed in all age-groups for : proportion of people with ≥1 hypoglycemia events ( 18.3–27.1 % and 11.0–12.7 % , at baseline and 24 weeks , respectively ) , ≥1 major hypoglycemia events ( 3.3–6.7 % and 0–0.2 % ) , and ≥1 nocturnal hypoglycemia events ( 9.2–13.7 % and 2.9–4.9 % ) ; glycated hemoglobin ( 9.6–9.8 % and 7.4 % ) ; fasting plasma glucose ( change from baseline ranged from −3.6 to −4.4 mmol/l ) ; and post-breakfast post-pr and ial plasma glucose ( change from baseline ranged from −5.5 to −5.9 mmol/l ) . Fourteen serious adverse drug reactions were reported . Health-related quality of life was significantly improved for all age-groups ( all , p < 0.001 ) . Conclusion All age-groups showed improved glycemic control and reduced risk of hypoglycemia when starting/switching to insulin aspart therapy within a basal-bolus regimen ; this may be particularly important for elderly patients given their greater risk of hypoglycemia versus younger patients BACKGROUND The primary objective of this study was to investigate the difference in the proportion of patients with conventionally detected hypoglycemia compared with continuous glucose monitoring system ( CGMS , Medtronic MiniMed , Sylmar , CA)-detected glucose values < or = 60 mg/dL ( < or = 3.3 mmol/L ) , during the 72-h CGMS measurement period after 8 weeks ' treatment with insulin glargine . METHODS This was a multicenter ( n = 125 ) , open-label , single-arm study in patients with Type 2 diabetes mellitus ( T2DM ) on multiple daily injections . Patients received NPH insulin ( 2-week run-in ) followed by glargine ( 8-week treatment phase ) . Glucose levels were measured by CGMS and self-monitored blood glucose ( SMBG ) profiles over the 72-h pre- and post-treatment phase . RESULTS The full analysis set contained 367 patients [ male 59 % ; mean age 59.2 years ; mean body mass index 31.7 kg/m(2 ) ; mean hemoglobin A1c ( HbA1c ) 6.9 % ] . At end point , 209 patients ( 56.9 % ) experienced hypoglycemia according to CGMS ; 97 ( 26.4 % ) recorded hypoglycemia by conventional methods . CGMS- and SMBG-determined mean daytime glucose levels were similar at baseline and end point ; however , nocturnal glucose levels were significantly lower with CGMS versus SMBG at baseline [ 130.2 vs. 145.0 mg/dL ( 7.2 vs. 8.1 mmol/L ) ] and at end point [ 123.3 vs. 137.3 mg/dL ( 6.8 vs. 7.6 mmol/L ) ] . Glucose levels measured by CGMS and SMBG decreased , and HbA1c levels decreased from 6.90 % at screening to 6.67 % at end point ( P < 0.001 ) . CONCLUSIONS This study demonstrates that CGMS can be successfully employed in large clinical trial setting s in patients with T2DM . This easy-to-implement method may provide additional insights into glucose levels and valuable information regarding the time patients spend within the preferred glucose range AIM The Physicians ' Routine Evaluation of Safety and Efficacy of NovoMix 30 Therapy ( PRESENT ) study was done to assess the safety and effectiveness of biphasic insulin aspart 30 ( BIAsp 30 ) in patients with type 2 diabetes mellitus in routine clinical practice . MATERIAL S AND METHODS This was a prospect i ve , multicentric , multinational , observational study in type 2 diabetes patients . The patients were transferred to BIAsp 30 with or without oral antidiabetic drugs ( OADs ) . We present the results of 6 months of treatment in the Indian cohort ( n = 3559 ) with type 2 diabetes mellitus who were inadequately controlled on current treatment . RESULTS At three and six months , significant reductions from baseline were observed in the mean glycated haemoglobin ( HbA1c ) ( -1.32 % and -1.94 % ) , fasting plasma glucose ( -56.16 mg/dl and -75.24 mg/dl ) and post-pr and ial plasma glucose ( -88.74 mg/dl and -119.16 mg/dl ) ( p < 0.001 ) . A significantly greater proportion of patients achieved target HbAlc of less than 7 % at six months ( 31.1 % ) , compared with baseline ( 3.1 % ) , of which 70.4 % did not report hypoglycaemia . The rate of total hypoglycaemia was reduced from 3.1 events per patient-year at baseline to 1.5 events per patient-year at end of the study . Episodes were mostly minor and diurnal . Except for two serious adverse drug reactions ( ADRs ) reported by one patient at 3 months , there were no reports of ADRs during the treatment period . More than 95 % of patients and doctors were " very satisfied " or " satisfied " with BIAsp 30 treatment , compared to previous treatment . CONCLUSIONS The use of BIAsp 30 monotherapy or in combination with OADs in clinical practice was effective and safe in poorly controlled Indian type 2 diabetes patients . Both patients and doctors showed a high degree of treatment satisfaction AIMS The choice of insulin at initiation in type 2 diabetes remains controversial . The aim of this study was to assess the occurrence of self-reported severe hypoglycaemia associated with premixed insulin analogues in routine clinical care . METHODS A 12-month , prospect i ve , observational , multicentre study in patients starting a commonly prescribed premixed insulin analogue ( either insulin lispro 25/75 or biphasic insulin aspart 30/70 , twice daily ) after suboptimal glycaemic control on oral antidiabetic agents . Treatment decisions were made solely in the course of usual practice . RESULTS Study follow-up was completed by 991 ( 85.5 % ) of the 1150 patients enrolled . At baseline , mean ( SD ) age was 57.9 ( 10.1 ) years ; mean diabetes duration was 9.2 ( 5.9 ) years ; mean haemoglobin A(1c ) ( HbA(1c ) ) was 9.9 ( 1.8 ) % and the rate of severe hypoglycaemia was 0.03 episode/patient-year . At 12 months , the rate of severe hypoglycaemia was 0.04 episode/patient-year ( 95 % CI 0.023 , 0.055 episode/patient-year ) and mean insulin dose was 41.5 ( 19.4 ) units . Changes from baseline to 12 months for mean fasting plasma glucose and HbA(1c ) were -5.1 mmol/l and -2.5 % , respectively . CONCLUSIONS After initiation of premixed insulin analogues in patients with type 2 diabetes in real-world setting s , the incidence of severe hypoglycaemia was lower than expected from previously reported studies Introduction This study aim ed at determining the clinical safety and efficacy of insulin detemir ( IDet ) in combination with oral anti-diabetic drugs ( OADs ) in type 2 diabetes ( T2D ) patients from four Near East Countries ( Israel , Jordan , Pakistan and Lebanon ) . Methods This prospect i ve observational study included T2D patients previously on OADs and newly diagnosed patients initiating IDet with or without OADs , at the discretion of physicians . Safety objectives included evaluation of hypoglycemia and adverse drug reactions ( ADRs ) from baseline to Week 24 . Efficacy outcomes included baseline to Week 24 changes in glucose control parameters ( glycated hemoglobin [ HbA1c ] , fasting plasma glucose [ FPG ] and post-breakfast post-pr and ial plasma glucose [ PPPG ] ) . Change in body weight during this period was also assessed . Results A total of 2,155 patients ( mean ± SD : age 57.1 ± 11.0 years , BMI 29.4 ± 5.1 kg/m2 , average diabetes duration 9.2 ± 5.4 years ) were included . IDet dose at baseline was 0.20 ± 0.09 U/kg titrated up to 0.34 ± 0.14 U/kg by Week 24 . From baseline to Week 24 , the total number of hypoglycemic episodes increased from 1.30 to 1.37 events/patient-year , while major hypoglycemic episodes decreased from 0.15 to 0.02 events/patient-year . A total of 9 ADRs were reported , of which one event was a serious ADR . Statistically significant improvements in glucose control were reported from baseline to Week 24 ( HbA1c : 9.6 ± 1.6 % vs. 7.6 ± 1.1 % ; FPG : 201.5 ± 59.5 mg/dL vs. 124.9 ± 31.6 mg/dL ; PPPG : 264.2 ± 65.7 mg/dL vs. 167.2 ± 36.8 mg/dL ; all p < 0.0001 ) . Body weight did not change significantly after 24 weeks of IDet therapy . Conclusion IDet therapy in combination with OADs improved glycemic control without increasing the risk of hypoglycemia or weight gain OBJECTIVE To explore the safety and effectiveness of treatment with the insulin analogue , biphasic insulin aspart 30 ( BIAsp 30 ) , in people with type 2 diabetes mellitus ( T2DM ) in a subgroup of a Pakistani population from the A1chieve study . METHODS A1chieve was a 24-week , international , prospect i ve , multicentre , open label , observational , non-interventional study design ed to evaluate the safety and clinical effectiveness of 66,726 people with T2DM who were initiated with basal insulin detemir , fast actinginsulin aspart , and BIAsp 30 ( 30 % soluble insulin aspart , 70 % protamine-crystallized insulin aspart ) . The study was conducted in 28 countries across Asia , Africa , Latin America , and Europe . Here , we report data from a subgroup of 762 people with T2DM from the Pakistani cohort ( insulin naïve and insulin users ) who were treated withpremix insulin ( BIAsp 30 ) + /- oral antidiabetic drugs ( OADs ) . RESULTS The decrease in HbAlc at week 24 was statistically significant in the entire cohort , the insulin naïve , and insulin users ( 1.7 + /- 1.1 % , 1.8 + /- 1.3 % and 1.7 + /- 0.9 % , respectively , p<0.001 for all).There was a statistically significant decrease in the mean fasting plasma glucose ( FPG ) and postpr and ial plasma glucose ( PPG ) from baseline toweek 24 in the entire cohort , in the insulin naïve and in the insulin users with BIAsp 30 treatment ( p<0.001 for all).No major hypoglycaemic events were reported during the entire study period . There was a statistically significant decrease in the systolic blood pressure ( SBP ) in all groups ( p<0.001 ) . The improvement in the quality of life score (QoL)was statistically significant in all groups ( p<0.001 for all ) . CONCLUSION BIAsp 30 treatment appeared to be well tolerated and effective as indicated byimproved glycaemiccontrol and QoL in people with T2DM in the Pakistani population after 24 weeks Purpose This sub- analysis of the A1chieve study evaluated the safety and effectiveness of changing from a basal-only insulin regimen to biphasic insulin aspart 30 . Methods A1chieve was an international , multicenter , prospect i ve , open-label , non-interventional , 24-week study in people with type 2 diabetes mellitus starting/switching to therapy with biphasic insulin aspart 30 , insulin detemir , or insulin aspart ( alone/in combination ) in routine clinical practice . This sub- analysis evaluated the safety and effectiveness of switching from basal insulin with either insulin glargine ( GLA group ) or insulin neutral protamine Hagedorn ( NEU group ) to biphasic insulin aspart 30 . Results A total of 2,818 participants received biphasic insulin aspart 30 ( 1,395 in the GLA group and 1,423 in the NEU group ) . After 24 weeks of treatment , there were significant reductions in the proportion of patients with at least one hypoglycemia event : total [ baseline vs. 24 weeks : 15.5 % vs. 9.7 % ( p < 0.001 ) and 12.3 % vs. 9.9 % ( p < 0.05 ) , in NEU and GLA groups , respectively ] , major [ 2.5 % vs. 0.08 % ( p < 0.001 ) and 1.2 % vs. 0.08 % ( p < 0.001 ) , in NEU and GLA groups , respectively ] and nocturnal hypoglycemia [ 7.2 % vs. 3.5 % ( p < 0.001 ) and 5.4 % vs. 3.9 % ( p < 0.05 ) , in NEU and GLA groups , respectively ] . After 24 weeks of biphasic insulin aspart 30 there were statistically significant improvements from baseline in glycated hemoglobin , fasting plasma glucose , and post-pr and ial plasma glucose levels ( p < 0.001 ) and in health-related quality of life ( p < 0.001 ) in both groups . Conclusions Biphasic insulin aspart 30 may benefit patients with poor glycemic control on basal insulin regimens who are seeking to change treatment AIMS To determine the effects on quality of life after starting insulin with , or switching to , insulin analogue therapies in the 24-week , prospect i ve , non-interventional , observational A(1)chieve study conducted across four continents in people with type 2 diabetes . METHODS Health-related quality of life ( HRQoL ) was assessed at baseline and at 24 weeks by the vali date d EQ-5D question naire ( visual analogue score [ VAS ] and five dimensions ) in 66,726 people who had started using basal insulin detemir , mealtime insulin aspart ( with or without a basal insulin ) or biphasic insulin aspart 30 . RESULTS For the overall cohort , reported HRQoL increased significantly by 13.8 points from 63.4 points at baseline to 77.2 points at 24 weeks ( p<0.001 ) ( scale 1 - 100 , 100=best health imaginable ) . Beginning or changing insulin was associated with a significant increase in HRQoL score ( + 15.0 points and + 11.1 points , respectively ) , result ing in a similar score at 24 weeks in the two population s ( 77.8 and 75.9 points ) . Reported HRQoL also increased statistically significantly in people administering any insulin analogue regimen and across all regions , although there were some marked regional differences in reported HRQoL at baseline . CONCLUSION Compared with baseline scores , beginning insulin with , or switching to , insulin analogue therapies are associated with increased Introduction This sub- analysis evaluated clinical safety and effectiveness of bolus insulin aspart [ with/without oral glucose-lowering drugs ( OGLDs ) ] as the only insulin therapy . Methods A1chieve was an international , multicenter , prospect i ve , open-label , non-interventional , observational , 24-week study in people with type 2 diabetes mellitus starting/switching to biphasic insulin aspart 30 , insulin detemir or insulin aspart treatment ( alone/in combination ) in routine clinical practice . This sub- analysis evaluated clinical safety and effectiveness of bolus insulin aspart ( ±OGLDs ) as the only insulin therapy . Data were analyzed for all patients , insulin-experienced and insulin-naive sub-groups , and sub-groups defined by the number of OGLDs prescribed at baseline ( no OGLDs , one OGLD or ≥two OGLDs ) . Safety and effectiveness endpoints were assessed at baseline and following 24 weeks ’ therapy . Results In total , 2,026 patients were included ( insulin-experienced , n = 561 ; insulin-naive , n = 1,465 ) in this sub- analysis . Significant improvements from baseline after 24 weeks ’ treatment with insulin aspart ± OGLDs were observed across all sub-groups for : glycated hemoglobin ( range of means across sub-groups −1.6 to −2.4 % ; p < 0.001 for all comparisons ) , fasting plasma glucose ( −2.5 to −3.8 mmol/l ; p < 0.001 for all comparisons ) , post-breakfast post-pr and ial glucose ( −3.4 to −5.8 mmol/l ; p < 0.001 for all comparisons ) , and health-related quality of life ( HRQoL ; p < 0.001 for all comparisons ) . The proportion of patients reporting hypoglycemia events was significantly reduced from baseline after 24 weeks ( insulin-naive cohort : 7.9–2.8 % ; p < 0.001 ; insulin-experienced cohort : 23.2–7.8 % ; p < 0.001 ) . There were no reports of major hypoglycemia events at 24 weeks ; risk of nocturnal hypoglycemia was < 0.6 events/person-year . No serious adverse drug reactions were reported . Conclusion Insulin aspart ± OGLDs is associated with significant improvements in glycemic control and HRQoL , without increased risk of hypoglycemia , in people with type 2 diabetes and sub-optimal glucose control Introduction Effective management of type 2 diabetes requires sustained glycemic control over many years , which can be particularly challenging for elderly people . This sub- analysis of the A1chieve study evaluated the clinical safety and effectiveness of biphasic insulin aspart 30 in 3 age-groups ( ≤40 , > 40–65 , and > 65 years ) of previously insulin-experienced and insulin-naïve people with type 2 diabetes . Methods A1chieve was an international , multicenter , prospect i ve , open-label , non-interventional , 24-week study in people with type 2 diabetes who had been receiving anti-diabetes medication before starting , or switching to , therapy with biphasic insulin aspart 30 , insulin detemir or insulin aspart ( alone or in combination ) in routine clinical practice . This sub- analysis evaluated clinical safety and effectiveness of biphasic insulin aspart 30 ( ±oral glucose-lowering drugs ) in different age-groups . Results Data on 40,122 participants were included . In all age-groups , the proportion of participants experiencing any hypoglycemia , major hypoglycemia or nocturnal hypoglycemia was significantly reduced from baseline , except for the following in insulin-naïve patients : a significant increase in any hypoglycemia in patients aged > 65 years ; no change in any hypoglycemia , major hypoglycemia , and nocturnal hypoglycemia in patients aged > 40–65 , ≤40 , and > 65 years , respectively . Significant improvements at 24 weeks vs. baseline were observed in insulin-experienced and insulin-naïve participants for : glycated hemoglobin ( change from baseline ranged from −1.8 % to −2.4 % ) ; fasting plasma glucose ( from −3.0 to −4.3 mmol/l ) ; post-breakfast post-pr and ial plasma glucose ( from −4.1 to −6.5 mmol/l ) ; and health-related quality of life ( HRQoL ) . Sixteen serious adverse drug reactions were reported . Conclusion After 24-week treatment with biphasic insulin aspart 30 , all age-groups of insulin-experienced and insulin-naïve patients experienced significantly improved glycemic control and HRQoL ; incidence of hypoglycemia was generally reduced . The tolerability and effectiveness of biphasic insulin aspart 30 may benefit all age-groups OBJECTIVES To assess the effect of a particular insulin regimen called " functional insulin therapy " using a short-acting insulin analog on the risk of severe hypoglycemia and the HbA(1c ) level among patients already under intensive insulin therapy . DESIGN A cohort of 110 patients with type 1 diabetes receiving intensive insulin therapy with regular insulin for several years was followed during one year after initiation of functional insulin therapy ( FIT ) with a short-acting insulin analog . The glycemic control was assessed by the mean value of the last three HbA(1c ) assays before the initiation of FIT and then by the mean of the following three . The number of severe hypoglycemic episodes/patient/year during the year preceding and the year following the initiation of FIT was recorded . RESULTS The mean HbA(1c ) level decreased on average by 0.7 percent during the 12-month study ( p=0.0001 ) and the number of episodes of severe hypoglycemia fell to 75 % of its previous level ( p<0.05 ) . CONCLUSION Substitution of intensive insulin therapy using regular insulin for functional insulin therapy using short-acting insulin analog may improve glycemic control and reduce the risk of severe hypoglycemia AIM ( S ) The aim of the PREDICTIVE study , a large , multinational observational trial , was to evaluate the efficacy and safety of insulin detemir ( IDet ) in routine clinical practice . METHODS Twelve-week follow-up data from patients with type 1 ( T1D ) or type 2 ( T2D ) diabetes in the European cohort switched from once ( qd ) or twice ( bid ) daily insulin glargine ( IGlarg ) ( + /-oral antidiabetic therapy ) to qd IDet in a basal-bolus regimen . End-points , assessed from patient recall/diaries , included incidence of serious adverse drug reactions , glycaemic parameters , hypoglycaemia and weight change . RESULTS The analysis included 1285 patients with T1D ( n = 508 ) or T2D ( n = 777 ) . At 12 weeks , glycosylated haemoglobin ( HbA1c ) was significantly reduced ( qd IGlarg to qd IDet : T1D , -0.47 % ; T2D , -0.51 % ; p < 0.0001 for both ; bid IGlarg to qd IDet : T1D , -0.31 % ; T2D , -0.89 % , p < 0.05 for both ) . Fasting blood glucose ( FBG ) and FBG variability were also reduced . Reductions in overall , major and nocturnal hypoglycaemic events were observed after switching from qd IGlarg to qd IDet ( overall , T1D , 39.7 - 18.85 episodes/patient-year ; overall , T2D , 11.57 - 2.99 episodes/patient-year , p < 0.0001 for both ) . Similar reductions were observed in bid IGlarg to qd IDet patients . Mean weight change was -0.3 to -0.4 kg across patient groups . DISCUSSION Switching from IGlarg to qd IDet was associated with improvements in glycaemic parameters with no associated increase in hypoglycaemic episodes or weight gain . CONCLUSION Patients with T1D and T2D may be switched from IGlarg to qd IDet as part of a basal-bolus regimen Objective : PREDICTIVE ( Predictable Results and Experience in Diabetes through Intensification and Control to Target : an International Variability Evaluation ) is a large , multinational , open-label , prospect i ve , observational study addressed to assess the efficacy and safety of insulin detemir in clinical practice . This paper reports 26 weeks of follow-up data , from 1298 type 2 diabetes patients from Italy . Research design and methods : In this observational study , the primary end point was the incidence of serious adverse drug reactions ( SADRs ) , including major hypoglycemia . Secondary end points were : hemoglobin A1c ( HbA1c ) , mean self-monitored fasting glucose , within-patient fasting glucose variability and body weight change . Results : Insulin detemir significantly improved glycemic control , with a decrease in mean HbA1c , fasting glucose and within-patient fasting glucose variability . Interestingly , the improvements in glycemic control occurred in association with a small , but significant reduction in weight . The safety results of this study showed that 26 weeks of treatment with insulin detemir was associated with a very low rate of SADRs ( only 14 events ) , which mainly consisted of hypoglycemia ( 78 % , of which 42 % were major hypoglycemia ) . Conclusions : Insulin detemir improves glycemic control , with low risk of hypoglycemia , no weight gain and an excellent safety profile ; these data support the overall findings of PREDICTIVE BACKGROUND Continuous subcutaneous insulin infusion ( CSII ) patients experience switches of pump systems on a regular basis . We investigated the impact of transition from older pumps to the Accu-Chek ( ® ) Combo system ( Roche Diagnostics Deutschl and GmbH , Mannheim , Germany ) on a patient 's glycemic control and diabetes management . PATIENTS AND METHODS In total , 299 patients ( 172 female , 127 male ; mean±SD age , 39.4±15.2 years ; CSII duration , 7.0±5.2 years ) were enrolled by 61 European sites into this uncontrolled prospect i ve trial . Glycemic control , safety , and diabetes management parameters were measured at baseline and after 3 and 6 months . Changes from baseline were analyzed . RESULTS After transition to the new insulin pump , mean±SD hemoglobin A1c ( HbA1c ) values decreased from 7.8±1.1 % ( baseline ) to 7.7±1.1 % ( end point ) . The proportion of patients with HbA1c < 7.0 % was slightly higher at the end of the study ( 29.6 % ) than at baseline ( 25.2 % ) , whereas the proportion of patients with HbA1c > 8.0 % decreased ( baseline , 36.2 % ; end point , 32.7 % ; P<0.05 ) . The number of hypoglycemic episodes ( blood glucose<70 mg/dL ) improved slightly during the study ( baseline , 40.4±34.0 events/quarter ; end point , 39.2±33.9 events/quarter ) . Glycemic control improved significantly in the group with an initial HbA1c > 8.0 % ( -0.46 % ; P<0.001 ) and remained solidly stable in the group with an initial HbA1c < 7 % ( + 0.04 % ; not significant ) . Short-term ( <3 years ) pump users ( n=48 ) had a larger HbA1c decrease ( -0.40 % ) than long-term ( ≥3 years ) users ( n=251 ) ( -0.07 % ; P<0.05 ) . The number of blood glucose measurements increased ( 3.7±1.9/day vs. 4.4±1.8/day ; P<0.05 ) , whereas the number of insulin boluses decreased ( 5.1±1.9/day vs. 4.6±1.5/day ; P<0.05 ) during the study . CONCLUSIONS Transition from older pump systems to the Accu-Chek Combo system in a large patient population result ed in stable glycemic control with significant improvements in HbA1c in patients with unsatisfactory baseline HbA1c and shorter pump use . Increased frequency of self-monitoring of blood glucose and decrease of bolus frequency could suggest a more confident diabetes management and a reduced need for correction boluses Background The effectiveness and safety of initiating biphasic insulin aspart 30 in patients who were poorly controlled on oral glucose‐lowering drugs were studied in r and omized controlled trials , while results from clinical practice remain limited . This subgroup analysis was to provide such findings from a large‐scale non‐interventional study . Methods A1chieve was a multinational , prospect i ve , open‐label , non‐interventional , 24‐week study in patients with type 2 diabetes initiating insulin analogues in 28 countries across Asia , Africa , Europe , and Latin America . After physician had taken the decision to use this insulin , any patient with type 2 diabetes who was not treated with or who had started the study insulin within 4 weeks before inclusion was eligible . Patients were treated with study insulin alone or in combination with oral glucose‐lowering drugs . Data on adverse drug reactions , hypoglycemia and glycemic control were collected at baseline , week 12 and 24 . This is a report of a Chinese subgroup analysis from the A1chieve study . Results Totally , 4 100 patients constituted this subgroup . No serious adverse drug reactions were reported . Rates of total , major , nocturnal hypoglycemic events ( events/patient per year ) were 1.47 , 0.10 , 0.31 at baseline and 1.35 , 0.00 , 0.22 at week 24 , respectively . Glycemic control was improved as measured by hemoglobin A1c ( mean 9.3 % to 7.0 % , reduction ‐2.3 % ) , fasting plasma glucose ( mean 10.2 to 6.8 mmol/L , reduction ‐3.5 mmol/L ) and postpr and ial plasma glucose ( mean 14.4 to 8.8 mmol/L , reduction ‐5.6 mmol/L ) , all P < 0.001 . Change in mean body weight was + 0.3 kg ( P < 0.001 ) . Conclusion In this subgroup analysis of the A1chieve study , biphasic insulin aspart 30 improved glycemic control with low risk of hypoglycemia AIM To compare the efficacy and safety of premixed insulin aspart ( 30 % free and 70 % protamine-bound , BIAsp 30 ) with human insulin premix ( BHI 30 ) used in a twice-daily injection regimen in people with Type 1 and Type 2 diabetes . METHODS People with Type 1 and Type 2 diabetes ( n = 294 ) using twice-daily insulin were r and omized to a 12-week open-label comparison of BIAsp 30 and BHI 30 . Efficacy was assessed by analysis of variance of 12-week data , adjusted for baseline level . RESULTS BIAsp 30 was as effective as BHI 30 based on the primary efficacy measure , HbA1c , mean difference -0.01 ( 90 % confidence interval ( CI ) -0.14 ; 0.12 ) % Hb . Meal-time self-measured blood glucose increment averaged over the three main meals was significantly lower in the BIAsp 30 group than in the BHI 30 group ( -0.68 ( -1.20 ; -0.16 ) mmol/l ; P < 0.02 ) . Significant improvements were observed after breakfast , before lunch , after dinner and at bedtime ( P < 0.02 - 0.05 ) , with blood glucose around 1.0 mmol/l lower in the BIAsp 30 group . The number of major hypoglycaemic episodes with BIAsp 30 was half that with BHI 30 . However , the overall risk of both minor and major hypoglycaemia did not differ significantly between treatments . CONCLUSION Post-pr and ial glycaemic control was significantly improved , without increasing the risk of hypoglycaemia , and overall control was similar when people with Type 1 and Type 2 diabetes were treated on a twice-daily regimen with immediate premeal injections of BIAsp 30 compared with BHI 30 AIMS The IMPROVE study is a multinational , open-label , non-r and omised , 26-week observational study assessing the safety and effectiveness of biphasic insulin aspart 30 ( BIAsp 30 ) treatment in type 2 diabetes in routine clinical practice . The principal aims of this report were to characterise the baseline population and physicians ' treatment decisions . METHODS Patients with type 2 diabetes who required insulin and whose physician had decided to initiate BIAsp 30 were eligible . At baseline , demographic data and detailed medical histories were collected and physicians recorded their reasons for starting BIAsp 30 , the glycaemic targets set and the regimens chosen . RESULTS Data from 51,286 patients were included in analyses . Baseline glycaemic control was poor in all eight countries in the present analysis and in all pre study treatment groups [ no therapy , oral antidiabetic drugs ( OADs ) only , insulin with or without OADs ] , and the rates of vascular complications were high . Although the management of each of the three main measures of glycaemic control were key reasons for starting BIAsp 30 , target- setting for postpr and ial glucose levels was variable . A twice-daily regimen was used to start BIAsp 30 therapy for 80 % or more of patients . CONCLUSIONS The IMPROVE baseline data reaffirm the global nature of poor glycaemic control in type 2 diabetes and echo the concerns that initiation of therapy , particularly insulin , is commonly delayed in clinical practice . Although postpr and ial glucose control was a key driver for physicians ' choice of BIAsp 30 , this was not consistently reflected in the targets set The prevalence of diabetes is increasing worldwide and India st and s second next only to china . The management of diabetes in real life setting s needs to be evaluated for deriving better management practice s. A1chieve observational study evaluated the use of modern insulin in real life setting s. This was a 24-week , international , prospect i ve , multicenter , non-interventional , observational study of people with type 2 diabetes . India recruited with 20,554 subjects and a total of 1815 patients were enrolled to receive insulin aspart as bolus insulin therapy of whom 1450 ( 79.9 % ) were insulin naïve and 365 ( 20.1 % ) were insulin users . At the end of 24 weeks , only one SAE was reported in this study and overall hypoglycemia events per patient year decreased from 2.49 ( 348 episodes ) to 0.17 ( 20 episodes ) . There were no major hypoglycemic episodes reported in either insulin naive or insulin treated subjects . There was a significant improvement in the HbA(1c ) values from the baseline in both insulin naive and insulin users . The mean HbA(1c ) value was reduced from 9.5 to 7.4 ( p < 0.001 ) for insulin naïve subjects and from 9.2 to 7.7 ( p < 0.001 ) in insulin experienced subjects . Fasting plasma glucose values decreased by 70 mg/dL and 50 mg/dL in insulin naive and insulin experienced , respectively and the difference from baseline was statistically significant ( P < 0.001 ) . The post pr and ial glucose value was also significantly ( p < 0.001 ) reduced by 105 mg/dL for insulin naïve subjects and 55 mg/dL for insulin experienced subjects . The composite end point was achieved by 46.6 % of insulin naive and 38.1 % of insulin-experienced subjects . The study concluded with good HbA(1c ) reduction along with lower incidence of hypoglycemia and better health related quality of life outcomes in both in insulin naive and insulin experienced subjects who used insulin aspart as bolus insulin treatment BACKGROUND Studies of the glucagon-like peptide-1 receptor agonists ( GLP-1RAs ) are needed to determine the durability of metabolic response and tolerability associated with long-term treatment . OBJECTIVE The present study was conducted to provide long-term data on glycemic control , weight changes , and tolerability of exenatide 10 μg BID treatment in patients with type 2 diabetes mellitus who have failed to achieve glycemic targets with oral antihyperglycemic medication . METHODS In this uncontrolled , open-label trial with treatment up to 156 weeks , patients received exenatide 10 μg BID while continuing treatment with metformin and /or a sulfonylurea ( SFU ) . Intent-to-treat ( ITT ) , 52- , 100- , and 132-week completer population s were defined . Metabolic changes were analyzed in the completer and ITT population s ; adverse events ( AEs ) were summarized in the ITT population . Descriptive statistics were used for absolute and change-from-baseline data . Within-treatment comparisons were conducted using the paired t test . RESULTS Of 155 patients in the ITT population ( mean [ SD ] : age , 59 [ 9 ] years ; 56 % female ; duration of diabetes , 9.1 [ 5.9 ] years ; weight , 88.8 [ 16.5 ] kg ; body mass index , 31.9 [ 4.7 ] kg/m(2 ) ; hemoglobin [ Hb ] A(1c ) , 8.7 % [ 1.2 % ] ) , 133 , 111 , and 103 patients completed 52 , 100 , and 132 weeks of treatment , respectively . In the ITT population , the mean ( SE ) change in HbA(1c ) from baseline to week 132 was -1.0 % ( 0.10 % ) ( P < 0.0001 ) . In patients completing 52 , 100 , and 132 weeks , HbA(1c ) changes from baseline to end point were -1.3 % ( 0.10 % ) , -1.0 % ( 0.12 % ) , and -1.0 ( 0.13 % ) ( P < 0.0001 ) , with 40 % of patients achieving HbA(1c ) < 7 % at 132 weeks . Patients in the ITT and completer population s experienced mean ( SE ) weight changes of -3.7 ( 0.39 ) kg and -3.9 ( 0.51 ) kg ( P < 0.0001 ) at week 132 . Improved glycemic control and weight loss occurred in 63 % of patients in the completer population at week 132 . In addition , 38 % of completers at week 132 achieved HbA(1c ) < 7 % without weight gain . No relationship was found between the development of antiexenatide antibodies and change in HbA(1c ) . The most common AEs were gastrointestinal in nature , reported in 46 % of patients and leading to discontinuation in 7 cases . Serious AEs were reported in 26 % of patients , and 18 % withdrew due to a treatment-emergent AE . Of 24 % of patients in whom hypoglycemia was reported , 22 % were on SFU or metformin + SFU combination , and 2 % were on metformin . CONCLUSIONS The findings from this open-label , single-arm study characterized the response to exenatide 10 μg BID for up to 132 weeks . Significant , persistent improvements in HbA(1c ) and weight were observed in patients receiving exenatide BID , with reported AEs consistent with those from studies of shorter duration . Clinical Trials.gov identifier : NCT00044668 OBJECTIVE To see if insulin glargine improves glycemic control in a clinical setting . RESEARCH DESIGN AND METHODS A question naire and electronic data base were used to assess glycemic parameters for 292 type 1 diabetic subjects taking > or = 4 injections per day and receiving glargine as their only long-acting basal insulin for at least 6 months . Sixty-three subjects were taking glargine in the morning , 125 were taking glargine in the evening , and 104 were splitting the glargine dose between the morning and evening . RESULTS The mean ( + /-S.D. ) age and duration of diabetes were 32 + /- 10 years and 15.9 + /- 10.3 years , respectively . The mean ( + /-S.E.M. ) duration s of treatment with glargine were 13.1 + /- 0.6 months , 12.2 + .- 0.4 months , and 14.3 + /- 0.5 months for the morning , evening , and split treatment groups , respectively ( P < 0.01 ) . The A1C values improved significantly from baseline for the evening and the split dosage groups or when all groups were combined . The mean basal insulin dose was significantly reduced at the end of the study in all the three groups from baseline with no change in the short-acting insulin dose . The number of severe hypoglycemic episodes decreased from 379 in the year prior to glargine treatment to 167 in the post-glargine year . The weight gain was significantly higher in the group that took the split glargine dose ( P < 0.01 ) . CONCLUSIONS Similar or improved glycemic control was achieved by administering glargine in the morning , evening , or using a split dose without any further increase in severe hypoglycemic episodes . Splitting the glargine dose did not offer any advantages in glycemic control parameters The aim was to compare clinical efficacy and safety of two treatment regimens : biphasic insulin aspart ( BIAsp ) injected at all three meals plus neutral protamine Hagedorn ( NPH ) insulin at bedtime vs. a human insulin regimen , premixed human insulin at breakfast and soluble insulin at lunch and dinner and NPH at bedtime . A total of 167 adolescents ( 80 males and 87 females ) with type 1 diabetes was included in the trial ( multinational , r and omized , open-label , and parallel group ) . Each subject received either of two treatment regimens for a 4-month period . BIAsp was injected immediately before main meals , human insulin products 30 min before meals , and NPH at night . Glycemic control was monitored by eight-point evaluations ( after 6 and 16 wks ) and hemoglobin A1c ( HbA1c ) ( after 2 , 6 , and 16 wks ) . Safety evaluations included adverse events and incidence of hypoglycemic episodes . HbA1c ( mean+/- SD ) after 4 months on BIAsp ( 9.39+/- 0.14 ) was not significantly different from that with human insulin ( 9.30+/- 0.15 ) . The average postpr and ial glucose increment in the BIAsp group was about half the increment in the human insulin group ; the difference not statistically significant . The body mass index ( BMI ) increased in both groups , but significantly ( p=0.005 ) less in the BIAsp group . However , in males on BIAsp , the BMI decreased compared with those on human insulin ( p=0.007 ) . No significant group differences were found for the rate of hypoglycemic episodes . We concluded that the BIAsp regimen was associated with similar glycemic control and similar incidence of hypoglycemic episodes as human insulin . However , the BIAsp regimen caused a significantly smaller increase in BMI , particularly in males , compared with the human insulin regimen ABSTRACT Aim : The Physician 's Routine Evaluation of Safety and Efficacy of NovoMix * 30 Therapy ( PRESENT ) aims to assess the safety and efficacy of biphasic insulin aspart ( BIAsp30 ) used in routine clinical practice . Methods : This was a large , multi-national , multi-centre , prospect i ve , 6-month study in type 2 diabetes mellitus patients who were prescribed BIAsp30 . Efficacy endpoints included changes in HbA1c , fasting plasma glucose ( FPG ) , postpr and ial plasma glucose ( PPPG ) , and proportion who achieved target HbA1c < 7 % . Changes from baseline were analysed using paired t-test . Safety endpoints were incidence and rate of hypoglycaemic episodes . A subgroup of patients previously uncontrolled ( HbA1c ≥ 7.0 % ) on biphasic human insulin ( BHI ) were analysed . Results : Glycaemia improved significantly ( mean ± SD ) : HbA1c by 1.58 ± 1.69 % points ( from 9.32 ± 1.64 % to 7.70 ± 1.29 % ) , FPG by 2.92 ± 3.71 mmol/L and PPPG by 4.75 ± 4.87 mmol/L. The incidence of hypoglycaemic episodes decreased over time , from 38.7 % ( baseline ) to 20.8 % ( 6 months ) . Episodes were mostly minor ( reduced from 37.7 to 20.6 % at 6 months ) , occurring during the day ( reduced from 31.5 to 17.1 % at 6 months ) . Major episodes were less frequently reported ( reduced from 5.0 to 0.4 % at 6 months ) . The rate of hypoglycaemia ( episodes/patient year ) from baseline to end of study decreased over time for overall ( 8.9–2.2 ) , major ( 0.7–0.1 ) , minor ( 8.2–2.2 ) and nocturnal ( 2.9–0.5 ) episodes . Conclusions : In this observational study , in the type 2 diabetes mellitus patients who were poorly controlled on BHI , glycaemia improved when transferred to BIAsp30 , and a lower incidence or rate of hypoglycaemia was observed in these patients BACKGROUND Individual sulfonylurea agents differ in pharmacokinetic properties and clinical effects . This study aim ed to describe the usage pattern , glycemic improvement , hypoglycemia , and change in body mass index ( BMI ) observed with commonly used sulfonylureas . SUBJECTS AND METHODS Patients of either gender with type 2 diabetes mellitus ( T2DM ) , between 18 and 75 years old and requiring addition of a sulfonylurea to an ongoing regimen of oral antihyperglycemic agent(s ) , were enrolled . Glycosylated hemoglobin ( HbA1c ) and BMI were assessed at both baseline and the end of 12 weeks of follow-up . The hypoglycemia score was assessed at the end of follow-up only . RESULTS In total , 1,069 patients were enrolled in the study , of whom 950 were considered evaluable . After a mean follow-up of 14.34±2.80 weeks , the HbA1c level decreased by 0.86±2.28 % , BMI increased by 0.13±0.78 kg/m2 , and mean hypoglycemia score was 0.98±1.42 . A weak negative , statistically significant correlation ( r = -0.093 ; P=0.0044 ) between hypoglycemic scores and increase in BMI was observed . No correlation was observed between change in HbA1c level and change in BMI . Glimepiride was the most commonly prescribed sulfonylurea ( 75.3 % ) . For patients on glimepiride , a weak positive , statistically significant correlation ( r=0.098 ; P=0.0082 ) between its dose and the hypoglycemic score was observed . CONCLUSIONS Various sulfonylurea agents appear to differ in their effect on glycemic control , tendency to cause hypoglycemia , and gain in BMI . Hypoglycemia caused by these agents appears not only to be dose related , but also correlates inversely with gain in BMI The objective of this study was to evaluate the efficacy and safety of stepwise introduction of insulin lispro mix 50 ( LM50 ) from once to 3 times daily in Japanese patients with type 2 diabetes mellitus inadequately controlled by oral therapy . This was a multicenter , open-label , non-r and omized trial consisting of three 16-week periods ( 48 weeks total ) ; all patients were given once-daily injections of LM50 in Period 1 . The regimen was intensified to twice daily in Period 2 , and 3 times daily in Period 3 if HbA1c was ≥ 6.9 % before the start of the period . A total of 135 patients were enrolled , and 116 patients completed the study . Main baseline characteristics of enrolled patients were a mean age of 60.3 years , mean diabetes duration of 11.4 years , mean BMI of 25.2 kg/m(2 ) , and mean HbA1c of 8.71 % . The percentages of patients who achieved HbA1c levels < 6.9 % and < 7.4 % at endpoint were 18.5 % ( 25/135 patients ) and 52.6 % ( 71/135 patients ) , respectively . Mean HbA1c decreased significantly from 8.70 % to 7.44 % ( p<0.001 ) . The incidence of hypoglycemic episodes over the treatment periods was 65.9 % ( 89/135 patients ) ; severe hypoglycemia occurred in 2.2 % ( 3/135 patients ) . There were no other clinical ly significant safety issues related to the study drug . Stepwise introduction of LM50 from once to 3 times daily can be a safe , effective , and simple therapy for Japanese patients with type 2 diabetes mellitus inadequately controlled by oral therapy OBJECTIVES Monitoring efficacy of insulin glargine administered to patients with diabetes mellitus type 2 ( DMT2 ) in combination with rapid-action insulin and analogues , where the hitherto fixed-mixture insulin therapy failed to achieve a satisfactory glycaemic control ( HbA1c < 7 % ) following a six-month fixed-mixture insulin therapy . DESIGN Open , observational , multicentric , non comparative , prospect i ve product registry . RESULTS 9-month prospect i ve observational study recruited DMT2 patients previously uncontrolled on premixed insulin ( HbA1c > 7 % ) . Total of 278 subjects were documented in the study . At 9 months of follow-up 45,3 % of patients reached a target HbA1c level < 7 % with a mean HbA1c change from 9.63 + /- 1.64 % to 7.10 + /- 0.77 % ( p<0.01 ) . Fasting plasma glucose values decreased from 12.7 + /- 4.3 mmol/L to 6.6 + /- 1.4 mmol/L ( p<0,01 ) . 93 patients ( 33,4 % ) experienced hypoglycemia events ( 3(1 ) hypoglycemic episode ) . Insulin glargine mean starting dose was 32,4 + /- 11,5 U. This dose was increased progressively over the study visits to a final mean dose of 42,0 + /- 11,9 U ( p<0.01 ) . The mean final daily dose of rapid-acting insulin was 24.8 + /- 13.7 U and was almost unchanged during the study . Patients who did not adhere to treatment were 4.9 times more likely to fail to achieve target HbA1c level ( RR [ 95%CI ] = 4.9 [ 1.7 - 12.11 , p<0.01 ) . CONCLUSION Results from the study suggest that basal-bolus regimen consisting of insulin glargine significantly improves glycaemic control without increasing hypoglycemia risk in DMT2 population with inadequate glycaemic control on previous premixed therapy Abstract Objective : To evaluate the efficacy , safety and treatment satisfaction of insulin glargine plus oral antidiabetic drugs ( OADs ) in Chinese individuals with Type 2 diabetes inadequately controlled with premixed insulin plus OADs . Methods : In this open-label , single-arm , 16-week , phase IV study , 313 subjects with Type 2 diabetes inadequately controlled with premixed insulin plus OADs were switched to insulin glargine plus OADs . Changes in glycaemic control , incidence of hypoglycaemia and treatment satisfaction using the Diabetes Treatment Satisfaction Question naire ( DTSQ ) were evaluated . Results : Switching to insulin glargine was associated with significant reductions in levels of glycosylated haemoglobin ( HbA1c ; 8.4 ± 0.6 to 7.9 ± 1.0 % ; p < 0.001 ) and fasting plasma glucose ( FPG ; 9.50 ± 2.10 to 6.58 ± 2.07 mmol/L ; p < 0.001 ) . A total of 32.9 % of subjects experienced hypoglycaemia , including two cases of severe hypoglycaemia . Treatment satisfaction was improved with insulin glargine ( DTSQ 8-item scores , all p < 0.001 ) . Logistic regression analysis showed a significant association between baseline HbA1c , disease duration , endpoint FPG and HbA1c < 7 % . Conclusion : This single-arm study suggested that switching to insulin glargine plus OADs significantly improved glycaemic control , with a low incidence of hypoglycaemia , in patients with Type 2 diabetes uncontrolled on premixed insulin plus OADs . Switching to insulin glargine was also associated with better patient treatment satisfaction compared with previous treatment . The main limitations to this study are the open-label design and the lack of a control arm BACKGROUND The goal of new therapies introduced for type 1 diabetes should be to decrease hypoglycemic episodes while improving glycemic control . METHODS A data base was used to computer match the baseline A1C values in 196 subjects with type 1 diabetes receiving multiple daily injections ( MDI ) consisting of four or more injections per day . There were 98 patients transferred from NPH to insulin glargine ( Lantus , Aventis Pharmaceuticals , Bridgewater , NJ ) , and 98 patients remained on NPH throughout the study . The gender distribution and mean age ( approximately 32 years ) , duration of diabetes ( approximately 16 years ) , and duration of treatment ( approximately 13 months ) were not significantly different between the groups . The majority of patients were well controlled ( > 50 % in both groups had an A1C < 7 % ) . RESULTS The mean A1c values were not significantly different in the groups at baseline or at follow-up . Severe hypoglycemic episodes per patient per year were significantly lower in the glargine group compared with the NPH group ( 0.5 vs. 1.2 , respectively ; P = 0.04 ) . The mean end-of- study total ( P = 0.03 ) and long-acting ( P = 0.0001 ) doses were significantly reduced from baseline in the group that switched to glargine , but not in the group that remained on NPH , with no change in the short-acting dose in either group . The weight gain was significantly higher in the NPH group at the end of the study ( P = 0.004 ) with no significant change in the glargine group . CONCLUSIONS Transfer to glargine treatment from NPH in MDI regimens significantly reduces severe hypoglycemic episodes despite a decline in long-acting basal insulin without significant weight gain AIMS This subgroup analysis of the A₁chieve study examined data from 15,545 people who started treatment with insulin detemir ± oral glucose-lowering drugs in routine clinical care . METHODS A₁chieve was a 24-week , international , prospect i ve , non-interventional study of people with type 2 diabetes from non-Western nations starting treatment with basal insulin detemir , bolus insulin aspart or biphasic insulin aspart 30 , alone or in combination , to evaluate their safety and effectiveness in routine clinical practice . RESULTS HbA₁c for the global cohort improved after 24 weeks from 9.5 ± 1.6 % by -2.0 ± 1.6 % [ 80 ± 17 by -22 ± 17 mmol/mol ] ( -2.1 ± 1.6 % [ -23 ± 17 mmol/mol ] for insulin-naïve participants ; -1.6 ± 1.7 % [ -17 ± 19 mmol/mol ] for prior insulin users ) . Fasting plasma glucose and postpr and ial plasma glucose were also significantly reduced ( p<0.001 ) , irrespective of prior therapy or geographical region . The incidence of major hypoglycaemia decreased significantly over 24 weeks in both the insulin-naïve and insulin-experienced groups ( p<0.0001 ) . Mean body weight decreased overall by -0.4 ± 4.0 kg and blood pressure , lipid profiles , and self-reported quality of life improved over 24 weeks for all people starting treatment with insulin detemir . CONCLUSION People with type 2 diabetes in poor glycaemic control starting treatment with insulin detemir reported significant improvements in glycaemic control with improved treatment tolerability , irrespective of prior treatment and geographical region , after 24 weeks In the United Kingdom Prospect i ve Diabetes Study ( UKPDS ) 33 , intensive blood glucose control with sulfonylureas or insulin in patients with newly diagnosed type 2 diabetes result ed in better glycemic control than conventional treatment ( 1 ) . However , the group that received intensive treatment had more hypoglycemic episodes and gained more weight than the group that received conventional treatment ( 1 ) . Overweight patients in a sub study of the same trial who received metformin gained less weight and had fewer hypoglycemic episodes than those treated with either insulin or sulfonylureas ( 2 ) . Patients who received metformin also had a more favorable outcome with respect to the development of diabetes-related end points , all-cause mortality , and stroke ( 2 ) . The UKPDS did not , however , address the usual clinical problem of how patients whose diabetes is poorly controlled with oral agents should be treated with insulin . Previous controlled trials comparing various insulin regimens in patients whose type 2 diabetes is poorly controlled with oral agents are sparse and have included small numbers of patients ; in addition , only a few have lasted 3 months or longer ( 3 - 8 ) . In the largest of these studies , patients previously treated with sulfonylureas and metformin gained more weight when they received multiple insulin injections than when they received a combination of bedtime insulin , sulfonylurea , and metformin ( 6 , 7 ) . Whether the difference in weight gain was attributable to the number of insulin injections ; serum insulin levels ; or the use of sulfonylurea , metformin , or both remained unclear . We compared four different bedtime insulin regimens to evaluate their effects on weight gain , frequency of hypoglycemic episodes , and glycemic control in patients with type 2 diabetes whose disease was inadequately controlled with sulfonylurea therapy alone . We r and omly assigned 96 patients with type 2 diabetes to 1 year of treatment with bedtime insulin plus glyburide and placebo , metformin and placebo , glyburide and metformin , or a second injection of insulin . Methods Design The study protocol , which was investigator initiated , consisted of a 6-week run-in period and 12 months of insulin therapy . Patients were recruited from regional health centers to four trial centers by using the following inclusion criteria : age 40 to 70 years , body mass index less than 35 kg/m2 , fasting blood glucose level greater than 8 mmol/L [ > 144 mg/dL ] , duration of diabetes more than 3 years , previous oral therapy with either glipizide ( > 15 mg/d ) or glyburide ( > 10 mg/d ) , and fasting serum C-peptide level more than 0.33 nmol/L ( reference range , 0.33 to 0.69 nmol/L [ > 0.99 ng/mL ; reference range , 1.0 to 2.0 ng/mL ] ) . Exclusion criteria were congestive heart failure , myocardial infa rct ion , or stroke in the past 6 months ; epilepsy or other severe disease ; liver disease , serum creatinine concentration greater than 120 mol/L [ 1.36 mg/dL ] , or macroalbuminuria ; proliferative retinopathy or severe maculopathy ; previous insulin therapy for more than 2 weeks ; excessive alcohol consumption ( > 20 g/d ) ; and night work . At each center , the patients gave written informed consent to participate in the study , which was approved by the respective ethical committees for human investigation . Six Weeks before Study Entry If they qualified for the study , patients visited the treatment center 6 weeks before the start of insulin therapy . The purpose of the run-in period was to ensure that the patients were able to accurately perform home glucose monitoring and that patients who still responded to conventional therapy would not be unnecessarily treated with insulin . The patients were asked to measure their fasting blood glucose level daily and the diurnal blood glucose level weekly until the end of the first 3 months of insulin therapy and every other week thereafter . For the diurnal blood glucose level , measurements were taken before and 1.5 hours after breakfast , lunch and dinner ; at 10 p.m. ; and at 4 a.m. Patients were asked to record daily the occurrence of hypoglycemic symptoms . Fasting plasma glucose , glycosylated hemoglobin , serum C-peptide , creatinine , and liver enzyme levels were measured , and the urinary albumin excretion rate was determined from collection of overnight urine . Three Weeks before Therapy Patient skills in home glucose monitoring and results from laboratory tests were checked . If they were acceptable , patient data were sent to the coordinating center for r and omization . R and omization Patients were r and omly assigned to four groups ( Table ) in four centers ( six patients per group within each center ) by using minimization of differences ( calculated for the variables listed below ) between the treatment groups ( 9 ) . The following variables ( relative weight of each variable is given in parentheses ) were considered : age ( 1 ) ; sex ( 0.5 ) ; body mass index ( 1.5 ) ; duration of diabetes ( 0.5 ) ; fasting glucose level ( 2 ) ; fasting serum C-peptide level ( 1.0 ) ; use of diuretics or -blocking agents ( 0.25 ) , angiotensin-converting enzyme inhibitors ( 0.25 ) , or other drugs ( 0.25 ) ; and family history of hypertension ( 0.25 ) . Table . Baseline Clinical and Biochemical Characteristics All patients in each group injected intermediate-acting neutral human isophane insulin , 100 IU/mL ( Orion , Espoo , Finl and ) , at 9 p.m. Additional therapy consisted of glyburide ( Euglucon , Orion ) , 10.5 mg , given as one 3.5-mg tablet before breakfast and two 3.5-mg tablets before dinner plus four tablets ( two before breakfast and two before dinner ) of metformin placebo ; metformin ( Metforem , Orion ) , 2 g , given as two 500-mg tablets before breakfast and two 500-mg tablets before dinner , and three tablets ( one before breakfast and two before dinner ) of glyburide placebo ; metformin , 2 g , and glyburide , 10.5 mg , given as described above ; or a second injection of neutral human isophane insulin before breakfast . Thus , the trial was only partially blinded . Insulin was injected subcutaneously in the abdomen . Initiation of Insulin Therapy and Self-Adjustment of the Insulin Dose ( 0-Month Visit ) A similar educational program was used in all participating centers . Insulin therapy was started if the fasting glucose level still exceeded 8 mmol/L ( 144 mg/dL ) . The initial bedtime insulin dosage ( measured in IU/d ) was equal to the fasting blood glucose level ( measured in mmol/L ) . Patients were given written instructions for self-adjustment of the insulin dose : increase the dose by 4 IU/d if the fasting glucose level exceeds 8 mmol/L on three consecutive measurements and by 2 IU/d if the fasting glucose level exceeds 6 mmol/L ( 108 mg/dL ) on three measurements . The goal was to decrease the fasting glucose level to less than 6 mmol/L , which was predicted to decrease the hemoglobin A1c value to less than 7.5 % ( 6 ) . Doses of oral agents remained the same . Before the start of insulin therapy , levels of glycosylated hemoglobin , fasting serum free insulin , C-peptide , triglycerides , cholesterol , and high-density lipoprotein cholesterol ; waist-to-hip ratio ( 10 ) ; and blood pressure were measured . The patients were not instructed to change their diet ( except for treatment of hypoglycemia ) or exercise habits because of insulin therapy . Follow-up Visits Follow-up visits took place at 3 and 6 weeks and every 3 months for 1 year . At these visits , body weight , blood pressure , insulin dose , and side effects were recorded and fasting blood glucose was measured . Glycosylated hemoglobin was measured every 3 months . Measurements of serum C-peptide and lipids and waist-to-hip ratio were repeated at 12 months . Compliance , monitored through pill counting , was more than 95 % for patients who completed the study . Analytical Methods Home blood glucose monitoring was performed by using the Hypocount Home Blood Glucose Monitor ( Oriola , Espoo , Finl and ) . Levels of serum free insulin ( 11 ) , glycosylated hemoglobin ( 7 ) , serum C-peptide ( 7 ) , high-density lipoprotein cholesterol ( 12 ) , total cholesterol , and triglycerides ( 7 ) were measured as previously described . Liver enzyme , serum creatinine , and blood glucose levels were measured by using st and ard techniques at each local treatment center . Statistical Analysis Comparison of normally distributed variables between the groups ( in patients who completed the trial ) during the 12-month treatment period was performed by using analysis of variance for repeated measures . If analysis of variance for repeated measures had significant results , post hoc pairwise comparisons between the four groups were performed by using a Bonferroni correction . For comparison of means when the variance was not normally distributed ( symptomatic hypoglycemic episodes ) , the Kruskal-Wallis test was used . The GraphPad Prism program ( GraphPad Software , San Diego , California ) was used to fit data relating indices of glycemia to frequency of biochemical hypoglycemias by search ing for the best fit among linear and various nonlinear regression models . Goodness of fit was evaluated by the runs test and the F test ( GraphPad Software ) . Frequencies of hypoglycemia among the groups were compared by using the chi-square test . The data collected at 0 months were used as the baseline against which changes during insulin therapy were compared . All statistical tests were two-tailed , and all data are given as the mean SE . Role of the Funding Source Funding authorities had no role in the analysis or interpretation of the data or in the subsequent decision to su bmi t the report for publication . Results Insulin Doses Initial doses of insulin were similar in all groups ( Figure 1 ) . After 12 months , the dosages of bedtime insulin were 24 3 IU/d in patients receiving bedtime insulin plus glyburide , 36 9 IU/d in patients receiving bedtime insulin plus metformin ( P<0.01 compared with all other groups ) , 20 3 IU/d in patients receiving bedtime insulin plus both oral drugs , and 24 3 IU/d in patients receiving bedtime and morning insulin . The dose of bedtime insulin was To estimate the frequency and morbidity of insulin-induced hypoglycaemia , a retrospective survey was undertaken of the frequency of severe hypoglycaemia in 600 r and omly selected patients with insulin-treated diabetes who were attending a large diabetic outpatient clinic in a teaching hospital . The result ing morbidity ( hypoglycaemia-related injuries , convulsions , and road traffic accidents ) was ascertained in 302 patients . One hundred and seventy-five ( 29.2 % ) of the 600 patients reported a total of 964 episodes of severe hypoglycaemia in the preceding year , giving an overall frequency for the group of 1.60 episodes patient-1year-1 . The frequency of severe hypoglycaemia which was documented in 544 Type 1 ( ketosis prone ) diabetic patients was double that observed in a subgroup of 56 Type 2 diabetic patients who were being treated with insulin ( 1.70 vs 0.73 episodes patient-1year-1 ) . In the subset of 302 patients , those who had experienced severe hypoglycaemia had greater morbidity associated with an estimated rate of injury of 0.04 injuries person-1year-1 . Twenty ( 6.6 % ) patients reported a total of 37 convulsions associated with hypoglycaemia , 5 of which had occurred in the preceding year ( 0.02 convulsions person-1year-1 ) . Five patients reported road traffic accidents in the preceding year which had been caused by hypoglycaemia . The only reliable predictors of severe hypoglycaemia were a history of previous severe hypoglycaemia ( p < 0.001 ) , a history of hypoglycaemia-related injury ( p < 0.001 ) or convulsion ( p < 0.001 ) , and the duration of insulin therapy ( p < 0.001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS Introduction The IMPROVE ™ study is an openlabel , nonr and omized , observational study aim ed at determining the safety and efficacy of biphasic insulin aspart 30 ( BIAsp 30 ) treatment in subjects with type 2 diabetes from 11 countries . Here , we report the baseline data of the Indian cohort . Methods All subjects with type 2 diabetes requiring insulin and considered suitable for BIAsp 30 therapy based on their physician ’s clinical judgment were eligible to enter the study . The data recorded at baseline included demographic characteristics , detailed medical histories , physician-cited reasons for starting BIAsp 30 treatment , and the chosen dosage regimens . Results The Indian cohort included 17,995 subjects with diabetes . Poor glycemic control ( glycated hemoglobin [ HbA1c ] , 8.7%–9.6 % ) was observed at baseline in all four geographical zones ( North , South , East , and West ) and pre study treatment groups ( no therapy , only oral antidiabetic drug [ OAD ] , OAD ± insulin , and OAD ± insulin ± BIAsp 30 ) . Prevalence of both micro- and macrovascular complications was high , also reflecting poor glycemic control . Improving HbA1c and fasting and postpr and ial blood glucose levels were the most common reasons for starting BIAsp 30 therapy . The subjects were prescribed a mean BIAsp 30 dose of approximately 24 IU , and a twice-daily regimen was employed in almost 80 % of subjects . Conclusion The baseline results of the IMPROVE study Indian cohort confirm the poor glycemic control and the delayed initiation and /or inadequacy of treatment in subjects with type 2 diabetes . These results also highlight the need for timely and appropriately intensive insulin-based therapy ABSTRACT Aim : The safety and efficacy of biphasic insulin aspart ( BIAsp30 ) were evaluated in patients uncontrolled on previous treatment ( human insulin ± oral hypoglycaemic agent [ OHA ] or OHA only ) in routine clinical practice . Methods : This was a large , multi-national , multi-centre , prospect i ve , 6-month study in type 2 diabetes mellitus patients who were prescribed BIAsp30 . Changes in glycated haemoglobin ( HbA1c ) , fasting plasma glucose ( FPG ) , postpr and ial plasma glucose ( PPPG ) , proportion who achieved target HbA1c < 7 % and rate of hypoglycaemic episodes were assessed . This paper evaluates outcomes in patients by diabetes duration ( < 5 , 5–10 , 10–20 or ≥ 20 years ) stratified by prior therapy . Results : After 6 months of treatment , glycaemia improved significantly across the duration subgroups . The improvement was better in insulin-naïve group versus prior insulin group : HbA1c decreased ~ 2.2%-points versus ~ 1.6%-points , FPG decreased ~ 4.5 mmol/L versus ~ 2.9 mmol/L and PPPG decreased ~ 6.8 mmol/L versus ~ 5.0 mmol/L. Target HbA1c was achieved by about one in four patients although insulin-naïve patients achieved this at comparatively lower BIAsp30 dose . Body weight remained relatively unchanged . Hypoglycaemic episodes appeared to be more frequent in the prior insulin group which decreased during the treatment period . Conclusions : According to this observational study , in clinical practice , initiating or transferring uncontrolled patients to biphasic insulin aspart improved glycaemic control without using a strict insulin algorithm WHAT IS KNOWN AND OBJECTIVE There are acknowledged benefits to continuing metformin when initiating insulin , but there appears to be growing concern over the role of sulphonylureas and thiazolidinediones when used in combination with insulin . This analysis investigates the effects of continuing or discontinuing oral antidiabetic drugs ( OADs ) following the initiation of once-daily insulin detemir . METHODS SOLVE is a 24-week , multinational observational study of insulin detemir initiation in patients with type 2 diabetes mellitus treated with one or more OADs . RESULTS In the total cohort ( n = 17 374 ) , there were significant improvements in HbA1c ( -1·3 % , 95 % CI -1·34 ; -1·27 % ) and weight ( -0·6 kg , 95 % CI -0·65 ; -0·47 kg ) , with an increase in the incidence rate of minor hypoglycaemia ( + 0·256 events ppy , P < 0·001 ) , but not severe hypoglycaemia ( -0·038 events ppy , P < 0·001 ) . Study participants had information on OAD use either prior to ( n = 17 086 ) or during insulin initiation ( n = 16 346 ) . HbA1c reductions were significantly greater in patients continuing treatment with metformin ( -1·3 % vs. -1·1 % , P < 0·01 ) , thiazolidinediones ( -1·3 % vs. -1·0 % , P < 0·01 ) and DPP-IV inhibitors ( -1·3 % vs. -0·9 % , P < 0·001 ) . Final insulin doses were significantly greater in patients discontinuing treatment with sulphonylureas ( 0·29 vs. 0·26 IU/kg , P < 0·001 ) , glinides ( 0·28 vs. 0·26 IU/kg , P < 0·01 ) , thiazolidinediones ( 0·31 vs. 0·26 IU/kg , P < 0·001 ) and DPP-IV inhibitors ( 0·35 vs. 0·29 IU/kg , P < 0·001 ) compared with patients continuing these respective agents . All patient subgroups had a mean weight loss irrespective of OAD continuation , apart from those continuing thiazolidinediones ( + 0·2 kg ) . The largest improvements in weight were seen following the withdrawal of sulphonylureas and thiazolidinediones ( -1·1 and -1·1 kg , respectively ) . WHAT IS NEW AND CONCLUSION Discontinuation ( or switching ) of OADs at the time of insulin initiation appears to be governed principally by concerns about hypoglycaemia and weight . HbA1c improvements were smaller in patients discontinuing OADs at the time of insulin initiation and may be associated with insufficient insulin titration OBJECTIVE To compare the diabetes-specific quality of life in subjects with type 1 diabetes treating their diabetes with multiple daily injections ( MDI ) to that of subjects on continuous subcutaneous insulin infusion ( CSII ) . METHODS Diabetes-specific quality of life was measured with the DSQOLS- Question naire in 81 adult subjects with type 1 diabetes on MDI and 78 subjects on CSII ( cross-sectional study ) . In addition , 19 subjects were followed prospect ively , measuring their quality of life before and after switching from MDI to CSII ( longitudinal study ) . RESULTS Preference-weighted treatment satisfaction score was significantly higher in subjects on CSII than in those on MDI in both the longitudinal ( + 63 points , 95%CI 37 - 89 ) and the cross-sectional study ( + 14 points , 95%CI 3 to 25 ) . " Diet restrictions " were significantly less of a burden for CSII subjects in both the longitudinal ( + 6 points , 95%CI 1 - 10 ) and the cross-sectional study ( + 3 points , 95%CI 0 to 6 ) . " Leisure time flexibility " ( + 3 points , 95%CI 0 to 7 ) , " Physical complaints " ( + 4 points , 95%CI 1 to 8) , " Daily hassles " ( + 4 , 95%CI 0 to 7 ) , and the overall quality of life ( + 29 points , 95%CI 3 to 54 ) were significantly better in CSII compared to MDI only in the longitudinal study . Despite a small overall rate of severe hypoglycaemia in both studies , subjects on CSII experienced fewer severe episodes than subjects on MDI . CONCLUSIONS Subjects with type 1 diabetes on CSII have a better quality of life than type 1 diabetic subjects on MDI . They are more satisfied with their treatment in respect to their metabolic goals as well as psychosocial factors , physical performance and protection from long-term complications and hypoglycaemia . Furthermore , the subjects on CSII experience greater flexibility in their daily routines , leisure time and diet than the subjects on MDI AIMS To conduct a multicentre , matched-pair cohort analysis comparing glycaemic control and adverse events of continuous subcutaneous insulin infusion ( CSII ) with multiple daily injections ( MDI ) in paediatric patients . METHODS Using st and ardized computer-based prospect i ve documentation , HbA(1c ) , insulin dose , body mass index-st and ard deviation score ( BMI -SDS ) , rate of hypoglycaemia , rate of diabetic ketoacidosis ( DKA ) and intensity of care were analysed in 434 matched pairs during a follow-up period of 3 years after initiation of MDI or CSII . RESULTS HbA(1c ) was significantly lower in the CSII group during the first year of new regimen ( CSII 7.5 + /- 0.05 vs. MDI 7.7 + /- 0.06 ; P < 0.05 ) , but rose to the same level as in the MDI group during year 3 . Insulin requirement remained significantly lower in the CSII group . The BMI -SDS increased in both study groups , with no significant difference . The rate of severe hypoglycaemia decreased significantly after the change of regimen ( CSII 17.87 + /- 2.85 vs. MDI 25.14 + /- 3.79 ; P < 0.05 ) and during year 3 of the regimen , particularly when compared with baseline ( -21 % vs. -16 % ) . The rate of DKA was lower at baseline in the CSII group and remained significantly lower over all 3 years . Intensity of care was the same in both subsets . CONCLUSIONS Employing a large cohort , this matched-pair analysis has demonstrated over a 3-year study period that CSII is a safe form of intensive insulin therapy with similar glycaemic effects , but with significantly reduced rates of hypoglycaemia and DKA and a lower insulin requirement when compared with MDI OBJECTIVE Hypoglycemia was examined in regularly employed people with insulin-treated diabetes to ascertain the frequency and consequences of this problem in the workplace . RESEARCH DESIGN AND METHODS A prospect i ve 12-month survey of 243 employed people ( age range 20 - 69 years ) with insulin-treated diabetes was performed to record the frequency , severity , and morbidity of hypoglycemia occurring at work . Details of hypoglycemic episodes included time of day , place , activity , causation , blood glucose , treatment , and morbidity . Serial HbA(1c ) measurements were recorded . RESULTS A total of 1,955 mild ( self-treated ) episodes of hypoglycemia ( 8 per person per annum ) and 238 severe ( requiring external help ) episodes ( 0.98 per person per annum ) were recorded . Of the severe hypoglycemic episodes , 148 ( 62 % ) occurred at home , 35 ( 15 % ) occurred at work in 27 ( 11 % ) people ( 0.14 episodes per person per annum ) , and 54 ( 23 % ) occurred elsewhere ; 52 % of severe episodes occurred during sleep . Of the severe hypoglycemic episodes reported , adverse events were described in 54 ( 23 % ) , with 29 losing consciousness ( 14 % ) , 21 having a seizure ( 9 % ) , 4 ( 2 % ) sustaining a head injury , 5 ( 2 % ) suffering another injury , 3 ( 1 % ) injuring someone else , and 2 ( 1 % ) damaging property . Severe hypoglycemia in the workplace was associated with six episodes of minor soft-tissue injuries . CONCLUSIONS In this cohort , severe hypoglycemia in the workplace was uncommon and seldom caused disruption or serious morbidity . On the basis of the frequency and severity of hypoglycemia observed in the present study , restriction of employment opportunities for most people with insulin-treated diabetes may be difficult to justify AIM To evaluate the safety and effectiveness of insulin analogues ( insulin aspart , insulin detemir and biphasic insulin aspart 30 , alone or in combination ) in type 2 diabetes mellitus ( T2DM ) patients in routine clinical practice in the Gulf as a subgroup of the A(1 ) chieve multi-national study . METHODS A total of 10,704 T2DM Gulf patients with uncontrolled T2DM on oral antidiabetics ± insulins other than insulin aspart , insulin detemir or biphasic insulin aspart 30 , who initiated or switched to study insulins were included and followed up for 24 weeks in the context of the A(1 ) chieve study . RESULTS Baseline HbA(1c ) ( ± SD ) was poor : 9.7 ± 1.7 % . At Week 24 , an improvement in HbA(1c ) of -2.3 ± 1.6 % was observed in the entire cohort , and -2.4 ± 1.5 % and -2.1 ± 1.7 % for insulin-naïve patients and prior insulin users respectively . Overall , rates of hypoglycaemia increased in those new to insulin therapy , whereas a reduction was observed in those switching from other insulins . A marginal reduction in body weight ( -0.8 ± 4.4 kg ) was noted in the entire cohort , whereas the overall lipid profile and systolic blood pressure ( -6.2 ± 15.3 mmHg ) improved . CONCLUSIONS Initiating or switching to insulin analogues was well tolerated and result ed in significant improvements in glycaemic control in T2DM patients in the Gulf AIM The Physicians ' Routine Evaluation of Safety and Efficacy of NovoMix 30 Therapy ( PRESENT ) study aims to assess the safety and efficacy of biphasic insulin aspart 30 ( BIAsp 30 ) in patients with type 2 diabetes mellitus in routine clinical practice . METHODS This was a 6-month , prospect i ve , multinational , multiethnic observational study involving 21 977 patients from 13 countries ( India , Iraq , Jordan , Kuwait , Lebanon , Qatar , Romania , Russia , Saudi Arabia , South Africa , South Korea , Turkey and the United Arab Emirates ) . The patients were transferred to BIAsp 30 with or without oral antidiabetic drugs ( OADs ) from prior treatment with OAD ( n = 8583 ) , insulin ( n = 5942 ) , OAD + insulin ( n = 4673 ) or diet ( i.e. treatment naive ) ( n = 1707 ) . One thous and and seventy-two patients had incomplete or no information on previous treatment . RESULTS At 3 and 6 months , significant reductions from baseline were observed in the mean haemoglobin A(1c ) ( HbA(1c ) ) ( -1.33 and -1.81 % ) , fasting plasma glucose ( -3.02 and -3.74 mmol/l ) and postpr and ial plasma glucose ( -4.76 and -5.82 mmol/l ) ( p < 0.001 ) . A significantly greater proportion of patients achieved target HbA(1c ) of less than 7 % at 3 months ( 15.3 % ) and 6 months ( 27.7 % ) compared with baseline ( 4.8 % ) ( p < 0.001 ) . Overall , the mean HbA(1c ) at 6 months was lowered in patients regardless of prior treatment : -2.15 % ( OAD ) , -1.45 % ( insulin ) , -1.47 % ( OAD + insulin ) and -2.35 % ( treatment naive ) . In the overall cohort , the rate of total hypoglycaemia was reduced from 5.4 events per patient-year at baseline to 2.2 events per patient-year at study end ( p < 0.001 ) . Among prior treatment subgroups , the rates of total hypoglycaemia were reduced from 2.5 to 2.1 events per patient-year in the OAD group , from 9.6 to 2.2 events per patient-year in the insulin group and from 7.6 to 2.5 events per patient-year in the OAD + insulin group but were increased from 1.0 to 1.8 events per patient-year in the treatment-naive group ( p < 0.001 ) . There were 444 adverse drug reactions ( ADRs ) , including 13 serious ADRs : lipodystrophy ( three events ) , symptoms of generalized hypersensitivity ( two events ) , acute painful neuropathy ( one event ) , worsening of diabetic retinopathy ( one event ) , oedema ( one event ) and unspecified ADRs ( five events ) . CONCLUSION The use of BIAsp 30 monotherapy or in combination with OADs in clinical practice was effective and safe in patients with poorly controlled type 2 diabetes mellitus AIMS This A1chieve ® study subgroup analysis examined clinical safety and effectiveness of biphasic insulin aspart 30 ( BIAsp30 ) ±OGLDs in 6323 individuals with T2D , switching from biphasic human insulin 30 ( BHI30 ) ±OGLDs . METHODS A1chieve was a 24-week , international , prospect i ve , observational , multi-centre , open-label study in individuals with T2D starting treatment with BIAsp30 , insulin detemir or insulin aspart as part of routine clinical care . RESULTS Mean baseline ( SD ) dose BHI was 0.56 ( 0.25 ) IU/kg . BIAsp30 was initiated at 0.57 ( 0.25 ) U/kg ; the daily dose was 0.62 (0.28)U/kg by Week 24 . Switching from BHI30 to BIAsp30 was associated with significant mean reduction in HbA1c of 1.7 % [ -18 mmol/mol ] ( 1.6 ) from a baseline of 9.1 % [ 76 mmol/mol ] ( p<0.001 ) ; FPG and PPG were also significantly reduced ( p<0.001 ) . Major hypoglycaemic episodes decreased from 0.69 events/patient/year at baseline to 0.03 events/patient/year at Week 24 . Minor hypoglycaemia decreased from 5.31 to 2.04 events/patient/year from baseline to study -end . Five serious adverse drug reactions ( hypoglycaemia ) were reported by five individuals ( 0.1 % ) . Mean bodyweight increased by 0.1 (3.3)kg from baseline to 24 weeks . Improved self-reported quality of life was observed . CONCLUSION Switching from BHI30 to BIAsp30 in individuals with T2D is associated with improvement in glycaemic control and reduced rates of hypoglycaemia , without tolerability or safety issues AIM To determine the safety and efficacy of insulin detemir in Indonesian patients with type 2 diabetes ( T2D ) as a sub- analysis of the 24-week , prospect i ve , multinational , non-interventional A₁chieve study . METHODS This study included 477 Indonesian T2D patients starting insulin detemir at the discretion of their physicians . Safety and efficacy was measured in routine clinical practice at baseline , interim ( around 12 weeks from baseline ) and final ( around 24 weeks from baseline ) visit . RESULTS At baseline the mean age , duration of diabetes and mean BMI were 55.3 ± 8.5 years , 5.9 ± 4.0 years and 24 ± 3.6 kg/m(2 ) , respectively . Of these patients , 78 % were insulin-naive and 22 % were prior insulin users . Glycaemic control was poor at baseline . After 24 weeks , significant reductions were observed in mean HbA1c ( 2.2 % , p < 0.001 ) , fasting plasma glucose ( 90.0 mg/dL , p < 0.001 ) and postpr and ial plasma glucose ( 115.4 mg/dL , p < 0.001 ) levels , in the entire cohort . Similar significant reductions were also seen in insulin-naive patients and prior insulin users . In the entire cohort , 32.5 % patients achieved HbA1c levels < 7.0 % while 32.0 % insulin-naive patients and 33.9 % prior insulin users achieved this target after 24 weeks . No hypoglycaemic events were reported in the entire cohort . Modest increase in body weight was noted in the insulin-naive group , while mean body weight decreased in prior insulin users after 24 weeks of insulin detemir therapy . CONCLUSION This sub- analysis suggests that insulin detemir can be a safe and effective option for initiating insulin therapy in people with T2D in Indonesia INTRODUCTION Observational studies are valuable tools for assessing the applicability of results from r and omised controlled trials to broader patient population s. They are especially important in chronic diseases such as diabetes , as they can provide a comprehensive picture of the safety and effectiveness of a particular therapy across cultures and phenotypes . MATERIAL AND METHODS Patients with type 2 diabetes who required insulin and whose physician had decided to initiate biphasic insulin aspart 30 ( BIAsp 30 ) were eligible . A total of 4117 type 2 diabetic patients were recruited to the study in Pol and , and 809 primary and secondary care physicians were involved . The aim of this study was to assess the safety and effectiveness of BIAsp 30 treatment in type 2 diabetes in routine clinical practice . RESULTS Baseline glycaemic control was poor in the Polish cohort enrolled in the IMPROVE(TM ) study , with a mean HbA(1c ) value of 9.0 + /- 1.7 % . A very high proportion of patients were thus at risk of macrovascular and microvascular complications . A twice-daily regimen for the start of BIAsp 30 therapy was the most common choice , including 72.2 % of patients at baseline . HbA(1c ) was significantly reduced by 1.66 % for the total cohort and by 3.07 % and 1.55 % in the pre- study no-therapy or oral antidiabetic drug group respectively ( p < 0.001 ) . The rates ( episodes per subject year ) of overall major hypoglycaemia were 0.012 and 0.12 at follow-up and final visits respectively . For minor hypoglycaemia rates of 5.12 per subject per year at follow-up visit and 4.54 episodes per subject per year at final visit were recorded . CONCLUSIONS BIAsp 30 appears to be an effective and flexible treatment approach and can be safely intensified to achieve glycaemic control in a majority of patients with type 2 diabetes INTRODUCTION To evaluate the clinical profile of BIAsp 30 ( 30 % soluble insulin aspart , 70 % protamine-crystallized insulin aspart ) (NovoMix ® )30 ) in type 2 diabetes patients in routine clinical practice in Iran . MATERIAL AND METHODS IMPROVE ™ was a 26-week , multinational , open-label , non-r and omized study in patients with type 2 diabetes . The safety and efficacy of BIAsp 30 were assessed at baseline and at 13 and 26 weeks . The titration of BIAsp30 was at the physician 's discretion . RESULTS In Iran , 478 patients ( 47 % male ) previously treated with oral antidiabetic drugs ( OADs ) ( N = 159 , 33.3 % ) and /or insulin other than BIAsp30 ( N = 317 , 66.3 % ) or a few who were treatment-naïve ( N = 2 , 0.4 % ) participated in the study . After 26 weeks of treatment with BIAsp 30 , the rate of reported major hypoglycaemic episodes was reduced by 88.1 % from baseline ( baseline v. Week 26 : 0.303 v. 0.037 episodes/pt-year ; p < 0.001 ) . No significant differences in minor hypoglycaemic episodes between baseline and Week 26 were found . Glycaemic control was significantly improved from baseline to Week 26 with a mean HbA(₁c ) reduction of 1.2 + /- 1.9 % . Patients ' quality of life as measured by the DiabMedSat question naire significantly improved from baseline ( 58.1 ) to the end of the study ( 75.4 , p < 0.001 ) . CONCLUSIONS BIAsp 30 therapy appeared safe and effective and improved quality of life in Iranian patients with type 2 diabetes after 26 weeks of treatment BACKGROUND Injection of insulin lispro ( LP ) before meals provides a more physiologic insulin activity profile than regular human insulin , but the relatively short duration of action of LP may allow the blood glucose ( BG ) level to increase during the late postpr and ial period ( 4 - 7 hours after meals ) unless basal insulin is optimally replaced . One approach to basal insulin optimization has been to combine small doses of NPH with LP before meals . When used in a similar fashion , premixed , fixed-ratio insulin preparations containing LP and NPL ( an LP-based intermediate-acting insulin ) may provide the basis for an optimized basal-bolus insulin regimen . OBJECTIVE This study assessed mean late postpr and ial glycemic control during treatment with a premixed formulation consisting of a high proportion of LP ( 75 % LP/25 % NPL ; H ) and a premixed formulation consisting of a medium proportion of LP ( 50 % LP/50 % NPL ; M ) . The H/M formulation was given before meals and was compared with treatment with prepr and ial LP + NPH ( LP + N ) in patients with type 1 diabetes mellitus ( DM ) . METHODS This multicenter , r and omized , open-label , 2-period crossover study was conducted at 4 centers in Italy and 1 center in France . Patients eligible for the study had type 1 DM , were > or = 18 years of age , and had a glycosylated hemoglobin ( HbA(1c ) ) < 150 % of the upper limit of normal . Patients were r and omly assigned to 1 of 2 treatment sequences : LP self-mixed with NPH before meals plus NPH alone at bedtime for 8 weeks ( LP + N ) followed by prepr and ial H or M , plus NPH alone at bedtime for 8 weeks ( H/M ) , or the opposite sequence . Assessment s included 8-point self-monitored BG profiles , HbA(1c ) , and hypoglycemia ( any sign or symptom of hypoglycemia or BG < 3.0 mmol/L [ < 54.0 mg/dL ] ) . The primary outcome measure was the late postpr and ial BG value , calculated as the mean of the combined prelunch ( late postbreakfast ) , predinner ( late postlunch ) , and bedtime ( late postdinner ) values . RESULTS A total of 89 patients with type 1 DM were enrolled ( 44 men , 45 women ; mean [ SD ] age , 38.3 [ 12.8 ] years ; mean [ SD ] body weight , 70.8 [ 11.6 ] kg ; mean [ SD ] body mass index , 24.6 [ 3.0 ] kg/m(2 ) ; mean [ SD ] duration of diabetes , 17.8 [ 10.5 ] years ; mean HbA(1c ) , 7.9 % [ 0.88 % ] ) . The mean ( SD ) late postpr and ial BG values were similar between treatments ( 8.9 [ 2.1 ] mmol/L [ 160.3 ( 37.8 ) mg/dL ] for H/M vs 9.0 [ 1.8 ] mmol/L [ 162.1 ( 32.4 ) mg/dL ] for LP + N ) , as were the end point HbA(1c ) values ( 7.8 % [ 0.9 % ] for H/M vs 7.9 % [ 0.8 % ] for LP + N ) . The rate of hypoglycemia was significantly higher during treatment with H/M , primarily because of episodes occurring between 12 PM and 6 PM , but was relatively low in both groups ( mean/median rate per patient per 30 days : 2.87/2.14 for H/M and 2.11/1.07 for LP + N ; P < 0.05 ) . CONCLUSIONS In this population of patients with type 1 DM , prepr and ial H/M provided an effective alternative regimen for pr and ial and basal insulin replacement . Late postpr and ial BG control , an indicator of basal insulin sufficiency , was similar to that achieved with an intensified regimen of LP + N injected separately before meals , and the end point HbA(1c ) was similar between the 2 treatments OBJECTIVE Predictable Results and Experience in Diabetes through Intensification and Control to Target : an International Variability Evaluation ( PREDICTIVE ) is a multi-national , open-label , prospect i ve , observational study assessing the safety and efficacy of insulin detemir in clinical practice . This post hoc sub analysis evaluates insulin-naïve patients on oral antidiabetic drugs ( OADs ) who were initiated on insulin detemir as basal therapy ( + /- OADs ) . METHODS The European cohort of the PREDICTIVE study currently includes 20,531 patients ( 12,981 with type 2 diabetes ) who were prescribed insulin detemir and followed up for 12 , 26 or 52 weeks . Here , we report data from a subgroup of 2377 OAD-treated , insulin-naïve type 2 diabetes patients for a mean follow-up of 14.4 weeks . Patients were prescribed insulin detemir as basal therapy ( + /- OADs ) by their physician , as part of routine clinical care . Results were reported in comparison with baseline observations . RESULTS One serious adverse drug reaction was reported , which was a major hypoglycaemic episode . Treatment with insulin detemir ( + /- OADs ) significantly reduced mean haemoglobin A(1c ) ( HbA(1c ) ) ( -1.3 % ; p < 0.0001 ) , fasting glucose ( -3.7 mmol/l ; p < 0.0001 ) , and within-patient fasting glucose variability ( -0.5 mmol/l ; p < 0.0001 ) . In the majority of patients ( 82 % ) , these improvements in glycaemic control were achieved with once daily administration of insulin detemir . There was a small reduction in mean body weight ( -0.7 kg ; p < 0.0001 ) , which was most apparent in patients with a higher body mass index ( BMI ) at baseline . A significant negative relationship between weight change and baseline BMI was observed ( greater the BMI , greater the weight reduction ) . Multiple regression analysis showed that BMI and HbA(1c ) at baseline , and change in HbA(1c ) , were all predictors for weight change ( p < 0.0001 for all ) , with BMI being the strongest predictor . CONCLUSIONS Patients with type 2 diabetes naïve to insulin can be effectively treated with once-daily insulin detemir ( + /- OADs ) to achieve improved glycaemic control with no adverse effect on weight and a low risk of hypoglycaemia . These short-term results are consistent with the findings of clinical trials AIMS To evaluate the efficacy , safety and treatment satisfaction with biphasic insulin aspart 30 ( BIAsp30 ) in elderly patients with type 2 diabetes . METHODS The Physicians ' Routine Evaluation of Safety and Efficacy of NovoMix 0 Therapy Korea study was a 6-month , prospect i ve , observational study . No study -specific interventions were involved except the collection of data . All patients with type 2 diabetes not adequately controlled on their previous therapy , and who were prescribed BIAsp30 as monotherapy , or in combination with oral hypoglycaemic agents , were eligible for the study . This subgroup analysis was based on the outcomes in patients > or years ( n = 1720 ) . RESULTS BIAsp30 treatment was associated with significant mean reductions in haemoglobin A1c , fasting plasma glucose and post-pr and ial plasma glucose levels of 1.2 + /- 1.6 % , 2.3 + /- 3.5 mmol/l and 4.8 + /- 5.3 mmol/l at 6 months ( p < 0.0001 for all ) , from baseline levels of 9.1 + /- 1.7 % , 10.7 + /- 3.4 mmol/l and 16.7 + /- 5.0 mmol/l , respectively . The rate of hypoglycaemia declined from 3.02 to 1.31 episodes per patient year , between baseline and study end . The proportion of patients reporting adverse drug reactions was low ( 0.3 and 0.1 % at 3 and 6 months , respectively ) . Body weight gain was mild at < 0.1 kg at 3 months , and 0.3 kg at 6 months . As compared to the previous treatment , > 80 % of patients were rated as being either ' very satisfied ' or ' satisfied ' with BIAsp30 treatment . CONCLUSIONS In this sub analysis of Korean elderly patients with type 2 diabetes inadequately controlled on their previous therapies , treatment with BIAsp30 offered improvements in glycaemic control and was well tolerated . Body weight gain was minimal with BIAsp30 , and treatment satisfaction among these patients appeared to be high AIM To evaluate the safety and effectiveness of biphasic insulin aspart 30 ( BIAsp 30 ) in Indonesian patients with type 2 diabetes ( T2D ) as part of the 24-week , international , prospect i ve , non-interventional A₁chieve study . METHODS Indonesian patients who started BIAsp 30 were included . Safety and efficacy was measured as part of routine clinical practice at baseline , Week 12 and Week 24 . RESULTS Overall , 1324 patients having a mean ± SD age , duration of diabetes and body mass index of 55.2 ± 9.9 yrs , 6.8 ± 5.2 yrs and 24.1 ± 3.6 kg/m(2 ) , respectively , were enrolled . 67 % of patients were insulin-naive and 33 % were prior insulin users . Glycaemic control was poor at baseline . After 24 weeks , significant reductions from baseline were observed in the mean glycated haemoglobin A1c ( HbA1c ) ( -2.6 % ) , fasting plasma glucose ( -93.8 mg/dL ) and postpr and ial plasma glucose ( -134.8 mg/dL ) levels in the entire cohort ( p < 0.001 ) . Significant reductions were also seen in insulin-naive patients and prior insulin users . At Week 24 , 29.9 % of patients in the entire cohort achieved target HbA1c level of < 7.0 % , while 26.7 % and 39.2 % achieved this target among insulin-naive patients and prior insulin users , respectively . The proportion of patients reporting overall hypoglycaemia significantly decreased in the entire cohort after 24 weeks of BIAsp 30 therapy . A small significant increase in body weight was noted in the entire cohort , insulin-naive patients and prior insulin users . CONCLUSION The current study suggests that BIAsp 30 can be considered as a safe and effective option for initiating as well as intensifying insulin therapy in Indonesian patients with T2D OBJECTIVE To investigate tolerability and glycemic control over 26 weeks in patients with type 2 diabetes ( T2D ) who initiated insulin with , or switched to , biphasic insulin aspart 30/70 ( BIAsp 30 ) in routine clinical care . METHODS This was a non-r and omized , non-interventional , open-label , observational study involving patients under the care of approximately 150 insulin-prescribing physicians in Denmark . All patients enrolled were prescribed BIAsp 30 in routine care . Starting dose , dose titration and injection frequency were determined individually by each physician . Information on serious adverse drug reactions ( SADR ) , glycemic parameters and hypoglycemic events were obtained from patients ' notes , patients ' diaries and recall , and transferred to case report forms by physicians at baseline ( during 4 weeks prior to BIAsp 30 therapy ) and after 12 and 26 weeks of treatment . RESULTS 421 subjects were recruited and 392 provided safety data . The age ( mean + /- SD ) was 62.0 + /- 11.4 years , body mass index ( BMI ) 30.4 + /- 6.4 kg/m(2 ) , duration of diabetes 9.1 + /- 8.1 years and HbA1c ( % ) 9.4 + /- 1.7 . 199 subjects were prior insulin users and 193 were insulin-naïve patients . Four patients reported a SADR ( 3 hypoglycemia , 1 severe hypoglycemia ) . HbA1c was significantly reduced after 26 weeks of BIAsp 30 therapy : prior insulin users -1.2 % , insulin-naïve patients -2.2 % ( both p < 0.001 ) . 28 % and 41 % of patients , respectively , reached target HbA1c < 7 % . Overall the hypoglycemia rate was lower for insulin-naïve patients than for prior insulin users : 5.0 vs. 6.6 episodes/patient-year ( p < 0.05 ) . CONCLUSION Initiating insulin with , or switching insulin to , BIAsp 30 in routine care was safe and effective in patients with T2D While evidence d-based guidelines promote glycated hemoglobin ( HbA(1c ) ) targets < 7.0 % in order to reduce the long-term risk of diabetic complications , many individuals with type 2 diabetes do not achieve these targets . Fear of hypoglycemia provides a major barrier to improving blood glucose control as a result of delayed insulin initiation and failure to appropriately titrate insulin following initiation . Modern insulin analogs were design ed to achieve improved blood glucose control with similar hypoglycemic risk compared with non-analog insulins ( or similar blood glucose control with reduced hypoglycemic risk ) . While this has been demonstrated in r and omized controlled trials , there is a need to confirm these findings in an everyday clinical setting . The A(1)chieve study will evaluate adverse events and effectiveness of premix ( biphasic insulin aspart 30 [ NovoMix 30 ] ) , basal ( insulin detemir [ Levemir ] ) , and meal-time ( insulin aspart [ NovoRapid ] ) insulin analogs in people with type 2 diabetes in near-routine clinical practice . A(1)chieve is an international , prospect i ve , multi-center , open-label , non-interventional , 24-week study of people with type 2 diabetes using an insulin analog . The study will recruit 60 000 people from 30 countries across four continents ( Asia , Africa , South America , and Europe ) . The primary aim of the study is to assess the adverse event profile of the study insulins in routine clinical practice , including rates of hypoglycemia . In addition , effectiveness ( HbA(1c ) , fasting plasma glucose , and postpr and ial plasma glucose ) and patient quality of life outcomes will be measured . Comprehensive epidemiological data will be collected at baseline , including recent plasma glucose results and hypoglycemic episodes , prevalence of diabetes-related complications , and measures of current st and ards of care . Thus , A(1)chieve should provide important information about how insulin analogs perform in daily clinical practice BACKGROUND To evaluate the efficacy and safety of glimepiride plus insulin glargine in ethnic Japanese patients with type 2 diabetes mellitus ( T2DM ) . METHODS This 24-week , open-label , single-arm study was conducted in eight centers in Brazil . One hundred ethnic Japanese T2DM patients with inadequate glycemic control [ HbA(1c ) : 8.0 - 11.0 % and fasting plasma glucose (FPG)>or=140 mg/dL ] on oral antidiabetic drugs ( OADs ) were enrolled . Patients were treated once daily with glimepiride 3 mg ( morning ) and glargine ( bedtime ) with dose titration to achieve FPG 72 - 100mg/dL. RESULTS At Week 24 , the mean dose of glargine was 37.6 IU/day . There were significant decreases ( p<0.0001 ) compared with baseline , for mean HbA(1c ) ( 1.5 % ) , mean FPG ( 88.3mg/dL ) ( p<0.0001 ) , mean PPG ( 112.0mg/dL ) , and mean fasting C-peptide ( 1.14 ng/mL ) . Peptide index ( peak-basal/basal ) in carbohydrate challenge test increased by 2.24 units . No severe adverse events , including severe hypoglycemia were reported . CONCLUSIONS Our study suggests that combined therapy of insulin glargine and glimepiride should be considered for T2DM patients who have unsatisfactory response to previous OAD treatment AIM This trial evaluated the potential for improving glycaemic control by intensifying a conventional twice-daily therapy with premixed human insulin ( HI ) to a thrice-daily regimen using premixed formulations of biphasic insulin aspart ( BIAsp ) in patients with type 1 or type 2 diabetes . METHODS This was a multicentre , open-label , parallel group trial . After a 4-week run-in period , patients were r and omized 1 : 1 to 16 weeks of treatment . A total of 748 patients were screened , 664 were exposed to trial drug and 604 completed the trial . RESULTS Haemoglobin A(1c ) , the primary efficacy endpoint , was shown to be significantly lower for the BIAsp treatment group compared with the biphasic HI ( BHI ) 30 group [ estimated mean difference : -0.32 , 95 % confidence interval ( CI ) ( -0.48 ; -0.16 ) , p = 0.0001 ] . The average blood glucose level was significantly lower in the BIAsp group [ estimated mean difference : -0.79 , 95 % CI ( -1.17 ; -0.40 ) , p = 0.0001 ] . There were few major hypoglycaemic episodes , 11 in the BIAsp group and 7 in the BHI 30 group . Although intensification of insulin therapy with BIAsp three times a day was associated with a higher risk of minor hypoglycaemia ( relative risk = 1.58 , p = 0.0038 ) , the overall rate of minor hypoglycaemia remained low with both the BIAsp and the BHI treatments ( 13.1 vs. 8.3 episodes/patient year respectively ) . Overall safety and patient satisfaction were similar with the two insulin therapies . CONCLUSIONS This trial confirmed that a thrice-daily BIAsp regimen can safely be used to intensify treatment for patients inadequately controlled on twice-daily BHI . A treat-to-target trial is required to explore the full potential of the BIAsp regimens and evaluate their use as a viable alternative to intensification with a basal-bolus regimen ABSTRACT Objective : PREDICTIVE is a multi-national , prospect i ve , observational study , assessing the safety and efficacy of insulin detemir in patients with diabetes . Research design and methods : The European cohort includes 20 531 patients with diabetes ( 7420 type 1 ) from 11 countries . A subgroup of 4782 type 1 patients were transferred from a basal-bolus regimen with NPH insulin ( n = 3117 ) or insulin glargine ( n = 1665 ) to insulin detemir basal-bolus therapy ; or from a human insulin basal-bolus regimen ( n = 570 ) to insulin detemir/insulin aspart ( part of the pre- study NPH group ) . Mean follow-up was 14.4 weeks . The primary endpoint was serious adverse drug reactions ( SADRs ) , including major hypoglycaemia . Secondary endpoints were : incidence of overall and nocturnal hypoglycaemia ; haemoglobin A1c ( HbA1c ) ; fasting glucose ; within-patient fasting glucose variability ; and change in body weight . Results : SADRs were reported by 62 ( 2.0 % ) patients previously receiving NPH insulin , 45 ( 2.7 % ) patients previously receiving insulin glargine and seven ( 1.2 % ) patients previously receiving human basal-bolus insulins . Major hypoglycaemia was significantly reduced in NPH insulin ( 55 % ) , insulin glargine ( 51 % ) , and human basal-bolus insulin groups ( 54 % ; p < 0.0001 for all ) . Total and nocturnal hypoglycaemic episodes were also significantly reduced in all groups ( p < 0.0001 for all ) . HbA1c was reduced in patients previously receiving NPH insulin ( 0.5 % ) , insulin glargine ( 0.4 % ) , and human basal-bolus insulins ( 0.6 % ; p < 0.0001 for all ) . Mean fasting glucose and within-patient fasting glucose variability significantly decreased in all patients ( p < 0.0001 for all ) . Body weight remained stable . Conclusions : In this open-label , prospect i ve , observational study , insulin detemir basal-bolus therapy improved glycaemic control and reduced hypoglycaemia with weight neutrality in type 1 patients in actual clinical practice BACKGROUND The present study evaluated the efficacy of biphasic human insulin 30 ( BHI 30 ) in type 2 diabetes patients who had failed in therapy with two or more oral antidiabetes drugs ( OADs ) . METHODS This open-label , nonr and omized , 4-month , multicenter , clinical observational study was conducted in Shanghai , China . A total of 660 insulin-naive type 2 diabetes patients with poor glycemic control ( glycosylated hemoglobin [ HbA1c ] ≥7.5 % ) , despite treatment with two or more OADs for more than 6 months , were recruited and received BHI 30 monotherapy or BHI 30 plus OAD(s ) ( metformin only , α-glucosidase inhibitor only , or both ) . RESULTS Among the 660 subjects , 644 completed the 4-month study . At the end of the study , the median level of HbA1c decreased by 2.0 % ( from 9.1 % to 7.0 % ) in the BHI 30 monotherapy group and also 2.0 % ( from 9.5 % to 7.3 % ) in the BHI 30 plus OAD group . More patients achieved the HbA1c < 7.0 % target in the BHI 30 monotherapy group than in the BHI 30 plus OAD(s ) group ( 47.9 % vs. 35.3 % , P=0.002 ) . Compared with the expenses of the prior treatment strategy , the median daily cost decreased by 39.8 % ( 4.5 yuan , Chinese RMB ) at the end point in the BHI 30 monotherapy group but increased by 20.0 % ( 2.2 yuan ) in the BHI 30 plus OAD(s ) group ( P<0.0001 ) . Moreover , patients in the BHI 30 plus OAD(s ) group had fewer minor hypoglycemic episodes than in the BHI 30 monotherapy group ( mean of 1.06 vs. 2.77 per patient per year , P<0.0001 ) . CONCLUSIONS Short-term BHI 30 therapy can improve glycemic control in insulin-naive type 2 diabetes patients after failure of two or more OADs . With higher baseline glucose level , the BHI 30 plus OAD(s ) group had lower pharmacoeconomic efficacy than the BHI 30 monotherapy group despite having fewer hypoglycemia events Abstract Aims : To explore safety and efficacy of BIAsp 30 as initiation or replacement therapy in routine clinical practice in patients with poorly controlled diabetes in the Chinese cohort of the IMPROVE study . Methods : In the 26-week , non-interventional , observational study , Chinese subjects with diabetes started BIAsp 30 treatment in routine care . Data from patients ’ diaries and medical records were transferred to CRFs by participating physicians . Clinical trial registration : NCT00659282 . Results : Of the 21,729 subjects enrolled ( mean age 54.0 years , BMI 24.6 kg/m2 , diabetes duration 4.86 years ) , 32.3 % were treatment-naïve , 59.3 % were from oral anti-diabetic drugs ( OADs ) only and 8.1 % were from insulin ± OADs . Overall , mean HbA1c and FBG decreased by 2.82 % and 5 mmol/L , respectively . In the subgroups , changes were : −3.27 % and −6.06 mmol/L ( treatment-naïve ) , −2.57 % and −4.54 mmol/L ( OADs only ) , −2.96 % and 3.51 mmol/L ( insulin ± OADs ) all p < 0.05 . HbA1c < 7 % was achieved by 71.4 % of patients . Only 0.1 % of subjects reported major hypoglycaemia and 73 SADRs were observed without significant difference compared to those at baseline . Body weight did not change significantly . Conclusions : Regardless of previous treatments , insulin initiation or replacement with BIAsp 30 improved glycaemic control without increasing major hypoglycaemia or weight gain in Chinese patients with diabetes Abstract Objective : Evaluation of the safety and efficacy of insulin detemir ( IDet ) in the observational and non-interventional PREDICTIVE study . Methods : A total of 2923 patients with type 1 or 2 diabetes on basal – bolus regimens were followed for 6 months : Group ( 1 ) NPH + human insulin ( HI ) bolus switching to IDet + analogue bolus ( n = 349 ) ; Group ( 2 ) NPH + HI bolus switching to IDet + HI bolus ( n = 500 ) ; Group ( 3 ) NPH + analogue bolus switching to IDet + analogue bolus ( n = 1144 ) ; Group ( 4 ) Glargine + analogue bolus switching to IDet + analogue bolus ( n = 704 ) . Primary endpoint was major hypoglycaemia ; change in HbA1c , fasting plasma glucose , fasting plasma glucose variability and bodyweight were secondary endpoints . Results : These results need critical review due to the observational nature of the study ( non-r and omisation , no control group ) as well as limitations of a possible study effect and the fact that some endpoints are based on patient recall , diaries or reports . Mean incidence of any hypoglycaemia was significantly reduced following the switch to insulin detemir therapy in all groups : the greatest reduction in total hypoglycaemia was in Group 1 from 42.38 to 20.28 episodes per patient-year ( mean difference −22.10 ; p < 0.0001 ) and in nocturnal hypoglycaemia from 11.83 to 2.08 episodes/patient-year ( mean difference −9.88 ; p < 0.0001 ) . HbA1c , FPG and FPG variability also improved significantly in all groups : the greatest reduction in HbA1c was in Group 1 from 8.13 to 7.42 % ( mean difference −0.71 ; p < 0.0001 ) . Bodyweight was reduced in all groups . Conclusions : Whichever basal – bolus insulins were previously used , switching to insulin detemir as the basal insulin component result ed in significant lowering of hypoglycaemia , HbA1c , FPG and bodyweight over a period of 6 months in patients with type 1 or 2 diabetes . Switching to an all-analogue regimen may be the most effective option when moving patients from human insulin-based basal – bolus regimens OBJECTIVE To determine the safety and effectiveness of biphasic insulin aspart 30 ( BIAsp 30 ) in type 2 diabetes subjects switched from biphasic human insulin 30 ( BHI 30 ) in the Pakistani subgroup of the multinational , prospect i ve , non-interventional A1chieve study . METHODS Subjects who switched therapy from BHI 30 to BIAsp 30 were included in this analysis . Serious adverse drug reactions ( SADRs , including major hypoglycaemia ) and effectiveness parameters ( glycated haemoglobin [ HbA1c ] , fasting plasma glucose [ FPG ] , postpr and ial plasma glucose [ PPPG ] , systolic blood pressure [ SBP ] ) and body weight were evaluated at the end of 24 weeks . RESULTS A total of 152 subjects ( 79 males , 73 females ; mean age , 53.4 + /- 10.3 years ; BMI , 28.4 + /- 5.8 kg/m2 ) with an average diabetes duration of 11.2 + /- 4.8 years switched therapy from BHI 30 to BIAsp 30 . The mean pre- study BHI 30 dose was 0.66 + /- 0.25 IU/kg and the mean starting BIAsp 30 dose was 0.65 + /- 0.23 U/kg , titrated up to 0.77 + /- 0.22 U/kg after 24 weeks . No SADRs were reported . From baseline to Week 24 , overall hypoglycaemia did not change and no major hypoglycaemia was reported at Week 24 . HbA1c levels decreased significantly from 9.1 + /- 1.1 % at baseline to 7.4 + /- 0.7 % ( 57 + /- 8 mmol/mol ) at Week 24 ( p < 0.001 ) . Significant improvements in FPG , post-breakfast PPPG and SBP were reported ( p < 0.001 ) . CONCLUSION Switching from BHI 30 to BIAsp 30 was well tolerated and improved glucose control without an increased incidence of hypoglycaemia in this Pakistani cohort PREDICTIVE ( Predictable Results and Experience in Diabetes through Intensification and Control to Target : An International Variability Evaluation ) is a large , multi-national , open-label , prospect i ve , observational study assessing the safety and efficacy of insulin detemir in clinical practice . A total of 20,531 patients with type 1 or 2 diabetes from 11 countries were prescribed insulin detemir and followed up after a mean of 14.4 weeks . The primary endpoint was incidence of serious adverse drug reactions ( SADRs ) , including major hypoglycaemia . Secondary endpoints were : haemoglobin A(1c ) ( HbA(1c ) ) , mean self-monitored fasting glucose , within-patient fasting glucose variability and body weight change . Two hundred and fourteen patients ( 1 % ) reported SADRs , including major hypoglycaemia . The incidence of major hypoglycaemic episodes was reduced from 3.0/patient-year at baseline to 0.7/patient-year at follow-up in type 1 patients ( p < 0.0001 ) , and from 0.8 to 0.1/patient-year in type 2 patients ( p < 0.0001 ) . Insulin detemir improved glycaemic control in type 1 and type 2 patients , with reductions in mean HbA(1c ) ( 0.5 % and 0.9 % , respectively , p < 0.0001 for both ) , fasting glucose ( 1.7 and 2.6 mmol/l , p < 0.0001 for both ) and within-patient fasting glucose variability ( 0.7 and 0.5 mmol/l , p < 0.0001 for both ) . There was a small decrease in mean body weight in both type 1 and 2 patients ( -0.1 kg , p < 0.01 and -0.4 kg , p < 0.0001 respectively ) . Insulin detemir was used once- or twice-daily in 49 % and 50 % of type 1 patients , and 77 % and 23 % of type 2 diabetes patients , respectively . The 14-week observations from PREDICTIVE support clinical trial data showing that insulin detemir improves glycaemic control , with a lowered risk of hypoglycaemia and no weight gain PREDICTIVEtrade mark is a large , multi-national , open-label , prospect i ve , observational study to assess the efficacy and safety of insulin detemir in clinical practice . We report 3-month follow-up data from 389 patients with type 1 ( n = 312 ) and type 2 ( n = 77 ) diabetes from Denmark . Insulin detemir improved glycemic control in type 1 patients , with decreases in mean HbA1c ( -0.2 % , p = 0.0026 ) , fasting glucose ( -1.7 mmol/l , p = 0.0033 ) and within-patient fasting glucose variability ( -0.6 mmol/l , p = 0.0472 ) . Non-significant reductions in glycemic parameters were observed in type 2 patients ( -0.3 % for HbA1c and -2.7 mmol/l for fasting glucose ) . There was a decrease in mean body weight in both type 1 and type 2 patients ( -0.6 kg , p = 0.025 and -1.0 kg , p = 0.0361 , respectively ) . Three patients ( 0.8 % ) reported 4 serious adverse drug reactions , including major hypoglycemia . The incidence of major hypoglycemic episodes was reduced from 3.9/patient-years at baseline to 0.4/patient-years at follow-up in type 1 patients ( p < 0.0001 ) , and from 1.0 to 0.0/patient-years in type 2 patients ( p = 0.1250 ) . In addition , the mean incidence of total and nocturnal hypoglycemic episodes was reduced in both type 1 ( -37.4 and -17.7/patient-years , p < 0.0001 for both ) and type 2 patients ( -17.7 and -7.8/patient-years , p = 0.0012 and p = 0.0020 , respectively ) . The observations from the Danish cohort of the PREDICTIVE study support the overall findings of PREDICTIVE , i.e. insulin detemir improves glycemic control , with a reduced risk of hypoglycemia and no weight gain BACKGROUND Sensor-augmented pump ( SAP ) therapy can improve glycemic control , compared with multiple daily insulin injections or with insulin pump therapy alone , without increasing the risk of hypoglycemia . SUBJECTS AND METHODS A 12-month observational study in patients with type 1 diabetes treated with continuous subcutaneous insulin infusion ( CSII ) , upon the introduction of continuous glucose monitoring ( CGM ) , was conducted in 15 countries ( in Europe and in Israel ) to document the real-life use of SAP and assess which variables are associated with improvement in type 1 diabetes management . RESULTS Data from 263 patients ( 38 % male ; mean age , 28.0 ± 15.7 years [ range , 1 - 69 years ] ; body mass index , 23.3 ± 4.9 kg/m(2 ) ; diabetes duration , 13.9 ± 10.7 years ; CSII duration , 2.6 ± 3 years ) were collected . Baseline mean glycated hemoglobin A1c ( HbA1c ) was 8.1 ± 1.4 % ; 82 % had suboptimal HbA1c ( ≥ 7 % ) . The average sensor use for 12 months was 30 % ( range , 0 - 94 % ) , and sensor use decreased with time ( first 3 months , 37 % ; last 3 months , 27 % ) . Factors associated with improvement in HbA1c after 12 months in patients with baseline HbA1c ≥ 7 % were high baseline HbA1c ( P<0.001 ) , older age group ( P<0.001 ) , and more frequent sensor use ( P = 0.047 ) . Significantly less hospitalization , increased treatment satisfaction , and reduced fear of hypoglycemia were reported after 12 months of SAP . CONCLUSIONS This is the largest and longest multicenter prospect i ve observational study providing real-life data on SAP . These results are consistent with those of controlled trials showing the effectiveness of CGM in pump users Abstract Objective : The aim of this sub analysis of the IMPROVE study was to evaluate the safety and effectiveness of initiating biphasic insulin aspart 30/70 ( BIAsp 30 ) in type 2 diabetes patients uncontrolled on oral antidiabetic drugs ( OADs ) . Methods : IMPROVE is a 26-week , open-label , non-r and omised , international observational study in type 2 diabetes patients prescribed BIAsp 30 in routine clinical practice . The total cohort comprised 52 419 patients from various pre- study therapies . Here results from the subgroup of previously insulin-naïve patients are reported . Changes in glycated haemoglobin ( HbA1c ) , fasting blood glucose ( FBG ) , postpr and ial blood glucose ( PPBG ) , weight , dose , proportion of patients achieving HbA1c < 7.0 % , and rates of major and minor hypoglycaemic events were recorded . Treatment satisfaction was assessed using a vali date d question naire . Results : A total of 29 160 insulin-naïve patients were included ; mean age 55.6 years , diabetes duration 7.3 years , baseline HbA1c 9.24 % . Significant reductions were seen for HbA1c ( −2.12 % ; p < 0.0001 ) , FBG ( −4.07 mmol/L ; p < 0.0001 ) and PPBG after all meals ( mean : −5.27 mmol/L ; p < 0.0001 ) ; 39.2 % of patients achieved HbA1c < 7.0 % without hypoglycaemia . Better glycaemic control was seen in patients treated with BIAsp 30 twice-daily ( BID ) both at baseline and final visit , or BID at baseline and three-times daily at final visit , compared with other regimens . The rate of major hypoglycaemic events decreased significantly , while the rate of minor hypoglycaemic events increased . Better glycaemic control and a lower rate of minor hypoglycaemia were observed in patients using BIAsp 30 without OADs than with OADs . There was no clinical ly relevant change in weight ( −0.07 kg ; p < 0.0001 ) . At final visit , 59.7 % of patients were extremely/very satisfied with treatment , compared with 10.2 % at baseline . Conclusions : This open-label , non-r and omised , observational study demonstrated that initiating insulin therapy with BIAsp 30 significantly improved glycaemic control in insulin-naïve patients previously poorly controlled on OADs . The rate of major hypoglycaemia was reduced and treatment satisfaction increased after initiation of BIAsp 30 . Furthermore , better glycaemic control was achieved with BIAsp 30 without OAD compared to with OAD Abstract Objective : To investigate the safety and efficacy of switching to biphasic insulin aspart ( BIAsp ) 30 , 50 or 70 in patients with type 2 diabetes previously treated with biphasic human insulin ( BHI ) 30/50 ( with or without oral glucose-lowering drugs ) in routine clinical practice . Methods : This was a 26-week , prospect i ve , observational study conducted in Belgium and Luxembourg . Data were collected at baseline before patients switched and at 12 and 26 weeks after starting BIAsp 30 , 50 or 70 . Safety endpoints were incidence and rate of hypoglycemia ( major , minor , nocturnal ) , adverse events and body-weight changes . Efficacy assessment s included HbA1c and 7-point self-measured plasma glucose ( PG ) profiles . Changes from baseline were analyzed using paired t-tests . Results : Of 592 patients analyzed , 72 % switched to twice-daily BIAsp and 20 % to three-times daily BIAsp . Upon switching , 27 % of patients received intensified treatment ( i.e. , more daily doses than with their previous BHI ) . At all three data - collection points , approximately two-thirds of patients were taking BIAsp 30 and approximately one-third were taking BIAsp 50 ; very few patients took BIAsp 70 . Mean total daily insulin dose increased significantly from baseline ( 51.2 U ) to 26 weeks ( 54.3 U ) and mean time of intake before meals changed from 17 minutes for BHI to ∼3 minutes with BIAsp . Incidence of hypoglycemia did not change during the study ( baseline : 30.7 % , week 26 : 29.2 % ) . HbA1c improved significantly from baseline ( 7.9 % ) to weeks 12 and 26 ( 7.6 % and 7.5 % , respectively ; p < 0.001 ) . Mean PG profiles also showed significant improvements . As this is an observational study , some limitations should be considered such as the absence of a control group and a possible bias of increased medical attention . Conclusions : Patients with long-st and ing type 2 diabetes can switch safely from BHI to BIAsp therapy , even if they receive intensified treatment , and they have no problems changing the timing of their insulin injections Abstract Objective : To investigate the efficacy and safety of glimepiride as initial mono-therapy in type 2 diabetes patients in China . Methods : This is a multi-center , open-label , single arm study . A total of 391 subjects were enrolled to receive glimepiride treatment for 16 weeks , the initiation dose was 1 mg/d , with titration to 2 mg/d and 4 mg/d according to the fasting blood glucose ( FBG ) level measured at each visit . The change in HbA1c , fasting plasma glucose ( FPG ) , 2 h postpr and ial blood glucose ( 2hPPG ) , HOMA-IR , weight , waist circumference and the incidence of hypoglycemia were evaluated . An exploratory analysis was conducted to identify the potential population prone to achieve target glycemic control . Results : HbA1c was reduced significantly from 8.6 ± 1.6 % to 6.9 ± 0.9 % ( p < 0.001 ) ; 60.9 % of the subjects achieved HbA1c < 7 % at study endpoint . The reduction in FPG and 2hPPG were 2.3 mmol/L and 4.4 mmol/L ( p < 0.001 ) respectively . Insulin resistance was improved significantly with HOMA-IR decreasing from 2.5 ± 2.3 to 2.2 ± 1.9 ( p = 0.009 ) . The incidence of confirmed hypoglycemia ( BG ≤ 3.9 mmol/L ) was 3.1 % . Conclusions : Glimepiride treatment as initial mono-therapy could effectively improve blood glucose control in type 2 diabetic patients , with a favorable safety profile . Lack of control group was the major limitation of this study . Clinical Trial.gov identifier : NCT00908921 Abstract Background : Early initiation of insulin therapy has widely been associated with numerous benefits , including improved glycaemic control and reduced long-term risk of developing microvascular diseases . Biphasic insulins offer a convenient option for insulin initiation , addressing both basal and postpr and ial insulin requirements with one injection , making them relatively simple for patients to dose . Development of biphasic insulin aspart ( BIAsp ) has further offered improved postpr and ial glycaemic control and lower rates of nocturnal and major hypoglycaemia than biphasic human insulin . Methods : The safety and efficacy of the 30/70 rapid-acting/intermediate-acting formulation of BIAsp ( BIAsp 30 ) in patients with type 2 diabetes was examined in the IMPROVE study , a 26-week , international , observational trial . In this sub analysis , baseline clinical factors that predicted treatment success , defined as HbA1c < 7 % ( < 53 mmol/mol ) without experiencing hypoglycaemia after 26 weeks on BIAsp 30 therapy , were assessed . Results : The composite endpoint was defined for 44,010 ( 77 % ) patients from the total cohort of 57,478 , and 28,696 of these were included in the statistical examination . The results of the analysis suggest that those with lower baseline HbA1c of ≤8 % ( ≤64 mmol/mol ) , shorter duration of diabetes at baseline ( < 5 years ) and no incidence of major hypoglycaemia at 13 weeks , or minor hypoglycaemia at 4 weeks , before the beginning of the trial were more likely to achieve treatment success . Conclusion : Lower baseline HbA1c , shorter duration of diabetes and no incidence of hypoglycaemia up to 13 weeks prior to initiation are predictors of achieving HbA1c < 7 % without hypoglycaemia with a BIAsp 30 regimen . These results suggest that it is easier to reach target without hypoglycaemia with BIAsp 30 when prescribed earlier . As this was an observational study , lack of control groups or r and omisation , as well as varying clinical practice s in study countries , potentially introduced bias . Trial registration : Clinical Trials.gov identifier : NCT00659282 Introduction The aim was to compare clinical outcomes by different dosing frequencies of insulin detemir ( detemir ) used over 52 weeks in various regimens . Methods : This analysis involved French patients enrolled in PREDICTIVE ( a large-scale , multinational , observational study of empirical use of detemir in everyday clinical practice ) for whom data have been collected over 52 weeks . Three cohorts were considered : patients with type 1 diabetes ; patients with type 2 diabetes using detemir in a basal insulin plus oral antidiabetic drug ( OAD ) regimen ; patients with type 2 diabetes using detemir as part of basal-bolus insulin therapy . In each cohort , data were stratified according to detemir dosing frequency at the beginning and end of 52 weeks : once daily ( o.d . ) at the beginning and end ; twice daily ( b.i.d . ) at the beginning and end ; o.d . at the beginning , but b.i.d . at the end . Endpoints assessed included glycated hemoglobin , fasting plasma glucose , hypoglycemia , weight , and insulin dose . Results There were improvements in glycemic control and tolerability in all subgroups . Patients completing on o.d . dosing tended to have better outcomes than those completing on b.i.d . dosing in all cohorts , and o.d . administration was associated with lower insulin dosing . There was little evidence that switching from o.d . to b.i.d . dosing influenced outcomes other than insulin dose . However , there were some baseline differences between subgroups selected for o.d . and b.i.d . dosing that might have influenced outcomes : many patients appeared to have been continued on previous basal dosing frequencies ; for others , b.i.d . detemir dosing seemed to be used to intensify previous therapy . Conclusions With the caveat that empirical choices of dose frequency were made , this analy-sis shows that empirical use of o.d . detemir produces results at least as good as empirical use of b.i.d . detemir in basal-bolus-treated type 1 and type 2 diabetes , and in basal plus OAD-treated type 2 diabetes |
13,662 | 25,907,181 | There was no evidence of an effect of PA and combined PA/SB interventions on reducing sedentary time .
CONCLUSIONS There was evidence that it is possible to intervene to reduce SB in adults .
More high quality research is needed to determine if SB interventions are sufficient to produce clinical ly meaningful and sustainable reductions in sedentary time | CONTEXT Time spent in sedentary behaviours ( SB ) is associated with poor health , irrespective of the level of physical activity .
The aim of this study was to evaluate the effect of interventions which included SB as an outcome measure in adults . | Background Aboriginal and Torres Strait Isl and er women experience higher rates of heart disease and type 2 diabetes than non-Indigenous Australian women . Increasing physical activity , improving diets and losing weight have been shown to reduce cardio metabolic risk . The primary aim was to evaluate the effectiveness of a 12-week structured exercise and nutrition program in a cohort of urban Indigenous Australian women on waist circumference , weight and biomedical markers of metabolic functioning from baseline ( T1 ) to program completion ( T2 ) . The secondary aim assessed whether these outcomes were maintained at 3-month follow-up . Methods One hundred Aboriginal and /or Torres Strait Isl and er women aged 18–64 years living in the Adelaide metropolitan area were recruited . The program included two 60-minute group cardiovascular and resistance training classes per week , and four nutrition education workshops . Participants were r and omly assigned to an ‘ active ’ group or ‘ waitlisted ’ control group . Body weight , height , waist and hip circumference , blood pressure , fasting glucose , fasting insulin , glycated haemoglobin ( HbA1C ) , lipid profile and C-reactive protein ( CRP ) were assessed at baseline ( T1 ) , immediately after the program ( T2 ) and three months post program ( T3 ) . Results The active group showed modest reductions in weight and body mass index ( BMI ) . Compared to the waitlisted group , the active group had a statistically significantly change in weight and BMI from baseline assessment s ; at T2 , -1.65 kg and -0.66 kg/m2 and at T3 , -2.50 kg and -1.03 kg/m2 , respectively . Systolic and diastolic blood pressure also had a statistically significant difference from baseline in the active group compared to the waitlisted group at T2 , -1.24 mmHg and -2.46 mmHg and at T3 , -4.09 mmHg and -2.17 mmHg , respectively . The findings were independent of the baseline measure of the outcome variable , age , households with children and employment status . Changes in waist circumference and other clinical measures were not significant at T2 or T3 . The primary outcome measure , waist circumference , proved problematic to assess reliably . Missing data and participants lost to follow-up were significant . Conclusions This 12-week exercise program demonstrated modest reductions in weight , BMI and blood pressure at T2 , which improved further at 3-month follow-up ( T3 ) . Positive intervention effects were observed despite low attendance at exercise classes . Structured exercise programs implemented in community setting s require attention to underst and ing the barriers to participation for this high risk group . Trial registration Australian New Zeal and Clinical Trials Registry AIMS Despite the known benefits , 60 % of individuals with diabetes do not engage in regular physical activity ( PA ) . This pilot study tested the effects of a counseling intervention using continuous glucose monitoring system ( CGMS ) feedback on PA self-efficacy , PA levels , and physiological variables . METHODS Adults ( N=52 ) with type 2 diabetes ( non-insulin requiring , inactive ) were r and omized to intervention ( n=27 ) or control ( n=25 ) groups . Both groups received 90min of diabetes education with a follow-up phone call 4 weeks later . The intervention group also received counseling derived from self-efficacy theory . This intervention included feedback on each participant 's CGMS graph and used role model CGMS graphs to clearly depict glucose reductions in response to PA . Outcomes were assessed at baseline and 8 weeks . RESULTS Participants receiving the intervention had higher self-efficacy scores than the control group for sticking to activity/resisting relapse at 8 weeks ( p<0.05 ) , indicating more confidence in maintaining a PA program . Intervention group participants light/sedentary activity minutes decreased significantly ( p<0.05 ) , moderate activity minutes increased significantly ( p<0.05 ) , and , HbA1c and BMI decreased significantly ( p<0.05 ) . CONCLUSIONS These data suggest that PA counseling interventions using CGMS feedback for individuals with type 2 diabetes may improve PA levels and reduce risk factors for diabetes-related complications Background Recent systematic review s have suggested that pedometers may be effective motivational tools to promote walking . However , studies tend to be of a relatively short duration , with small clinical based sample s. Further research is required to demonstrate their effectiveness in adequately powered , community based studies . Objective Using a r and omized controlled trial design , this study assessed the impact of a 12-week graduated pedometer-based walking intervention on daily step-counts , self-reported physical activity and health outcomes in a Scottish community sample not meeting current physical activity recommendations . MethodS ixty-three women and 16 men ( 49.2 years ± 8.8 ) were r and omly assigned to either an intervention ( physical activity consultation and 12-week pedometer-based walking program ) or control ( no action ) group . Measures for step-counts , 7-day physical activity recall , affect , quality of life ( n = 79 ) , body mass , BMI , % body fat , waist and hip circumference ( n = 76 ) , systolic/diastolic blood pressure , total cholesterol and HDL cholesterol ( n = 66 ) were taken at baseline and week 12 . Analyses were performed on an intention to treat basis using 2-way mixed factorial analyses of variance for parametric data and Mann Whitney and Wilcoxon tests for non-parametric data . Results Significant increases were found in the intervention group for step-counts ( p < .001 ) , time spent in leisure walking ( p = .02 ) and positive affect ( p = .027 ) . Significant decreases were found in this group for time spent in weekday ( p = .003 ) , weekend ( p = .001 ) and total sitting ( p = .001 ) with no corresponding changes in the control group . No significant changes in any other health outcomes were found in either group . In comparison with the control group at week 12 , the intervention group reported a significantly greater number of minutes spent in leisure time ( p = .008 ) , occupational ( p = .045 ) and total walking ( p = .03 ) , and significantly fewer minutes in time spent in weekend ( p = .003 ) and total sitting ( p = .022 ) . Conclusion A pedometer-based walking program , incorporating a physical activity consultation , is effective in promoting walking and improving positive affect over 12 weeks in community based individuals . The discussion examines possible explanations for the lack of significant changes in health outcomes . Continued follow-up of this study will examine adherence to the intervention and possible result ing effects on health outcomes BACKGROUND Sedentary behavior is a risk factor for cardiometabolic disease . Regularly interrupting sedentary behavior with activity breaks may lower this risk . OBJECTIVE We compared the effects of prolonged sitting , continuous physical activity combined with prolonged sitting , and regular activity breaks on postpr and ial metabolism . DESIGN Seventy adults participated in a r and omized crossover study . The prolonged sitting intervention involved sitting for 9 h , the physical activity intervention involved walking for 30 min and then sitting , and the regular-activity-break intervention involved walking for 1 min 40 s every 30 min . Participants consumed a meal-replacement beverage at 60 , 240 , and 420 min . RESULTS The plasma incremental area under the curve ( iAUC ) for insulin differed between interventions ( overall P < 0.001 ) . Regular activity breaks lowered values by 866.7 IU · L(-1 ) · 9 h(-1 ) ( 95 % CI : 506.0 , 1227.5 IU · L(-1 ) · 9 h(-1 ) ; P < 0.001 ) when compared with prolonged sitting and by 542.0 IU · L(-1 ) · 9 h(-1 ) ( 95 % CI : 179.9 , 904.2 IU · L(-1 ) · 9 h(-1 ) ; P = 0.003 ) when compared with physical activity . Plasma glucose iAUC also differed between interventions ( overall P < 0.001 ) . Regular activity breaks lowered values by 18.9 mmol · L(-1 ) · 9 h(-1 ) ( 95 % CI : 10.0 , 28.0 mmol · L(-1 ) · 9 h(-1 ) ; P < 0.001 ) when compared with prolonged sitting and by 17.4 mmol · L(-1 ) · 9 h(-1 ) ( 95 % CI : 8.4 , 26.3 mmol · L(-1 ) · 9 h(-1 ) ; P < 0.001 ) when compared with physical activity . Plasma triglyceride iAUC differed between interventions ( overall P = 0.023 ) . Physical activity lowered values by 6.3 mmol · L(-1 ) · 9 h(-1 ) ( 95 % CI : 1.8 , 10.7 mmol · L(-1 ) · 9 h(-1 ) ; P = 0.006 ) when compared with regular activity breaks . CONCLUSION Regular activity breaks were more effective than continuous physical activity at decreasing postpr and ial glycemia and insulinemia in healthy , normal-weight adults . This trial was registered with the Australian New Zeal and Clinical Trials registry as ACTRN12610000953033 Background Pedometers provide a simple , cost effective means of motivating individuals to increase walking yet few studies have considered if short term changes in walking behaviour can be maintained in the long-term . The role of physical activity consultations in such interventions is unclear . The purpose of this study was to assess the sustainability of pedometer-based interventions and empirically examine the role of physical activity consultations using long-term results of a community-based walking study . Methods 79 low active Scottish men and women ( 63 women and 16 men ) from the Walking for Wellbeing in the West intervention study were r and omly assigned to receive either : Group 1 ; pedometer-based walking programme plus physical activity consultations or Group 2 ; pedometer-based walking programme and minimal advice . Step counts ( Omron HJ-109E Step-O-Meter pedometer ) , 7 day recall of physical activity ( IPAQ long ) , mood ( PANAS ) and quality of life ( EuroQol EQ-5D ) were assessed pre-intervention and 12 , 24 and 48 weeks after receiving the intervention . Body mass , body mass index and waist and hip circumference were assessed pre-intervention and 12 and 24 weeks after receiving the intervention . Analyses were performed on an intention to treat basis ( baseline value carried forward for missing data ) using mixed-factorial ANOVAs and follow-up t-tests . Results A significant main effect of time ( p < 0.001 ) was found for step-counts attributable to significant increases in steps/day between : pre-intervention ( M = 6941 , SD = 3047 ) and 12 weeks ( M = 9327 , SD = 4136 ) , t(78 ) = - 6.52 , p < 0.001 , d = 0.66 ; pre-intervention and 24 weeks ( M = 8804 , SD = 4145 ) , t(78 ) = - 4.82 , p < 0.001 , d = 0.52 ; and pre-intervention and 48 weeks ( M = 8450 , SD = 3855 ) , t(78 ) = - 4.15 , p < 0.001 , d = 0.44 . Significant effects were found for several variables of self-reported physical activity , mood and quality of life and are discussed . No other significant effects in health related outcomes were found . Conclusion Both interventions successfully increased and maintained step counts over 12 months . Physical activity consultations may encourage individuals to be active in other ways beyond walking and to reduce sitting time . Trial Registration NumberCurrent Controlled Trials Ltd IS RCT BACKGROUND Although epidemiologic studies have shown associations between sedentary behavior and mortality , few have focused on older women with adequate minority representation and few have controlled for both physical activity and functional status . PURPOSE The objective of this study was to determine the relationship between sedentary time and total ; cardiovascular disease ( CVD ) ; coronary heart disease ( CHD ) ; and cancer mortality in a prospect i ve , multiethnic cohort of postmenopausal women . METHODS The study population included 92,234 women aged 50 - 79 years at baseline ( 1993 - 1998 ) who participated in the Women 's Health Initiative Observational Study through September 2010 . Self-reported sedentary time was assessed by question naire and examined in 4 categories ( ≤4 , > 4 - 8 , ≥8 - 11 , > 11 hours ) . Mortality risks were examined using Cox proportional hazard models adjusting for confounders . Models were also stratified by age , race/ethnicity , body mass index , physical activity , physical function , and chronic disease to examine possible effect modification . Analyses were conducted in 2012 - 2013 . RESULTS The mean follow-up period was 12 years . Compared with women who reported the least sedentary time , women reporting the highest sedentary time had increased risk of all-cause mortality in the multivariate model ( HR=1.12 , 95 % CI=1.05 , 1.21 ) . Results comparing the highest versus lowest categories for CVD , CHD , and cancer mortality were as follows : HR=1.13 , 95 % CI=0.99 , 1.29 ; HR=1.27 , 95 % CI=1.04 , 1.55 ; and HR=1.21 , 95 % CI=1.07 , 1.37 , respectively . For all mortality outcomes , there were significant linear tests for trend . CONCLUSIONS There was a linear relationship between greater amounts of sedentary time and mortality risk after controlling for multiple potential confounders Background The construct of total wellness includes a holistic approach to the body , mind and spirit components of life . While the health benefits of reducing sedentary behavior and increasing physical activity are well documented , little is known about the influence on total wellness of an internet-based physical activity monitor design ed to help people to achieve higher physical activity levels . Purpose The purpose of this four-week , personal activity monitor-based intervention program was to reduce sedentary behavior and increase physical activity levels in daily living for sedentary adults and to determine if these changes would also be associated with improvement in total wellness . Methods Twenty-two men and 11 women ( 27 years ± 4.0 ) were r and omly assigned to either an intervention ( n = 18 ) or control group ( n = 15 ) . The intervention group interacted with an online personal activity monitor ( Gruve Solution ™ ) design ed to reduce sedentary time and increase physical activity during activities of daily living . The control group did not interact with the monitor , as they were asked to follow their normal daily physical activities and sedentary behavior routines . The Wellness Evaluation of Lifestyle ( WEL ) inventory was used to assess total wellness . Sedentary time , light , walking , moderate and vigorous intensity physical activities were assessed for both intervention and control groups at baseline and at week-4 by the 7-day Sedentary and Light Intensity Physical Activity Log ( 7-day SLIPA Log ) and the International Physical Activity Question naire ( IPAQ ) . Results Significant increases in pre-post total wellness scores ( from 64 % ± 5.7 to 75 % ± 8.5 ) ( t ( 17 ) = -6.5 , p < 0.001 ) were observed in the intervention group by the end of week four . Intervention participants decreased their sedentary time ( 21 % , 2.3 hours/day ) and increased their light ( 36.7 % , 2.5 hours/day ) , walking ( 65 % , 1057 MET-min/week ) , moderate ( 67 % , 455 MET-min/week ) and vigorous intensity ( 60 % , 442 MET-min/week ) physical activity ( all p < 0.001 ) . No significant differences for total wellness were observed between the groups at baseline and no pre-post significant differences were observed for any outcome variable in the control group . Conclusion Total wellness is improved when sedentary , but sufficiently physically active adults , reduce sedentary time and increase physical activity levels ( i.e. light , waking , moderate and vigorous ) Background This intervention aim ed to ascertain whether a low-cost , accessible , physical activity and nutrition program could improve physical activity and nutrition behaviours of insufficiently active 60–70 year olds residing in Perth , Australia . Methods A 6-month home-based r and omised controlled trial was conducted on 478 older adults ( intervention , n = 248 ; control , n = 230 ) of low to medium socioeconomic status . Both intervention and control groups completed postal question naires at baseline and post-program , but only the intervention participants received project material s. A modified fat and fibre question naire measured nutritional behaviours , whereas physical activity was measured using the International Physical Activity Question naire . Generalised estimating equation models were used to assess the repeated outcomes over both time points . Results The final sample consisted of 176 intervention participants and 199 controls ( response rate 78.5 % ) with complete data . After controlling for demographic and other confounding factors , the intervention group demonstrated increased participation in strength exercise ( p < 0.001 ) , walking ( p = 0.029 ) and vigorous activity ( p = 0.015 ) , together with significant reduction in mean sitting time ( p < 0.001 ) relative to controls . Improvements in nutritional behaviours for the intervention group were also evident in terms of fat avoidance ( p < 0.001 ) , fat intake ( p = 0.021 ) and prevalence of frequent fruit intake ( p = 0.008 ) . Conclusions A minimal contact , low-cost and home-based physical activity program can positively influence seniors ’ physical activity and nutrition behaviours . Trial registration anzctr.org.au Identifier : Inadequate dietary patterns and sedentary lifestyles are believed to be important factors in predisposing people to obesity . This study analyzed the potential interaction between habitual physical activity and the carbohydrate (CHO)-fat distribution in 2 hypocaloric diets and the impact of such interplay on body composition changes . Forty healthy obese women , 20 - 50 years old , were r and omly assigned to a high- or low-CHO energy-restricted diet , which was low or high in fat , respectively , during 10 weeks . Baseline and final measurements were performed to assess dietary habits , resting metabolic rate , and body composition changes . Physical activity was measured with a triaxial accelerometer and with a question naire . There were no significant differences in anthropometric and metabolic variables between both dietary groups at baseline . However , there was a positive correlation between total free-living physical activity and arm muscle preservation after 10 weeks ( r = 0.371 ; p = 0.024 ) . Interestingly , an interaction between macronutrient ( CHO-fat distribution ) intake and physical activity was found , since less-active subjects with a high-CHO-low-fat diet showed a greater fat loss than those more active with a lower-CHO-high-fat diet , whereas more-active subjects with a high-CHO-low-fat diet showed a smaller fat loss than those receiving a low-CHO-high-fat diet . Physical activity and the macronutrient content of energy-restricted diets , when design ed to promote body fat mass reduction , should be considered together to better predict the outcome CONTEXT Even though the strong association between physical inactivity and ill health is well documented , 60 % of the population is inadequately active or completely inactive . Traditional methods of prescribing exercise have not proven effective for increasing and maintaining a program of regular physical activity . OBJECTIVE To compare the 24-month intervention effects of a lifestyle physical activity program with traditional structured exercise on improving physical activity , cardiorespiratory fitness , and cardiovascular disease risk factors . DESIGN R and omized clinical trial conducted from August 1 , 1993 , through July 31 , 1997 . PARTICIPANTS Sedentary men ( n = 116 ) and women ( n = 119 ) with self-reported physical activity of less than 36 and 34 kcal/kg per day , respectively . INTERVENTIONS Six months of intensive and 18 months of maintenance intervention on either a lifestyle physical activity or a traditional structured exercise program . MAIN OUTCOME MEASURES Primary outcomes were physical activity assessed by the 7-Day Physical Activity Recall and peak oxygen consumption ( VO2peak ) by a maximal exercise treadmill test . Secondary outcomes were plasma lipid and lipoprotein cholesterol concentrations , blood pressure , and body composition . All measures were obtained at baseline and at 6 and 24 months . RESULTS Both the lifestyle and structured activity groups had significant and comparable improvements in physical activity and cardiorespiratory fitness from baseline to 24 months . Adjusted mean changes ( 95 % confidence intervals [ CIs ] ) were 0.84 ( 95 % CI , 0.42 - 1.25 kcal/kg per day ; P<.001 ) and 0.69 ( 95 % CI , 0.25 - 1.12 kcal/kg day ; P = .002 ) for activity , and 0.77 ( 95 % CI , 0.18 - 1.36 mL/kg per minute ; P = .01 ) and 1.34 ( 95 % CI , 0.72 - 1.96 mL/kg per minute ; P<.001 ) for VO2peak for the lifestyle and structured activity groups , respectively . There were significant and comparable reductions in systolic blood pressure ( -3.63 [ 95 % CI , -5.54 to -1.72 mm Hg ; P<.001 ] and -3.26 [ 95 % CI , -5.26 to -1.25 mm Hg ; P = .002 ] ) and diastolic blood pressure ( -5.38 [ 95 % CI , -6.90 to -3.86 mm Hg ; P<.001 ] and -5.14 [ 95 % CI , -6.73 to -3.54 mm Hg ; P<.001 ) for the lifestyle and structured activity groups , respectively . Neither group significantly changed their weight ( -0.05 [ 95 % CI , -1.05 to 0.96 kg ; P = .93 ] and 0.69 [ 95 % CI , -0.37 to 1.74 kg ; P = .20 ] ) , but each group significantly reduced their percentage of body fat ( -2.39 % [ 95 % CI , -2.92 % to -1.85 % ; P<.001 ] and -1.85 % [ 95 % CI , -2.41 % to -1.28 % ; P<.001 ] ) in the lifestyle and structured activity groups , respectively . CONCLUSIONS In previously sedentary healthy adults , a lifestyle physical activity intervention is as effective as a structured exercise program in improving physical activity , cardiorespiratory fitness , and blood pressure Background Complex interventions in obese pregnant women should be theoretically based , feasible and shown to demonstrate anticipated behavioural change prior to inception of large r and omised controlled trials ( RCTs ) . The aim was to determine if a ) a complex intervention in obese pregnant women leads to anticipated changes in diet and physical activity behaviours , and b ) to refine the intervention protocol through process evaluation of intervention fidelity . Methods We undertook a pilot RCT of a complex intervention in obese pregnant women , comparing routine antenatal care with an intervention to reduce dietary glycaemic load and saturated fat intake , and increase physical activity . Subjects included 183 obese pregnant women ( mean BMI 36.3 kg/m2).Diet was assessed by repeated triple pass 24-hour dietary recall and physical activity by accelerometry and question naire , at 16 + 0 to 18 + 6 and at 27 + 0 to 28 + 6 weeks ’ gestation in women in control and intervention arms . Attitudes to behaviour change and quality of life were assessed and a process evaluation undertaken . The full RCT protocol was undertaken to assess feasibility . Results Compared to women in the control arm , women in the intervention arm had a significant reduction in dietary glycaemic load ( 33 points , 95 % CI −47 to −20 ) , ( p < 0.001 ) and saturated fat intake ( −1.6 % energy , 95 % CI −2.8 to −0 . 3 ) at 28 weeks ’ gestation . Objective ly measured physical activity did not change . Physical discomfort and sustained barriers to physical activity were common at 28 weeks ’ gestation . Process evaluation identified barriers to recruitment , group attendance and compliance , leading to modification of intervention delivery . Conclusions This pilot trial of a complex intervention in obese pregnant women suggests greater potential for change in dietary intake than for change in physical activity , and through process evaluation illustrates the considerable advantage of performing an exploratory trial of a complex intervention in obese pregnant women before undertaking a large RCT .Trial registration Trial Registration Number : IS RCT Background The purpose of this study was to determine if a short-term pedometer-based intervention results in immediate increases in time spent in moderate-to-vigorous physical activity ( MVPA ) compared to a minimal educational intervention . Methods A sample of 43 overweight adults 35 to 64 years of age participated in a one week pedometer-based feasibility trial monitored by accelerometry . Participants were r and omized into a one-week education-only group or a group that also wore a pedometer . Accelerometer-measured MVPA was measured over 7 days at baseline and again for 7 days immediately post-intervention . Results Minutes of MVPA increased significantly in the overall sample ( p = 0.02 ) ; however , the effect of adding the pedometer to the education program was not significant ( p = 0.89 ) . Mean ( ±SE ) MVPA increased from 12.7±2.4 min/day to 16.2±3.6 min/day in the education-only group and from 13.2±3.3 min/day to 16.3±3.9 min/day in the education+pedometer group . The correlation between change in steps/day and change in MVPA was 0.69 ( p<0.0001 ) . Conclusions The results of this study suggest that the addition of a pedometer to a short-term education program does not produce added benefits with respect to increasing physical activity in the Lower Mississippi Delta . Trial Registration Clinical Trials.gov OBJECTIVE Observational studies show breaking up prolonged sitting has beneficial associations with cardiometabolic risk markers , but intervention studies are required to investigate causality . We examined the acute effects on postpr and ial glucose and insulin levels of uninterrupted sitting compared with sitting interrupted by brief bouts of light- or moderate-intensity walking . RESEARCH DESIGN AND METHODS Overweight/obese adults ( n = 19 ) , aged 45–65 years , were recruited for a r and omized three-period , three-treatment acute crossover trial : 1 ) uninterrupted sitting ; 2 ) seated with 2-min bouts of light-intensity walking every 20 min ; and 3 ) seated with 2-min bouts of moderate-intensity walking every 20 min . A st and ardized test drink was provided after an initial 2-h period of uninterrupted sitting . The positive incremental area under curves ( iAUC ) for glucose and insulin ( mean [ 95 % CI ] ) for the 5 h after the test drink ( 75 g glucose , 50 g fat ) were calculated for the respective treatments . RESULTS The glucose iAUC ( mmol/L ) ⋅ h after both activity-break conditions was reduced ( light : 5.2 [ 4.1–6.6 ] ; moderate : 4.9 [ 3.8–6.1 ] ; both P < 0.01 ) compared with uninterrupted sitting ( 6.9 [ 5.5–8.7 ] ) . Insulin iAUC ( pmol/L ) ⋅ h was also reduced with both activity-break conditions ( light : 633.6 [ 552.4–727.1 ] ; moderate : 637.6 [ 555.5–731.9 ] , P < 0.0001 ) compared with uninterrupted sitting ( 828.6 [ 722.0–950.9 ] ) . CONCLUSIONS Interrupting sitting time with short bouts of light- or moderate-intensity walking lowers postpr and ial glucose and insulin levels in overweight/obese adults . This may improve glucose metabolism and potentially be an important public health and clinical intervention strategy for reducing cardiovascular risk Background Levels of physical activity ( PA ) in UK children are much lower than recommended and novel approaches to its promotion are needed . The Children , Parents and Pets Exercising Together ( CPET ) study is the first exploratory r and omised controlled trial ( RCT ) to develop and evaluate an intervention aim ed at dog-based PA promotion in families . CPET aim ed to assess the feasibility , acceptability and potential efficacy of a theory-driven , family-based , dog walking intervention for 9–11 year olds . Methods Twenty-eight families were allocated r and omly to either receive a 10-week dog based PA intervention or to a control group . Families in the intervention group were motivated and supported to increase the frequency , intensity and duration of dog walking using a number of behaviour change techniques . Parents in the intervention group were asked to complete a short study exit question naire . In addition , focus groups with parents and children in the intervention group , and with key stakeholders were undertaken . The primary outcome measure was 10 week change in total volume of PA using the mean accelerometer count per minute ( cpm ) . Intervention and control groups were compared using analysis of covariance . Analysis was performed on an intention to treat basis . Results Twenty five families were retained at follow up ( 89 % ) and 97 % of all outcome data were collected at baseline and follow up . Thirteen of 14 ( 93 % ) intervention group parents available at follow up completed the study exit question naire and noted that study outcome measures were acceptable . There was a mean difference in child total volume of PA of 27 cpm ( 95 % CI -70 , 123 ) and -3 cpm ( 95 % CI -60 , 54 ) for intervention and control group children , respectively . This was not statistically significant . Approximately 21 % of dog walking time for parents and 39 % of dog walking time for children was moderate-vigorous PA . Conclusions The acceptability of the CPET intervention and outcome measures was high . Using pet dogs as the agent of lifestyle change in PA interventions in children and their parents is both feasible and acceptable , but did not result in a significant increase in child PA in this exploratory trial . Trial registration IS RCT Background Inactive people are often not aware of the fact that they are insufficiently active . Providing insight into their actual physical activity ( PA ) levels may raise awareness and could , in combination with tailored PA advice , stimulate a physically active lifestyle . Objective This study evaluated the feasibility and effectiveness of a 3-month intervention in which Dutch office workers were provided with a personal activity monitor ( PAM ) coupled to simple and concise Web-based tailored PA advice ( PAM COACH ) . Method Participants were r and omly assigned to the 3-month PAM intervention ( n = 51 ) or received a single written information brochure with brief general PA recommendations ( n = 51 ) . Study outcome measures were changes in PA ( recall of minutes per week spent on PA , as measured by the Activity Question naire for Adolescents and Adults ) , determinants of PA , aerobic fitness , and body composition . Follow-up measurements were performed immediately after the 3-month intervention and at 8-months , 5 months after the end of the 3-month intervention period . Results A total of 102 workers , 23 to 39 years old , completed the baseline measurement at the worksite . 48 completed the 3-month follow up and 38 the 8-month follow-up in the intervention group , 50 completed the 3-month follow up and 42 the 8-month follow up in the control group . 35 out of 48 ( 73 % ) participants in the PAM intervention group reported wearing the PAM regularly , and the PAM COACH was used almost once a week ; 24 out of 46 ( 52 % ) PAM users set a personal goal , and 33 ( 72 % ) entered their favorite activities on the website . Main reasons for not using these items were lack of interest or not being able to find the item on the website . The majority of PAM users ( 34 out of 46 , 74 % ) read the advice , of whom 14 ( 39 % ) found it unappealing . After the 3-month intervention , no significant intervention effect was observed ( adjusted difference in min/week ) for sedentary behavior ( β = 10 , 95 % CI = −435 to 455 ) , light-intensity PA ( β = −129 , 95 % CI = −337 to 79 ) , moderate-intensity PA ( β = −13 , 95 % CI = −89 to 63 ) , vigorous-intensity PA ( β= −6 , 95 % CI = −75 to 62 ) , and moderate- to vigorous-intensity PA ( β = −23 , 95 % CI = −121 to 76 ) . No significant intervention effect was observed in the PA outcomes at the 8-month follow-up . For the determinants of PA , aerobic fitness , and body composition , no statistically significant intervention effect was observed in the total study population immediately after the 3-month intervention or the 8-month follow-up . Conclusions The intervention appeared to be easily applicable to real-life setting s. The intervention was ineffective in improving PA behavior or its determinants in healthy office workers . More attention should have been given to the quality and appropriateness of the tailored advice . Trial Registration International St and ard R and omized Controlled Trial Number ( IS RCT N ) : 93896459 ; http://www.controlled-trials.com/IS RCT N93896459/ ( Archived by WebCite at http://www.webcitation.org/5iR3mf7ex Background The diets , physical activity and sedentary behavior levels of both children and adults in Australia are suboptimal . The family environment , as the first ecological niche of children , exerts an important influence on the onset of children ’s habits . Parent modeling is one part of this environment and a logical focus for child obesity prevention initiatives . The focus on parent ’s own behaviors provides a potential opportunity to decrease obesity risk behaviors in parents as well . Objective To assess the effect of a parent-focused early childhood obesity prevention intervention on first-time mothers ’ diets , physical activity and TV viewing time . Methods The Melbourne InFANT Program is a cluster-r and omized controlled trial which involved 542 mothers over their newborn ’s first 18 months of life . The intervention focused on parenting skills and strategies , including parental modeling , and aim ed to promote development of healthy child and parent behaviors from birth , including healthy diet , increased physical activity and reduced TV viewing time . Data regarding mothers ’ diet ( food frequency question naire ) , physical activity and TV viewing times ( self-reported question naire ) were collected using vali date d tools at both baseline and post-intervention . Four dietary patterns were derived at baseline using principal components analyses including frequencies of 55 food groups . Analysis of covariance was used to measure the impact of the intervention . Results The scores of both the " High-energy snack and processed foods " and the " High-fat foods " dietary patterns decreased more in the intervention group : -0.22 ( −0.42;-0.02 ) and −0.25 ( −0.50;-0.01 ) , respectively . No other significant intervention vs. control effects were observed regarding total physical activity , TV viewing time , and the two other dietary patterns , i.e. “ Fruits and vegetables ” and “ Cereals and sweet foods ” . Conclusions These findings suggest that supporting first-time mothers to promote healthy lifestyle behaviors in their infants impacts maternal dietary intakes positively . Further research needs to assess ways in which we might further enhance those lifestyle behaviors not impacted by the InFANT intervention BACKGROUND Sedentary behavior is regarded as a distinct risk factor for cardiometabolic morbidity and mortality , but knowledge of the efficacy of interventions targeting reductions in sedentary behavior is limited . PURPOSE To investigate the effect of an individualized face-to-face motivational counseling intervention aim ed at reducing sitting time . DESIGN A r and omized , controlled , observer-blinded , community-based trial with two parallel groups using open-end r and omization with 1:1 allocation . SETTING / PARTICIPANTS A total of 166 sedentary adults were consecutively recruited from the population -based Health2010 Study . INTERVENTION Participants were r and omized to a control ( usual lifestyle ) or intervention group with four individual theory-based counseling sessions . MAIN OUTCOME MEASURES Objective ly measured overall sitting time ( ActivPAL 3TM , 7 days ) ; secondary measures were breaks in sitting time , anthropometric measures , and cardiometabolic biomarkers , assessed at baseline and after 6 months . Data were collected in 2010 - 2012 and analyzed in 2013 - 2014 using repeated measures multiple regression analyses . RESULTS Ninety-three participants were r and omized to the intervention group and 73 to the control group , and 149 completed the study . The intervention group had a mean sitting time decrease of -0.27 hours/day , corresponding to 2.9 % of baseline sitting time ( hours/day ) ; the control group increased mean sitting time by 0.06 hours/day . The between-group difference in change , -0.32 hours/day ( 95 % CI=-0.87 , 0.24 , p=0.26 ) , was not statistically significant . Significant differences in change in fasting serum insulin of -5.9 pmol/L ( 95 % CI=-11.4 , -0.5 , p=0.03 ) ; homeostasis model assessment -estimated insulin resistance of -0.28 ( 95 % CI=-0.53 , -0.03 , p=0.03 ) ; and waist circumference of -1.42 cm ( 95 % CI=-2.54 , -0.29 , p=0.01 ) were observed in favor of the intervention group . CONCLUSIONS Although the observed decrease in sitting time was not significant , a community-based , individually tailored , theory-based intervention program aim ed at reducing sitting time may be effective for increasing st and ing and improving cardiometabolic health in sedentary adults . TRIAL REGISTRATION This study is registered at Clinical trials.gov ( NCT00289237 ) Background Occupational sedentary behaviour is an important contributor to overall sedentary risk . There is limited evidence for effective workplace interventions to reduce occupational sedentary time and increase light activity during work hours . The purpose of the study was to determine if participatory workplace interventions could reduce total sedentary time , sustained sedentary time ( bouts > 30 minutes ) , increase the frequency of breaks in sedentary time and promote light intensity activity and moderate/vigorous activity ( MVPA ) during work hours . Methods A r and omised controlled trial ( ANZCTR number : ACTN12612000743864 ) was conducted using clerical , call centre and data processing workers ( n = 62 , aged 25–59 years ) in 3 large government organisations in Perth , Australia . Three groups developed interventions with a participatory approach : ‘ Active office ’ ( n = 19 ) , ‘ Active Workstation ’ and promotion of incidental office activity ; ‘ Traditional physical activity ’ ( n = 14 ) , pedometer challenge to increase activity between productive work time and ‘ Office ergonomics ’ ( n = 29 ) , computer workstation design and breaking up computer tasks . Accelerometer ( ActiGraph GT3X , 7 days ) determined sedentary time , sustained sedentary time , breaks in sedentary time , light intensity activity and MVPA on work days and during work hours were measured before and following a 12 week intervention period . Results For all participants there was a significant reduction in sedentary time on work days ( −1.6 % , p = 0.006 ) and during work hours ( −1.7 % , p = 0.014 ) and a significant increase in number of breaks/sedentary hour on work days ( 0.64 , p = 0.005 ) and during work hours ( 0.72 , p = 0.015 ) ; there was a concurrent significant increase in light activity during work hours ( 1.5 % , p = 0.012 ) and MVPA on work days ( 0.6 % , p = 0.012 ) . Conclusions This study explored novel ways to modify work practice s to reduce occupational sedentary behaviour . Participatory workplace interventions can reduce sedentary time , increase the frequency of breaks and improve light activity and MVPA of office workers by using a variety of interventions . Trial Registration Australian New Zeal and Clinical Trials Registry ACTN12612000743864 PURPOSE Although moderate-to-vigorous physical activity is related to premature mortality , the relationship between sedentary behaviors and mortality has not been fully explored and may represent a different paradigm than that associated with lack of exercise . We prospect ively examined sitting time and mortality in a representative sample of 17,013 Canadians 18 - 90 yr of age . METHODS Evaluation of daily sitting time ( almost none of the time , one fourth of the time , half of the time , three fourths of the time , almost all of the time ) , leisure time physical activity , smoking status , and alcohol consumption was conducted at baseline . Participants were followed prospect ively for an average of 12.0 yr for the ascertainment of mortality status . RESULTS There were 1832 deaths ( 759 of cardiovascular disease ( CVD ) and 547 of cancer ) during 204,732 person-yr of follow-up . After adjustment for potential confounders , there was a progressively higher risk of mortality across higher levels of sitting time from all causes ( hazard ratios ( HR ) : 1.00 , 1.00 , 1.11 , 1.36 , 1.54 ; P for trend < 0.0001 ) and CVD ( HR:1.00 , 1.01 , 1.22 , 1.47 , 1.54 ; P for trend < 0.0001 ) but not cancer . Similar results were obtained when stratified by sex , age , smoking status , and body mass index . Age-adjusted all-cause mortality rates per 10,000 person-yr of follow-up were 87 , 86 , 105 , 130 , and 161 ( P for trend < 0.0001 ) in physically inactive participants and 75 , 69 , 76 , 98 , 105 ( P for trend = 0.008 ) in active participants across sitting time categories . CONCLUSIONS These data demonstrate a dose-response association between sitting time and mortality from all causes and CVD , independent of leisure time physical activity . In addition to the promotion of moderate-to-vigorous physical activity and a healthy weight , physicians should discourage sitting for extended periods The purpose of this study was to investigate the benefits of a pedometer and a cognitive-behavioural group intervention for promoting physical activity ( PA ) in type 2 diabetes patients . We recruited 41 participants and r and omized them into an intervention group ( IG ) ( n = 20 ) and a control group ( CG ) ( n = 21 ) . The intervention consisted of five sessions within 12 weeks , a booster session after 22 weeks and a pedometer . Primary outcome was PA assessed by accelerometer ( minutes per day ) and pedometer ( steps per day ) . Secondary outcomes were weight , body mass index , blood pressure , haemoglobin A1c and total cholesterol . After 12 weeks , the IG increased with more than 2000 steps day−1 compared with the CG , whereas sedentary behaviour decreased more than 1 hour day−1 in the IG and showed no change in the CG . There was no intervention effect on the accelerometer-based PA nor on health measurements . After 1 year , the increase in steps per day remained significant in the IG , but sedentary activity increased again to baseline levels . This pilot study showed that the combination of a 12-week cognitive-behavioura intervention and a pedometer has a significant short-term impact on daily steps and sedentary behaviour but that the effects on total PA and long-term effects were limited The present study was design ed to evaluate the 3 year effects of a lifestyle intervention on weight loss and maintenance , dietary , and physical activity habits and eating behavior of patients following vertical b and ed gastroplasty ( VBG ) . Thirty severely obese female volunteers were included in the study and they were r and omly assigned to one of two intervention groups : usual care ( UC ) or lifestyle intervention ( LS ) group . Patients were followed for 3 years postoperatively . Outcome measures included weight loss , dietary habits , physical activity level ( PAL ) , and eating behavior changes . Weight was significantly lower in the LS group after 12 months ( 84.4 + /- 3.9 kg vs. 98.4 + /- 4.4 kg , P < 0.05 ) , 24 months ( 83.0 + /- 3.3 vs. 101.9 + /- 5.3 kg , P < 0.05 ) , and 36 months following surgery ( 84.2 + /- 3.3 vs. 102.5 + /- 3.5 kg , P < 0.05 ) . Repeated measures ANOVA revealed significant differences between the two groups overall and at specific time points for the PAL and TV viewing . With regard to eating behavior , the LS group scored significantly better in total Dutch Eating Behavior Question naire ( DEBQ ) , Restraint Eating and External Eating scales at all postoperative time points . Similarly , significant differences were found between the two groups in dietary intake . These findings outline the importance of lifestyle intervention on weight loss and maintenance following bariatric surgery . The favorable effects of lifestyle intervention may be through adoption of healthier eating behaviors and increased physical activity Background . Physical activity can positively influence health for older adults . Primary care is a good setting for physical activity promotion . Objective . To assess the feasibility of a pedometer-based walking programme in combination with physical activity consultations . Methods . Design : Two-arm ( intervention/control ) 12-week r and omized controlled trial with a 12-week follow-up for the intervention group . Setting : One general practice in Glasgow , UK . Participants : Participants were aged ≥65 years . The intervention group received two 30-minute physical activity consultations from a trained practice nurse , a pedometer and a walking programme . The control group continued as normal for 12 weeks and then received the intervention . Both groups were followed up at 12 and 24 weeks . Outcome measures : Step counts were measured by sealed pedometers and an activPALTM monitor . Psychosocial variables were assessed and focus groups conducted . Results . The response rate was 66 % ( 187/284 ) , and 90 % of those r and omized ( 37/41 ) completed the study . Qualitative data suggested that the pedometer and nurse were helpful to the intervention . Step counts ( activPAL ) showed a significant increase from baseline to week 12 for the intervention group , while the control group showed no change . Between weeks 12 and 24 , step counts were maintained in the intervention group , and increased for the control group after receiving the intervention . The intervention was associated with improved quality of life and reduced sedentary time . Conclusions . It is feasible to recruit and retain older adults from primary care and help them increase walking . A larger trial is necessary to confirm findings and consider cost-effectiveness PA energy expenditure ( PAEE ) is the most variable component of Total Energy Expenditure ( TEE ) and largely due to the balance of sedentary time ( SedT ) and low intensity physical activity ( LIPA ) . There has been an emergence for seeking an underst and ing of factors which determine variations in SedT , LIPA , and PAEE . Sedentary behavior and physical activity are relatively resistant to change by experimental dietary treatments and significant body weight changes . Although caffeine ( Caf ) is by far the most heavily used nutritional agent ingested to promote a sense of vigor/alertness , it is still unknown if Caf is effective in increasing PAEE and physical activity . The aim of the study was to test the hypothesis that 2 daily doses of Caf ( as a capsule to blind the treatment and divided equally during breakfast and lunch ) increase PAEE and TEE , and it would do so through increasing the frequent and brief bouts of physical activity ( ~1 - 5 min long ) through the day as measured by accelerometry . In 21 low Caf users ( < 100 mg day-1 ) , we used a double-blind crossover trial ( Clinical Trials.govID;NCT01477294 ) with two conditions ( 4-day each with a 3-day washout period ) r and omly ordered as 5 mg kg-1 day-1 of Caf and maltodextrin as placebo ( Plc ) . Resting energy expenditure ( REE ) by indirect calorimetry , total energy expenditure ( TEE ) from doubly labeled water , PAEE calculated as TEE-(REE+0.1TEE ) , and accelerometry measurements of both LIPA and MVPA were not different between conditions . However , regardless of caffeine or placebo , there were several significant relationships between brief bouts of LIPA and MVPA with PAEE . In conclusion , this double-blind study found that low and moderate-vigorous activity as well as the total volume of PAEE in free-living conditions is resistant to dietary caffeine intake that was equivalent to 5 cups of espresso or 7 cups of tea . Trial Registration Clinical Trials.gov Background There is a growing problem of physical inactivity in America , and approximately a quarter of the population report being completely sedentary during their leisure time . In the U.S. , TV viewing is the most common leisure-time activity . Stepping in place during TV commercials ( TV Commercial Stepping ) could increase physical activity . The purpose of this study was to examine the feasibility of incorporating physical activity ( PA ) into a traditionally sedentary activity , by comparing TV Commercial Stepping during 90 min/d of TV programming to traditional exercise ( Walking ) . Methods A r and omized controlled pilot study of the impact of 6 months of TV Commercial Stepping versus Walking 30 min/day in adults was conducted . 58 sedentary , overweight ( body mass index 33.5 ± 4.8 kg/m2 ) adults ( age 52.0 ± 8.6 y ) were r and omly assigned to one of two 6-mo behavioral PA programs : 1 ) TV Commercial Stepping ; or 2 ) Walking 30 min/day . To help facilitate behavior changes participants received 6 monthly phone calls , attended monthly meetings for the first 3 months , and received monthly newsletters for the last 3 months . Using intent-to-treat analysis , changes in daily steps , TV viewing , diet , body weight , waist and hip circumference , and percent fat were compared at baseline , 3 , and 6 mo . Data were collected in 2010–2011 , and analyzed in 2011 . Results Of the 58 subjects , 47 ( 81 % ) were retained for follow-up at the completion of the 6-mo program . From baseline to 6-mo , both groups significantly increased their daily steps [ 4611 ± 1553 steps/d vs. 7605 ± 2471 steps/d ( TV Commercial Stepping ) ; 4909 ± 1335 steps/d vs. 7865 ± 1939 steps/d ( Walking ) ; P < 0.05 ] with no significant difference between groups . TV viewing and dietary intake decreased significantly in both groups . Body weight did not change , but both groups had significant decreases in percent body fat ( 3-mo to 6-mo ) , and waist and hip circumference ( baseline to 6-mo ) over time . Conclusions Participants in both the TV Commercial Stepping and Walking groups had favorable changes in daily steps , TV viewing , diet , and anthropometrics . PA can be performed while viewing TV commercials and this may be a feasible alternative to traditional approaches for increasing daily steps in overweight and obese adults . Trial Registration This study is registered at Clinical Trials.gov , Objectives To test the efficacy of a multicomponent technology intervention for reducing daily sedentary time and improving cardiometabolic disease risk among sedentary , overweight university employees . Design Blinded , r and omised controlled trial . Setting A large south-eastern university in the USA . Participants 49 middle-aged , primarily female , sedentary and overweight adults working in sedentary jobs enrolled in the study . A total of 40 participants completed the study . Interventions Participants were r and omised to either : ( 1 ) an intervention group ( N=23 ; 47.6 + 9.9 years ; 94.1 % female ; 33.2 + 4.5 kg/m2 ) ; ( 2 ) or wait-list control group ( N=17 ; 42.6 + 8.9 years ; 86.9 % female ; 31.7 + 4.9 kg/m2 ) . The intervention group received a theory-based , internet-delivered programme , a portable pedal machine at work and a pedometer for 12 weeks . The wait-list control group maintained their behaviours for 12 weeks . Outcome measures Primary ( sedentary and physical activity behaviour measured objective ly through StepWatch ) and secondary ( heart rate , blood pressure , height , weight , waist circumference , per cent body fat , cardiorespiratory fitness , fasting lipids ) outcomes were measured at baseline and postintervention ( 12 weeks ) . Exploratory outcomes including intervention compliance and process evaluation measures were also assessed postintervention . Results Compared to controls , the intervention group reduced daily sedentary time ( mean change ( 95%CI ) : −58.7 min/day ( −118.4 to 0.99 ; p<0.01 ) ) after adjusting for baseline values and monitor wear time . Intervention participants logged on to the website 71.3 % of all intervention days , used the pedal machine 37.7 % of all working intervention days and pedalled an average of 31.1 min/day . Conclusions These findings suggest that the intervention was engaging and result ed in reductions in daily sedentary time among full-time sedentary employees . These findings hold public health significance due to the growing number of sedentary jobs and the potential of these technologies in large-scale worksite programmes . Trial Registration Clinical Trials.gov # NCT01371084 Background Large-scale RCTs comparing different types of exercise training in institutionalised older people are scarce , especially regarding effects on habitual physical activity and constipation . This study investigated the effects of different training protocol s on habitual physical activity and constipation of older adults living in long-term care facilities . Methods A r and omized controlled trial with 157 participants , aged 64 to 94 years , who were r and omly assigned to 1 ) resistance training ; 2 ) all-round functional-skills training ; 3 ) both ; or 4 ) an ' educational ' control condition . Habitual physical activity was assessed with a physical activity question naire and accelerometers . Constipation was assessed by a question naire . Measurements were performed at baseline and after six months of training . Results At baseline the median time spent sitting was 8.2 hr/d , the median time spent on activity of at least moderate intensity was 32 min/d . At baseline , about 22 % of the subjects were diagnosed with constipation and 23 % were taking laxatives . There were no between-group differences for changes in habitual physical activity or constipation over 6-months . ConclusionS ix months of moderate intensity exercise training neither enhances habitual physical activity nor affects complaints of constipation among older people living in long-term care facilities Introduction Overweight and obesity are associated with an increased risk of morbidity . Mindfulness training could be an effective strategy to optimize lifestyle behaviors related to body weight gain . The aim of this study was to evaluate the effectiveness of a worksite mindfulness-based multi-component intervention on vigorous physical activity in leisure time , sedentary behavior at work , fruit intake and determinants of these behaviors . The control group received information on existing lifestyle behavior- related facilities that were already available at the worksite . Methods In a r and omized controlled trial design ( n = 257 ) , 129 workers received a mindfulness training , followed by e-coaching , lunch walking routes and fruit . Outcome measures were assessed at baseline and after 6 and 12 months using question naires . Physical activity was also measured using accelerometers . Effects were analyzed using linear mixed effect models according to the intention-to-treat principle . Linear regression models ( complete case analyses ) were used as sensitivity analyses . Results There were no significant differences in lifestyle behaviors and determinants of these behaviors between the intervention and control group after 6 or 12 months . The sensitivity analyses showed effect modification for gender in sedentary behavior at work at 6-month follow-up , although the main analyses did not . Conclusions This study did not show an effect of a worksite mindfulness-based multi-component intervention on lifestyle behaviors and behavioral determinants after 6 and 12 months . The effectiveness of a worksite mindfulness-based multi-component intervention as a health promotion intervention for all workers could not be established Background Interventions design ed to increase workplace physical activity may not automatically reduce high volumes of sitting , a behaviour independently linked to chronic diseases such as obesity and type II diabetes . This study compared the impact two different walking strategies had on step counts and reported sitting times . Methods Participants were white-collar university employees ( n = 179 ; age 41.3 ± 10.1 years ; 141 women ) , who volunteered and undertook a st and ardised ten-week intervention at three sites . Pre-intervention step counts ( Yamax SW-200 ) and self-reported sitting times were measured over five consecutive workdays . Using pre-intervention step counts , employees at each site were r and omly allocated to a control group ( n = 60 ; maintain normal behaviour ) , a route-based walking group ( n = 60 ; at least 10 minutes sustained walking each workday ) or an incidental walking group ( n = 59 ; walking in workday tasks ) . Workday step counts and reported sitting times were re-assessed at the beginning , mid- and endpoint of intervention and group mean± SD steps/day and reported sitting times for pre-intervention and intervention measurement points compared using a mixed factorial ANOVA ; paired sample -t-tests were used for follow-up , simple effect analyses . Results A significant interactive effect ( F = 3.5 ; p < 0.003 ) was found between group and step counts . Daily steps for controls decreased over the intervention period ( -391 steps/day ) and increased for route ( 968 steps/day ; t = 3.9 , p < 0.000 ) and incidental ( 699 steps/day ; t = 2.5 , p < 0.014 ) groups . There were no significant changes for reported sitting times , but average values did decrease relative to the control ( routes group = 7 minutes/day ; incidental group = 15 minutes/day ) . Reductions were most evident for the incidental group in the first week of intervention , where reported sitting decreased by an average of 21 minutes/day ( t = 1.9 ; p < 0.057 ) . Conclusion Compared to controls , both route and incidental walking increased physical activity in white-collar employees . Our data suggests that workplace walking , particularly through incidental movement , also has the potential to decrease employee sitting times , but there is a need for on-going research using concurrent and objective measures of sitting , st and ing and walking BACKGROUND Many patients exhibit multiple chronic disease risk behaviors . Research provides little information about advice that can maximize simultaneous health behavior changes . METHODS To test which combination of diet and activity advice maximizes healthy change , we r and omized 204 adults with elevated saturated fat and low fruit and vegetable intake , high sedentary leisure time , and low physical activity to 1 of 4 treatments : increase fruit/vegetable intake and physical activity , decrease fat and sedentary leisure , decrease fat and increase physical activity , and increase fruit/vegetable intake and decrease sedentary leisure . Treatments provided 3 weeks of remote coaching supported by mobile decision support technology and financial incentives . During treatment , incentives were contingent on using the mobile device to self-monitor and attain behavioral targets ; during follow-up , incentives were contingent only on recording . The outcome was st and ardized , composite improvement on the 4 diet and activity behaviors at the end of treatment and at 5-month follow-up . RESULTS Of the 204 individuals r and omized , 200 ( 98.0 % ) completed follow-up . The increase fruits/vegetables and decrease sedentary leisure treatments improved more than the other 3 treatments ( P < .001 ) . Specifically , daily fruit/vegetable intake increased from 1.2 servings to 5.5 servings , sedentary leisure decreased from 219.2 minutes to 89.3 minutes , and saturated fat decreased from 12.0 % to 9.5 % of calories consumed . Differences between treatment groups were maintained through follow-up . Traditional dieting ( decrease fat and increase physical activity ) improved less than the other 3 treatments ( P < .001 ) . CONCLUSIONS Remote coaching supported by mobile technology and financial incentives holds promise to improve diet and activity . Targeting fruits/vegetables and sedentary leisure together maximizes overall adoption and maintenance of multiple healthy behavior changes Background Computer tailoring is a relatively innovative and promising physical activity intervention approach . However , few computer-tailored physical activity interventions in adults have provided feedback based on pedometer use . Objectives To ( 1 ) describe the development of a Web-based , pedometer-based , computer-tailored step advice intervention , ( 2 ) report on the dissemination of this tool through general practice , ( 3 ) report on its perceived acceptability , and ( 4 ) evaluate the preliminary efficacy of this tool in comparison with a st and ard intervention . Methods We recruited 92 participants through general practitioners and r and omly assigned them to a st and ard condition ( receiving a pedometer-only intervention , n = 47 ) and a tailored condition ( receiving a pedometer plus newly developed , automated , computer-tailored step advice intervention , n = 45 ) . Step counts , self-reported data obtained via telephone interview on physical activity , time spent sitting , and body mass index were assessed at baseline and postintervention . The present sample was mostly female ( 54/92 , 59 % ) , highly educated ( 59/92 , 64 % ) , employed ( 65/92 , 71 % ) , and in good health ( 62/92 , 67 % ) . Results Recruitment through general practitioners was poor ( n = 107 , initial response rate 107/1737 , 6.2 % ) ; however , the majority of participants ( 50/69 , 73 % ) believed it is useful that general practitioners help patients find ways to increase physical activity . In the tailored condition , 30/43 ( 70 % ) participants requested the computer-tailored step advice and the majority found it underst and able ( 21/21 , 100 % ) , credible ( 17/18 , 94 % ) , relevant ( 15/18 , 83 % ) , not too long ( 13/18 , 72 % ) , instructive ( 13/18 , 72 % ) , and encouraging to increase steps ( 16/24 , 67 % ) . Daily step counts increased from baseline ( mean 9237 , SD 3749 steps/day ) to postintervention ( mean 11,876 , SD 4574 steps/day ) in the total sample ( change of 2639 , 95 % confidence interval 105–5172 ; F 1 = 5.0 , P = .04 ) . No interaction or other time effects were found . Conclusions The majority of participants in the tailored condition accepted the step advice and indicated it was useful . However , in this selected sample of adults , the tailored condition did not show superior effects compared with the st and ard condition Background Many children spend too much time screen-viewing ( watching TV , surfing the internet and playing video games ) and do not meet physical activity ( PA ) guidelines . Parents are important influences on children ’s PA and screen-viewing ( SV ) . There is a shortage of parent-focused interventions to change children ’s PA and SV . Methods Teamplay was a two arm individualized r and omized controlled feasibility trial . Participants were parents of 6–8 year old children . Intervention participants were invited to attend an eight week parenting program with each session lasting 2 hours . Children and parents wore an accelerometer for seven days and minutes of moderate-to-vigorous intensity PA ( MVPA ) were derived . Parents were also asked to report the average number of hours per day that both they and the target child spent watching TV . Measures were assessed at baseline ( time 0 ) at the end of the intervention ( week 8) and 2 months after the intervention had ended ( week 16 ) . Results There were 75 participants who provided consent and were r and omized but 27 participants withdrew post-r and omization . Children in the intervention group engaged in 2.6 fewer minutes of weekday MVPA at Time 1 but engaged in 11 more minutes of weekend MVPA . At Time 1 the intervention parents engaged in 9 more minutes of weekday MVPA and 13 more minutes of weekend MVPA . The proportion of children in the intervention group watching ≥ 2 hours per day of TV on weekend days decreased after the intervention ( time 0 = 76 % , time 1 = 39 % , time 2 = 50 % ) , while the control group proportion increased slightly ( 79 % , 86 % and 87 % ) . Parental weekday TV watching decreased in both groups . In post- study interviews many mothers reported problems associated with wearing the accelerometers . In terms of a future full-scale trial , a sample of between 80 and 340 families would be needed to detect a mean difference of 10-minutes of weekend MVPA . Conclusions Teamplay is a promising parenting program in an under- research ed area . The intervention was acceptable to parents , and all elements of the study protocol were successfully completed . Simple changes to the trial protocol could result in more complete data collection and study engagement Background To our knowledge , no studies have aim ed at improving the PA level in south Asian immigrant men residing in Western countries , and few studies have considered the relevance of SCT constructs to the PA behaviour of this group in the long term . The observed low physical activity ( PA ) level among south Asian immigrants in Western countries may partly explain the high prevalence of cardiovascular diseases ( CVD ) and type 2 diabetes ( T2D ) in this group . We have shown previously in a r and omised controlled trial , the Physical Activity and Minority Health study ( PAMH ) that a social cognitive based intervention can beneficially influence PA level and subsequently reduce waist circumference and insulin resistance in the short-term . In an extended follow-up of the PAMH study : we aim ed 1 ) to determine if the intervention produced long-term positive effects on PA level six months after intervention ( follow-up 2 ( FU2 ) ) , and 2 ) to identify the social cognitive mediators of any intervention effects . Methods Physically inactive Pakistani immigrant men ( n = 150 ) who were free of CVD and T2D were r and omly assigned to a five months PA intervention or a control group . Six months after the intervention ended , we telephoned all those who attended FU1 and invited them for a second follow-up test ( FU2 ) ( n = 133 ) . PA was measured using ActiGraph accelerometers . Statistical differences between groups were determined by use of ANCOVA . Results Significant differences ( baseline to FU2 ) between the groups were found for all PA variables ( e.g. , total PA level , sedentary time , PA intensity ) . Support from family and outcome expectancies increased more in the intervention group compared with the control group . Self-efficacy did not differ significantly between groups . Conclusions Our results show that a multi component PA programme can increase PA over the short and long term in a group of immigrant Pakistani men . However , we could not identify the factors that mediated these changes in PA . Protocol ID07112001326 , NCT ID : PURPOSE : The present study evaluated the cross-section and prospect i ve associations between the Eating Inventory 's ( EI ) total , flexible and rigid dietary restraint scales and changes in weight and behaviors in a community sample of adults enrolled in a 3 y weight gain prevention study . METHODS : Subjects were participants in the Pound of Prevention ( POP ) study , a community-based weight gain prevention trial . RESULTS : Higher levels of baseline total , flexible and rigid dietary restraint were related to lower weight and more weight-controlling behaviors at the baseline assessment . Baseline restraint measures positively predicted increases in weighing frequency over the 3 y follow-up . Increases in restraint over the follow-up period were related to decreases in weight , energy intake and television watching , and increases in self-weighing and physical activity . CONCLUSION : The EI 's total , flexible and rigid restraint scales were not differently associated with weight and behaviors in this heterogeneous sample of adults who were attempting to lose weight . Developing methods to increase behavioral and cognitive strategies to control weight may help to prevent weight gain in clinical and community sample s . International Journal of Obesity ( 2001 ) 25 , BACKGROUND Prolonged sitting is prevalent in the workplace and is associated with adverse health markers . PURPOSE Investigate the effects of point-of-choice ( PoC ) prompting software , on the computer used at work ( PC ) , to reduce long uninterrupted sedentary periods and total sedentary time at work . DESIGN Assessor-blinded , parallel group , active-controlled r and omized trial . SETTING / PARTICIPANTS A convenience sample of office workers from Glasgow , United Kingdom . Data were collected April to June 2010 , and analyzed October 2010 to June 2011 . INTERVENTION The education group ( n=14 ) received a brief education session on the importance of reducing long sitting periods at work . The PoC group ( n=14 ) received the same education along with prompting software on their PC for 5 workdays , which reminded them to st and up every 30 minutes . MAIN OUTCOME MEASURES Sitting time was measured objective ly using the activPAL ™ activity monitor for 5 workdays at baseline and 5 workdays during the intervention . The number and time spent sitting in events > 30 minutes ' duration were the main outcome measures . RESULTS At baseline , participants spent 5.7±1.0 hours/day ( 76%±9 % ) of their time at work sitting . Of that time , 3.3±1.3 hours/day was spent sitting in 3.7±1.4 events > 30 minutes . There was a significant difference between the groups in the change ( intervention to baseline ) of both the number ( ANCOVA ; -6.8 % , p=0.014 ) and duration ( -15.5 % , p=0.007 ) of sitting events > 30 minutes . During the intervention , compared with baseline , the PoC group reduced the number ( paired t-test ; -0.11 events/hour , p=0.045 ) and duration ( -12.2 % , p=0.035 ) of sitting events > 30 minutes . However , there was no significant difference in total sitting time between groups ( -4.4 % , p=0.084 ) . CONCLUSIONS Point-of-choice prompting software on work computers recommending taking a break from sitting plus education is superior to education alone in reducing long uninterrupted sedentary periods at work . TRIAL REGISTRATION This trial was registered at Clinical Trials.govNCT01628861 Work Related Musculoskeletal Disorders ( WMSDs ) among office workers with intensive computer use is widespread and the prevalence of symptoms is growing . This r and omized controlled trial investigated the effects of an office ergonomics training combined with a sit-st and workstation on musculoskeletal and visual discomfort , behaviors and performance . Participants performed a lab-based customer service job for 8 h per day , over 15 days and were assigned to : Ergonomics Trained ( n = 11 ) or Minimally Trained ( n = 11 ) . The training consisted of : a 1.5-h interactive instruction , a sit/st and practice period , and ergonomic reminders . Ergonomics Trained participants experienced minimal musculoskeletal and visual discomfort across the 15 days , varied their postures , with significantly higher performance compared to the Minimally Trained group who had a significantly higher number of symptoms , suggesting that training plays a critical role . The ability to mitigate symptoms , change behaviors and enhance performance through training combined with a sit-st and workstation has implication s for preventing discomforts in office workers BACKGROUND Follow-up support increases the effectiveness of physical activity interventions . This study evaluates the effectiveness of 2 support modes on physical activity and mental health . METHODS University employees were r and omly assigned to a coaching program with 4 face-to-face ( N = 33 ) or telephone-based ( N = 33 ) support contacts . Both programs included an initial face-to-face intake session and an informational brochure . Physical activity , trait anxiety , self-efficacy , and social support were measured by self-report before and after the interventions that lasted 3 months . RESULTS Both groups increased leisure-time physical activity , self-efficacy , and social support and decreased sitting time and trait anxiety . The only significant time by group interaction was found for active transportation . More specifically , participants in the face-to-face group reported a significant increase in their active transportation from pretest to posttest , whereas participants in the telephone group reported no significant change . CONCLUSIONS Both face-to-face support and telephone support proved to be effective in increasing the physical activity level and mental health of university employees BACKGROUND Mediated physical activity interventions can reach large numbers of people at low cost . Programs delivered through the mail that target the stage of motivational readiness have been shown to increase activity . Communication technology ( websites and e-mail ) might provide a means for delivering similar programs . METHODS R and omized trial conducted between August and October 2001 . Participants included staff at an Australian university ( n=655 ; mean age=43 , st and ard deviation , 10 years ) . Participants were r and omized to either an 8-week , stage-targeted print program ( Print ) or 8-week , stage-targeted website ( Web ) program . The main outcome was change in self-reported physical activity . RESULTS There was no significant increase in total reported physical activity within or between groups when analyzed by intention to treat ( F [1,653]=0.41 , p=0.52 ) . There was a significant increase in total physical activity reported by the Print participants who were inactive at baseline ( t [1,173]=-2.21 , p=0.04 ) , and a significant decrease in the average time spent sitting on a weekday in the Web group ( t [1,326]=2.2 , p=0.03 ) . CONCLUSIONS There were no differences between the Print and Web program effects on reported physical activity . The Print group demonstrated slightly larger effects and a higher level of recognition of program material Background Many people in Western countries do not follow public health physical activity ( PA ) recommendations . Web-based interventions provide cost- and time-efficient means of delivering individually targeted lifestyle modification at a population level . Objective To examine whether access to a website with individually tailored feedback and suggestions on how to increase PA led to improved PA , anthropometrics , and health measurements . Methods Physically inactive adults ( n = 12,287 ) participating in a nationwide eHealth survey and health examination in Denmark were r and omly assigned to either an intervention ( website ) ( n = 6055 ) or a no-intervention control group ( n = 6232 ) in 2008 . The intervention website was founded on the theories of stages of change and of planned behavior and , apart from a forum page where a physiotherapist answered questions about PA and training , was fully automated . After 3 and again after 6 months we emailed participants invitations to answer a Web-based follow-up question naire , which included the long version of the International Physical Activity Question naire . A subgroup of participants ( n = 1190 ) were invited to a follow-up health examination at 3 months . Results Less than 22.0 % ( 694/3156 ) of the participants logged on to the website once and only 7.0 % ( 222/3159 ) logged on frequently . We found no difference in PA level between the website and control groups at 3- and 6-month follow-ups . By dividing participants into three groups according to use of the intervention website , we found a significant difference in total and leisure-time PA in the website group . The follow-up health examination showed no significant reductions in body mass index , waist circumference , body fat percentage , and blood pressure , or improvements in arm strength and aerobic fitness in the website group . Conclusions Based on our findings , we suggest that active users of a Web-based PA intervention can improve their level of PA . However , for unmotivated users , single-tailored feedback may be too brief . Future research should focus on developing more sophisticated interventions with the potential to reach both motivated and unmotivated sedentary individuals . Trial Registration Clinical trials.gov NCT01295203 ; http:// clinical trials.gov/ct2/show/NCT01295203 ( Archived by WebCite at http://www.webcitation.org/6B7HDMqiQ OBJECTIVE This study set out to assess the short- and long-term effects of a primary care-based lifestyle intervention on different domains of leisure-time sedentary behaviors in Dutch adults at risk of type 2 diabetes and cardiovascular diseases . METHODS Between 2007 and 2009 , adults ( n=622 ) at risk were r and omly assigned to a counseling intervention aim ed at adopting healthy lifestyle behaviors , or a control group that only received health brochures . Follow-up measures were done after 6 , 12 and 24months . Linear regression analysis was used to examine between-group differences in self-report minutes per day sedentary behaviors , adjusted for baseline values . Stratified analyses were performed for sex and educational attainment . RESULTS Seventy-nine percent ( n=490 ) of participants completed the last follow-up . Mean baseline sedentary behaviors were 254.6min per day ( SD=136.2 ) . Intention-to-treat analyses showed no significant differences in overall or domain-specific sedentary behaviors between the two groups at follow-up . Stratified analyses for educational attainment revealed a small and temporary between-group difference in favor of the intervention group , in those who finished secondary school . CONCLUSIONS A primary care-based general lifestyle intervention was not more effective in reducing leisure-time sedentary behaviors than providing brochures in adults at risk for chronic diseases OBJECTIVE To assess whether lifestyle intervention can reduce type 2 diabetes risk in women with prior GDM in the Tianjin Gestational Diabetes Mellitus ( GDM ) Prevention Program . METHODS 1180 women who were diagnosed with GDM from 2005 to 2009 were r and omly assigned to either a lifestyle intervention ( n=586 ) or a control group ( n=594 ) . Major elements of the intervention include six face-to-face meetings with study dietitians in the first year , and two additional sessions and two telephone calls in second year . RESULTS During the first year , average body weight loss in the first 404 subjects was 1.40 kg ( 2.1 % ) in the intervention group vs 0.21 kg ( 0.3 % ) in the control group ( P=0.001 ) , and the decrease was more significant among baseline overweight women ( body bass index [ BMI ] ≥24 kg/m² ) in the intervention ( 2.91 kg/4.2 % ) compared with that in the control group ( 0.51 kg/0.7 % ) ( P<0.001 ) . In addition , women in the intervention group , compared with those in the control group , have decreased BMI , body fat , waist circumference , and plasma insulin levels , and have improved behaviors including increased leisure time activity and dietary fiber intake and decreased sedentary time and fat consumptions . CONCLUSION The interim results support the efficacy and feasibility of the lifestyle intervention program BACKGROUND The average adult watches almost 5 hours of television ( TV ) per day , an amount associated with increased risks for obesity . This trial examines the effects of TV reduction on energy intake ( EI ) , energy expenditure ( EE ) , energy balance , body mass index ( BMI ) , ( calculated as weight in kilograms divided by height in meters squared ) , and sleep in overweight and obese adults . METHODS R and omized controlled trial of 36 adults with a BMI of 25 to 50 who self-reported a minimum of 3 h/d of TV viewing . Participants were enrolled in home-based protocol s from January through July 2008 . After a 3-week observation phase , participants were stratified by BMI and r and omized to an observation-only control group ( n = 16 ) or an intervention group ( n = 20 ) for 3 additional weeks . The intervention consisted of reducing TV viewing by 50 % of each participant 's objective ly measured baseline enforced by an electronic lock-out system . RESULTS Although not statistically significant , both groups reduced their EI ( -125 kcal/d [ 95 % CI , -303 to 52 ] vs -38 [ 95 % CI , -265 to 190 ] ) ( P = .52 ) for intervention and control group participants , respectively , where CI indicates confidence interval . The intervention group significantly increased EE ( 119 kcal/d [ 95 % CI , 23 to 215 ] ) compared with controls ( -95 kcal/d [ 95 % CI , -254 to 65 ] ) ( P = .02 ) . Energy balance was negative in the intervention group between phases ( -244 kcal/d [ 95 % CI , -459 to -30 ] ) but positive in controls ( 57 kcal/d [ 95 % CI , -216 to 330 ] ) ( P = .07 ) . The intervention group showed a greater reduction in BMI ( -0.25 [ 95 % CI , -0.45 to -0.05 ] vs -0.06 [ 95 % CI , -0.43 to 0.31 ] in controls ) ( P = .33 ) . There was no change in sleep . CONCLUSION Reducing TV viewing in our sample produced a statistically significant increase in EE but no apparent change in EI after 3 weeks of intervention . Trial Registration clinical trials.gov Identifier : NCT00622050 OBJECTIVE Effectiveness of a behavioral modification program on physical activity ( PA ) and sedentary behavior in diabetes patients . METHODS Ninety-two patients were r and omly assigned to an intervention or control group . The 24-weeks intervention consisted of a face-to-face session , pedometer and seven telephone follow-ups . Mean selection criteria were 35 - 75 years ; 25 - 35 kg/m(2 ) ; ≤ 12 % HbA1c , treated for type 2 diabetes ; no PA limitations . PA and sedentary behavior were measured by pedometer , accelerometer and question naire over the short- ( 24 weeks ) and intermediate- ( 1 year ) term . RESULTS The intervention group increased their steps/day by 2744 , their total PA by 23 min/day ( p<0.001 ) and decreased their sedentary behavior by 23 min/day ( p<0.05 ) post-intervention . After 1 year the intervention group still had an increase of 1872 steps/day , 11 min/day total PA and a decrease of 12 min/day in sedentary behavior ( p<0.001 ) . CONCLUSION This pedometer-based behavioral modification program with telephone support showed lasting positive effects on steps/day , PA and sedentary behavior . PRACTICE IMPLICATION S This study tested a convenient way to increase PA among type 2 diabetes patients The more time adults spend being sedentary , the greater the risk of obesity . The effect of reducing television ( TV ) watching , a prominent sedentary behavior , on weight loss has not been tested in an adult st and ard behavioral obesity intervention , and the mechanisms by which reducing TV watching influences energy balance behaviors are not well understood . Two , 8-week , pilot , r and omized controlled trials were conducted examining the effect of a reduced TV watching prescription on energy balance behaviors and weight loss within an adult st and ard behavioral obesity intervention . In the first study , participants ( n=24 ) were r and omized into one of two conditions : ( a ) reduce energy intake and increase moderate to vigorous physical activity ( MVPA ) ( INCREASE PA ) ; or ( b ) reduce energy intake and decrease TV watching ( DECREASE TV ) . As findings from the first pilot study did not show an increase in MVPA in the DECREASE TV group , the second study was design ed to examine the effect of adding a reduced TV prescription to a st and ard intervention to optimize outcomes . In Pilot Study 2 , participants ( n=28 ) were r and omized to INCREASE PA or to INCREASE PA+DECREASE TV . Outcomes included objective ly measured TV watching and MVPA , self-reported light physical activity ( LPA-Pilot Study 2 only ) , self-reported dietary intake while watching TV , and weight . Conditions with TV watching prescriptions significantly reduced TV watching . Both studies showed medium to large effect sizes for conditions with TV watching prescriptions to show greater reductions in dietary intake while watching TV . Pilot Study 1 found a trend for an increase in MVPA in INCREASE PA and Pilot Study 2 found significant increases in MVPA in both conditions . Pilot Study 2 found a significant increase in LPA in the INCREASE PA+DECREASE TV . Results indicate adding a TV watching prescription to a st and ard obesity intervention did not enhance increases in MVPA , but may assist with reducing dietary intake while TV watching and increasing LPA . Future research should examine the effect of reducing TV watching during obesity treatment over a longer time frame in a larger sample BACKGROUND Overall incidence of breast cancer is slightly lower , but mortality rates are higher , for Black women compared to White women . Higher body mass index ( BMI ) , sedentary lifestyles , and lower compliance with recommended breast health behaviors may contribute to higher risk and mortality . METHODS A r and omized pilot intervention trial was conducted to assess feasibility and efficacy of a combined breast health/weight loss intervention for 64 overweight or obese Black women , ages 35 - 65 . The primary objectives were to determine whether a 20-week ( twice weekly ) intervention could decrease weight and dietary fat intake and increase physical activity and breast self-exam ( BSE ) proficiency . RESULTS The project was implemented in two cohorts and retention was high for both ( 96 % and 89 % , respectively ) . Both cohorts showed increased proficiency in BSE in the intervention versus the control group ( 2.4 vs. -0.4 , P<0.05 ; 3.3 vs. -0.2 , P<0.001 , respectively ) , but only cohort 2 showed decreased percent body weight ( 4.0 % decrease vs. 0.9 % increase , P<0.01 ) , increased physical activity frequency ( 2.4 vs. 0.1 times/week , P<0.05 ) , and a trend for decreased dietary fat ( -2.6 % kcal vs. 0.0 % kcal , P=0.07 ) in the intervention compared to the control group . CONCLUSION Few studies have documented weight loss among Black women , and no combined breast health/weight loss intervention has been conducted . This study documents the feasibility of recruiting , r and omizing , and retaining women in a combined intervention and demonstrated weight loss and associated lifestyle changes BACKGROUND American Indians experience high rates of type 2 diabetes . The impact of low-intensity interventions on diabetes risk among young American Indian women is unknown . DESIGN R and omized controlled trial . SETTING / PARTICIPANTS Community-based ; participants were 200 young urban American Indian women who were block-r and omized on fasting blood glucose ( FBG ) into intervention and control groups . Inclusion criteria included self-reported identity , aged 18 - 40 years , not pregnant , willingness to stay in urban area for 2 years , and not having type 2 diabetes . Measures were taken at baseline , 6 , 12 , and 18 months . Data were gathered in 2002 - 2006 and analyzed in 2006 - 2007 . INTERVENTION Five discussion group sessions ( one meeting per month for 5 months ) were held focusing on healthful eating , physical activity , goal - setting , and social support . MAIN OUTCOME MEASURES Primary outcomes included dietary fat and vegetable consumption and self-reported physical activity . Secondary outcomes included cardiorespiratory fitness , insulin sensitivity , blood pressure , lipid profiles , percent body fat , BMI , intake of fruit , total sugar and sweetened beverages , FBG , and television viewing . RESULTS Mean vegetable and fruit intake increased significantly more in the intervention group than in the control group over time ( group by visit interaction , p=0.02 and p=0.002 , respectively ) . Both groups had significant increases in percent body fat and decreases in waist circumference , insulin sensitivity , blood cholesterol , LDL , television viewing , and total intakes of energy , saturated fat , sugar , and sweetened beverages . CONCLUSIONS A culturally influenced , low-intensity lifestyle intervention can improve self-reported intakes of vegetables and fruit over 18 months in young , urban American Indian women Objective To evaluate the effectiveness of a draft occupational health practice guideline aim ed at preventing weight gain on employees ' physical activity , sedentary behaviour and dietary behaviour and on body weight-related outcomes . Methods A r and omised controlled trial was performed comparing guideline -based care to usual care among 16 occupational physicians and 523 employees in the Netherl and s between 2009 and 2011 . Occupational physicians in the intervention group followed the draft guideline by providing advice to employers on how to assess and intervene on the obesogenic work environment and conducted five face-to-face behavioural change counselling sessions with employees to improve their lifestyle . Data of employees were collected by question naire and physical measurements at baseline and 6-months follow-up . Linear and logistic regression analyses were performed to determine effects . Results The intervention showed significant effects on sedentary behaviour at work ( β −28 min/day , 95 % CI −2 to −54 ) and on fruit intake ( β 2.1 pieces/week ; 95 % CI 0.6 to 3.6 ) . No significant intervention effects were found for physical activity , sedentary behaviour in leisure time or during weekend days , snack intake and body weight-related outcomes . Conclusion Guideline -based care result ed in a more favourable sedentary behaviour at work and increased fruit intake but did not improve employees ' physical activity , snack intake or body weight-related outcomes . Trial registration number IS RCT N/73545254 and NTR/1190 OBJECTIVES To explore the effects of breaking up prolonged sitting time with st and ing or light-intensity walking on a range of cardiometabolic risk markers . DESIGN A r and omised three-period , three-treatment acute crossover trial . METHODS Ten non-obese adults took part in three trials : ( 1 ) uninterrupted sitting ; ( 2 ) seated with 2-min bouts of st and ing every 20 min ; and ( 3 ) seated with 2-min bouts of light-intensity walking every 20 min . Two st and ardised test drinks ( total 80.3 carbohydrate , 50 g fat ) were provided after an initial 1-h period of uninterrupted sitting . Plasma glucose and blood pressure were assessed hourly to calculate area under the curve . Total cholesterol , HDL , and triglycerides were assessed at baseline and 5-h . ANOVAs were used to explore between-trial differences . RESULTS Glucose area under the curve was lower in the activity-break condition compared to the uninterrupted sitting and st and ing-break conditions : mean area under the curve 18.5 ( 95 % CI 17 , 20 ) , 22.0 ( 20.5 , 23.5 ) , and 22.2 ( 20.7 , 23.7 ) mmol L/5-h , respectively , p<0.001 ; no difference between uninterrupted sitting and st and ing-break conditions ( p>0.05 ) . Systolic and diastolic blood pressure area under the curve did not differ significantly between conditions , nor did responses in lipid parameters ( p>0.05 ) . CONCLUSIONS This study suggests that interrupting sitting time with frequent brief bouts of light-intensity activity , but not st and ing , imparts beneficial postpr and ial responses that may enhance cardiometabolic health . These findings may have importance in the design of effective interventions to reduce cardiometabolic disease risk |
13,663 | 26,787,740 | Locally hosted software programmes and remotely hosted internet programmes consistently increased knowledge and behaviours .
Kiosk programmes showed evidence of modest knowledge and behaviour gains .
Both programmes using mobile technology improved behaviours .
Virtual-reality programmes consistently improved behaviours , but there were little gains in knowledge .
Conclusions There is much potential for computer-based programmes to be used for injury-prevention behaviour change .
The review ed studies provide evidence that computer-based communication is effective in conveying information and influencing how participants think about an injury topic and adopt safety behaviours | Objective The aims of this literature review are to ( 1 ) summarise how computer and mobile technology-based health behaviour change applications have been evaluated in unintentional injury prevention , ( 2 ) describe how these successes can be applied to injury-prevention programmes in the future and ( 3 ) identify research gaps . | Sixty percent to 70 % of pedestrian injuries in children under the age of 10 years are the result of the child either improperly crossing intersections or dashing out in the street between intersections . The purpose of this injury prevention research study was to evaluate a desktop virtual reality ( VR ) program that was design ed to educate and train children to safely cross intersections . Specifically , the objectives were to determine whether children can learn pedestrian safety skills while working in a virtual environment and whether pedestrian safety learning in VR transfers to real world behavior . Following focus groups with a number of key experts , a virtual city with eight interactive intersections was developed . Ninety-five children participated in a community trial from two schools ( urban and suburban ) . Approximately half were assigned to a control group who received an unrelated VR program , and half received the pedestrian safety VR intervention . Children were identified by group and grade by colored tags on their backpacks , and actual street crossing behavior of all children was observed 1 week before and 1 week after the interventions . There was a significant change in performance after three trials with the VR intervention . Children learned safe street crossing within the virtual environment . Learning , identified as improved street-crossing behavior , transferred to real world behavior in the suburban school children but not in the urban school . The results are discussed in relation to possibilities for future VR interventions for injury prevention BACKGROUND . Innovations to improve the delivery of pediatric preventive care are needed . METHODS . We enrolled children , 0 to 11 years of age , into a factorial , r and omized , controlled trial of a tailored , evidence -based , Web site ( MyHealthyChild ) that provided information on prevention topics before a scheduled well-child visit . There were 2 components of the intervention , namely , parental Web content and provider notification . Parental Web content provided information to parents about prevention topics ; provider notification communicated to physicians topics that were of interest to parents . We assigned 887 children r and omly to 4 groups ( usual care , content only , content and notification , or notification only ) . Outcomes were determined with telephone follow-up surveys conducted 2 to 4 weeks after the visit . Poisson regression analysis was used to determine the independent effects of each intervention on the number of topics discussed and the number of preventive practice s implemented . RESULTS . Parents in the notification/content group and in the notification-only group reported discussing more MyHealthyChild topics with their provider . Parents in the notification/content group and in the content-only group reported implementing more MyHealthyChild topic suggestions ( such as use of a safety device ) . CONCLUSIONS . A Web-based intervention can activate parents to discuss prevention topics with their child 's provider . Delivery of tailored content can promote preventive practice Background : Neurologically impaired persons seem to benefit from driving-training programs , but there is no convincing evidence to support this notion . The authors therefore investigated the effect of simulator-based training on driving after stroke . Methods : Eighty-three first-ever subacute stroke patients entered a 5-week 15-hour training program in which they were r and omly allocated to either an experimental ( simulator-based training ) or control ( driving-related cognitive tasks ) group . Performance in off-road evaluations and an on-road test were used to assess the driving ability of subjects pre- and post-training . Outcome of an official predriving assessment administered 6 to 9 months poststroke was also considered . Results : Both groups significantly improved in a visual and many neuropsychological evaluations and in the on-road test after training . There were no significant differences between both groups in improvements from pre- to post-training except in the “ road sign recognition test ” in which the experimental subjects improved more . Significant improvements in the three-class decision ( “ fit to drive , ” “ temporarily unfit to drive , ” and “ unfit to drive ” ) were found in favor of the experimental group post-training . Academic qualification and overall disability together determined subjects that benefited most from the simulator-based driving training . Significantly more experimental subjects ( 73 % ) than control subjects ( 42 % ) passed the follow-up official predriving assessment and were legally allowed to resume driving . Conclusions : Simulator-based driving training improved driving ability , especially for well educated and less disabled stroke patients . However , the findings of the study may have been modified as a result of the large number of dropouts and the possibility of some neurologic recovery unrelated to training Background Injuries at home are a major cause of death , disability , and loss of quality of life among young children . Despite current safety education , required safety behavior of parents is often lacking . To prevent various childhood disorders , the application of Web-based tools has increased the effectiveness of health promotion efforts . Therefore , an intervention with Web-based , tailored , safety advice combined with personal counseling ( E-Health4Uth home safety ) was developed and applied . Objective To evaluate the effect of E-Health4Uth home safety on parents ’ safety behaviors with regard to the prevention of falls , poisoning , drowning , and burns . Methods A r and omized controlled trial was conducted ( 2009 - 2011 ) among parents visiting well-baby clinics in the Netherl and s. Parents were r and omly assigned to the intervention group ( E-Health4Uth home safety intervention ) or to the control condition consisting of usual care . Parents in the intervention condition completed a Web-based safety behavior assessment question naire ; the result ing tailored safety advice was discussed with their child health care professional at a well-baby visit ( age approximately 11 months ) . Parents in the control condition received counseling using generic safety information leaflets at this well-baby visit . Parents ’ child safety behaviors were derived from self-report question naires at baseline ( age 7 months ) and at follow-up ( age 17 months ) . Each specific safety behavior was classified as safe/unsafe and a total risk score was calculated . Logistic and linear regression analyses were used to reveal differences in safety behavior between the intervention and the control condition at follow-up . Results A total of 1292 parents ( response rate 44.79 % ) were analyzed . At follow-up , parents in the intervention condition ( n=643 ) showed significantly less unsafe behavior compared to parents in the control condition ( n=649 ) : top of staircase ( 23.91 % vs 32.19 % ; OR 0.65 , 95 % CI 0.50 - 0.85 ) ; bottom of staircase ( 63.53 % vs 71.94 % ; OR 0.69 , 95 % CI 0.53 - 0.88 ) ; top and bottom of staircase ( 68.94 % vs 78.28 % ; OR 0.62 , 95 % CI 0.48 - 0.81 ) ; storage of cleaning products ( 30.33 % vs 39.91 % ; OR 0.67 , 95 % CI 0.53 - 0.85 ) ; bathing of the child ( 23.46 % vs 32.25 % ; OR 0.65 , 95 % CI 0.51 - 0.84 ) ; drinking hot fluids ( 34.84 % vs 41.73 % ; OR 0.76 , 95 % CI 0.61 - 0.96 ) ; using rear hotplates ( 79.34 % vs 85.27 % ; OR 0.67 , 95 % CI 0.50 - 0.90 ) ; and the total risk score in which a higher score indicates more unsafe behavior ( mean 13.63 , SD 6.12 vs mean 15.34 , SD 6.07 ; beta –1.59 , 95 % CI –2.26 to –0.93 ) . There were no significant differences for other specific behaviors between the two study conditions . Conclusions Compared to generic written material s , the E-Health4Uth home safety intervention seems more effective in promoting parents ’ safety behavior for safe staircases , storage of cleaning products , bathing , drinking hot fluids , and cooking . This study supports the application of Web-based , tailored , safety advice for the prevention of unintentional injuries in the youth health care setting . Trial Registration Nederl and s Trial Register : NTR1836 ; http://www.trialregister.nl/trialreg/admin/ rct view.asp?TC=1836 ( Archived by WebCite at http://www.webcitation.org/6MPIGQxpx ) Objective This study aim ed to evaluate the impact of a computer kiosk intervention on parents ’ self-reported safety knowledge as well as observed child safety seat , smoke alarm use , and safe poison storage and to compare self-reported versus observed behaviors . Methods A r and omized controlled trial with 720 parents of young children ( 4 months to 5 years ) was conducted in the pediatric emergency department of a level 1 pediatric trauma center . Enrolled parents received tailored safety information ( intervention ) or generic information ( control ) from a computer kiosk after completing a safety assessment . Parents were telephoned 4 to 6 months after the intervention to assess self-reported safety knowledge and behaviors ; in-home observations were made 1 week after the telephone interview for a subset of 100 r and omly selected participants . Positive and negative predictive values were compared between the intervention and control groups . Results The intervention group had significantly higher smoke alarm ( 82 % vs 78 % ) and poison storage ( 83 % vs 78 % ) knowledge scores . The intervention group was more likely to report correct child safety seat use ( odds ratio , 1.36 ; 95 % confidence interval , 1.05–1.77 ; P = 0.02 ) . Observed safety behaviors were lower than self-reported use for both groups . No differences were found between groups for positive or negative predictive values . Conclusions These results add to the limited literature on the impact of computer tailoring home safety information . Knowledge gains were evident 4 months after intervention . Discrepancies between observed and self-reported behavior are concerning because the quality of a tailored intervention depends on the accuracy of participant self-reporting . Improved measures should be developed to encourage accurate reporting of safety behaviors Background Injuries in or around the home are the most important cause of death among children aged 0 - 4 years old . It is also a major source of morbidity and loss of quality of life . In order to reduce the number of injuries , the Consumer Safety Institute introduced the use of Safety Information Leaflets in the Netherl and s to provide safety education to parents of children aged 0 - 4 years . Despite current safety education , necessary safety behaviours are still not taken by a large number of parents , causing unnecessary risk of injury among young children . In an earlier study an E-health module with internet-based , tailored safety information was developed and applied . It concerns an advice for parents on safety behaviours in their homes regarding their child . The aim of this study is to evaluate the effect of this safety information combined with personal counselling on parents ' child safety behaviours . Methods / Design Parents who are eligible for the regular well-child visit with their child at child age 5 - 8 months are invited to participate in this study . Participating parents are r and omized into one of two groups : 1 ) internet-based , tailored safety information combined with personal counselling ( intervention group ) , or 2 ) personal counselling using the Safety Information Leaflets of the Consumer Safety Institute in the Netherl and s for children aged 12 to 24 months ( control group ) . All parents receive safety information on safety topics regarding the prevention of falling , poisoning , drowning and burning . Parents of the intervention group will access the internet-based , tailored safety information module when their child is approximately 10 months old . After completion of the assessment questions , the program compiles a tailored safety advice . The parents are asked to devise and inscribe a personal implementation intention . During the next well-child visit , the Child Health Clinic professional will discuss this tailored safety information and the implementation intention with the parents . The control group will receive usual care , i.e. the provision of Safety Information Leaflets during their well-child visit at the child 's age of 11 months . Discussion It is hypothesized that the intervention , internet-based , tailored safety information combined with personal counselling results in more parents ' child safety behaviours . Trial registration Current Controlled Trials Background Nonadherence and medication errors are common among patients with complex drug regimens . Apps for smartphones and tablets are effective for improving adherence , but they have not been tested in elderly patients with complex chronic conditions and who typically have less experience with this type of technology . Objective The objective of this study was to design , implement , and evaluate a medication self-management app ( called ALICE ) for elderly patients taking multiple medications with the intention of improving adherence and safe medication use . Methods A single-blind r and omized controlled trial was conducted with a control and an experimental group ( N=99 ) in Spain in 2013 . The characteristics of ALICE were specified based on the suggestions of 3 nominal groups with a total of 23 patients and a focus group with 7 professionals . ALICE was design ed for And roid and iOS to allow for the personalization of prescriptions and medical advice , showing images of each of the medications ( the packaging and the medication itself ) together with alerts and multiple reminders for each alert . The r and omly assigned patients in the control group received oral and written information on the safe use of their medications and the patients in the experimental group used ALICE for 3 months . Pre and post measures included rate of missed doses and medication errors reported by patients , scores from the 4-item Morisky Medication Adherence Scale ( MMAS-4 ) , level of independence , self-perceived health status , and biochemical test results . In the experimental group , data were collected on their previous experience with information and communication technologies , their rating of ALICE , and their perception of the level of independence they had achieved . The intergroup intervention effects were calculated by univariate linear models and ANOVA , with the pre to post intervention differences as the dependent variables . Results Data were obtained from 99 patients ( 48 and 51 in the control and experimental groups , respectively ) . Patients in the experimental group obtained better MMAS-4 scores ( P<.001 ) and reported fewer missed doses of medication ( P=.02 ) . ALICE only helped to significantly reduce medication errors in patients with an initially higher rate of errors ( P<.001 ) . Patients with no experience with information and communication technologies reported better adherence ( P<.001 ) , fewer missed doses ( P<.001 ) , and fewer medication errors ( P=.02 ) . The mean satisfaction score for ALICE was 8.5 out of 10 . In all , 45 of 51 patients ( 88 % ) felt that ALICE improved their independence in managing their medications . Conclusions The ALICE app improves adherence , helps reduce rates of forgetting and of medication errors , and increases perceived independence in managing medication . Elderly patients with no previous experience with information and communication technologies are capable of effectively using an app design ed to help them take their medicine more safely . Trial Registration Clinical trials.gov NCT02071498 ; http:// clinical trials.gov/ct2/show/NCT02071498 ( Archived by WebCite at http://www.webcitation.org/6OJjdHVhD ) OBJECTIVE Pre-post-r and omized design evaluated The Blue Dog , a dog safety software program . METHODS 76 children aged 3.5 - 6 years completed 3 tasks to evaluate dog safety pre- and postintervention : ( a ) pictures ( recognition of safe/risky behavior ) , ( b ) dollhouse ( recall of safe behavior via simulated dollhouse scenarios ) , and ( c ) live dog ( actual behavior with unfamiliar live dog ) . Following preintervention evaluation , children were r and omly assigned to dog or fire safety conditions , each involving 3 weeks of home computer software use . RESULTS Children using Blue Dog had greater change in recognition of risky dog situations than children learning fire safety . No between-group differences emerged in recall ( dollhouse ) or engagement ( live-dog ) in risky behavior . Families enjoyed using the software . CONCLUSIONS Blue Dog taught children knowledge about safe engagement with dogs , but did not influence recall or implementation of safe behaviors . Dog bites represent a significant pediatric injury concern and continued development of effective interventions is needed The purpose of this study was to determine the efficacy of providing ( i ) tailored injury prevention information ( T-IPI ) to parents and ( ii ) concurrent T-IPI to parents and providers to promote parent adoption of safety practice s. During well-child visits , parents of children ages 4 and younger completed a computer assessment and were r and omized to receive generic injury prevention information , T-IPI or T-IPI supplemented with a tailored summary for providers . Follow-up assessment s were completed by telephone 1 month later . Parents receiving T-IPI alone or with supplementary provider information were more likely to report adopting a new injury prevention behavior than those receiving generic information ( 49 and 45 % , respectively , compared with 32 % ; odds ratio=2.0 and 1.9 , respectively ) , and these effects were greatest among the least educated parents . In addition , more complicated behavior changes were reported by those receiving tailored information . Provider receipt of feedback did not result in significantly different provider-parent communication or change in parents ' safety practice s. Providing parents with individually tailored pediatric injury prevention information may be an effective method for delivering injury prevention anticipatory guidance . Tailoring may have particular utility for more complicated behaviors and for communication with less educated parents OBJECTIVE The purpose of this study was to evaluate the " Bike Smart " program , an eHealth software program that teaches bicycle safety behaviors to young children . METHODS Participants were 206 elementary students in grade s kindergarten to 3 . A r and om control design was employed to evaluate the program , with students assigned to either the treatment condition ( Bike Smart ) or the control condition ( a video on childhood safety ) . Outcome measures included computer-based knowledge items ( safety rules , helmet placement , hazard discrimination ) and a behavioral measure of helmet placement . RESULTS Results demonstrated that regardless of gender , cohort , and grade the participants in the treatment group showed greater gains than control participants in both the computer-presented knowledge items ( p > .01 ) and the observational helmet measure ( p > .05 ) . CONCLUSIONS Findings suggest that the Bike Smart program can be a low cost , effective component of safety training packages that include both skills-based and experiential training This study offers evidence that computer-based instruction is a feasible and effective alternative training method for long-term care staff . Participants were 289 nursing facility staff r and omly divided into two treatment groups . One group completed instructor-led ( IL ) fire safety training and the other completed computer-based ( CB ) training adapted from the IL version . Both the CB and IL groups significantly increased their scores from pre- to posttest . Differences between the two groups were not significant Two experiments investigated the effect of making errors during training ( error training ) on a driving simulator versus learning from examples of errors ( guided error training ) on driving skill and confidence . Experiment 1 indicated that compared with errorless learning ( where participants drove through a training run not design ed to elicit errors ) , error training led to significantly better transfer to driving tests that were analogous to those situations encountered in training and more effective use of strategies for coping with a novel driving situation . Error training also reduced self-confidence in driving skill at the end of training relative to errorless learning . Experiment 2 provided weak evidence of the superiority of guided error training over errorless learning ( where the driver in the video did not make any errors ) on analogous tests , and no evidence of transfer to a novel test . Furthermore , guided error training did not influence self-confidence in driving skill . The potential value of driving simulators in providing active processing during driver training is discussed , along with the effects of passive and active exposure to errors on driver confidence OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity OBJECTIVES . Residential injuries cause significant morbidity and mortality in infants and young children . The American Academy of Pediatrics recommends initiating injury-prevention counseling during health supervision visits in the first 6 months of life . The objectives of this study were to describe and compare self-reported and observed home safety practice s in urban , low-income families who were expecting or had a child < 12 months old and to assess the feasibility of using safety products depending on the design and repair of urban homes . PARTICIPANTS AND METHODS . Women who were pregnant or had an infant < 12 months old and who were enrolled in East Baltimore 's Healthy Start home-visiting program were eligible for the study . For this pilot project , we used a prospect i ve pre design /post design . Maternal self-report and investigator home observations documented the use of working smoke alarms on each level of the home , stair gates or doors blocking the top and bottom of all staircases , adult medication storage in locked cabinets , and the environmental feasibility of safety-product use . RESULTS . Home safety practice s were higher by maternal self-report than by investigator observation . Fifty-five percent of families who reported a working smoke alarm on every level of the home had nonworking or absent smoke alarms noted during investigator observation . Of assessed staircases , 67 % could not accommo date a wall-mounted gate at the top of the stairs , and 38 % could not accommo date a pressure-mounted gate at the bottom of the stairs . Although most families reported locked storage of medications , 77 % had unlocked medication storage documented during home observation . CONCLUSIONS . In this sample of urban families , implementation of American Academy of Pediatrics-recommended safety practice s is low . The structural design of urban homes may be a significant barrier to home safety-product use . The American Academy of Pediatrics Injury Prevention Program sheets , manufacturers of safety products , and legislators need to address injury-prevention issues unique to urban , low-income families OBJECTIVE Child pedestrian injury is a global public health challenge . This r and omized , controlled trial considered comparative efficacy of individualized streetside training , training in a virtual pedestrian environment , training using videos and Web sites , plus no-training control , to improve children 's street-crossing ability . METHODS Pedestrian safety was evaluated among 231 7- and 8-year-olds using both streetside ( field ) and laboratory-based ( virtual environment ) trials before intervention group assignment , immediately posttraining , and 6 months posttraining . All training groups received 6 30-min sessions . Four outcomes assessed pedestrian safety : start delay ( temporal lag before initiating crossing ) , hits/close calls ( collisions/near-misses with vehicles in simulated crossings ) , attention to traffic ( looks left and right , controlled for time ) , and missed opportunities ( safe crossing opportunities that were missed ) . RESULTS Results showed training in the virtual pedestrian environment and especially individualized streetside training result ed in safer pedestrian behavior postintervention and at follow-up . As examples , children trained streetside entered safe traffic gaps more quickly posttraining than control group children and children trained streetside or in the virtual environment had somewhat fewer hits/close calls in postintervention VR trials . Children showed minimal change in attention to traffic posttraining . Children trained with videos/websites showed minimal learning . CONCLUSION Both individualized streetside training and training within virtual pedestrian environments may improve 7- and 8-year-olds ' street-crossing safety . Individualized training has limitations of adult time and labor . Virtual environment training has limitations of accessibility and cost . Given the public health burden of child pedestrian injuries , future research should explore innovative strategies for effective training that can be broadly disseminated PURPOSE This study was design ed to test the effectiveness and acceptance of multimedia home safety programming by community-dwelling seniors . DESIGN AND METHODS A prototype CD-ROM was produced that required no reading or computer skills because the program included an audio narration of content and directions for operating the program on a touchscreen computer monitor . Volunteers ( N = 126 ) from a senior center aged 55 and older were r and omly assigned to ( 1 ) a multimedia group that used the interactive program to learn about home safety , ( 2 ) a traditional learning group that read well-established booklets on home safety , and ( 3 ) a control group that received no instruction on safety between the pre- and posttests . RESULTS Repeated- measures multivariate analysis of variance showed that the multimedia group was the only group to improve in knowledge . The group was also very satisfied with the approach . IMPLICATION S Multimedia formats can effectively and economically provide information to older clients Injuries are a major cause of morbidity and mortality to young children . The provision of individually tailored educational material s in primary care setting s may be an effective and efficient way to promote adoption of injury prevention measures by parents . A r and omized controlled study compared the effectiveness of tailored and generic persuasive communications delivered in a primary care setting on the adoption of home and car safety behaviors . During routine well-child visits , a primarily African-American sample of parents of children ages 6 - 20 months ( n=213 ) was r and omized to receive either tailored or generic information regarding the prevention of injuries to their child . At follow-up , participants who received tailored information reported greater adoption of home and car safety behaviors than those receiving generic information . In addition , within the tailored information group , those who discussed the information with their physician showed significantly greater change than those who did not . However , this difference was not observed among those receiving generic information . Findings support the use of office-based tailored injury prevention education as a component of routine well-child care BACKGROUND Despite widespread application in aviation and other fields , there has been limited use of computerized simulation in driver education . We prospect ively studied a group of novice drivers subjected to comprehensive virtual driving simulation modules to identify the subsequent effects on their driving records . We hypothesized that participation in a simulation program would result in fewer offences and crashes . METHODS Forty high school students who recently obtained their driver ’s license were r and omized into driving simulator ( DS ) or control groups . The DS group went through 12 modules of driver education . Upon completion , driving records for all the individuals were collected at 6 months , 12 months , and 18 months , and comparisons were made . Statistical analysis was performed using & khgr;2 , Fisher ’s exact tests , t tests , and Mann Whitney U-test where appropriate . RESULTS Of the 20 subjects , 16 in the DS group completed all modules and were compared with 19 individuals in the control group . Sixty-nine percent in the DS group were male versus 89 % in the control group . Mean age was similar in both groups . The average time to the first offense after completion in the DS group was 117 days versus 105 days in control group ( p = 0.8 ) . At 18 months , 18.8 % in the DS group were involved in a driving incident compared with 47.4 % in the control group ( p = 0.1516 ) . At 18 months , there were 4 incidents ( 0.25 incidents per person ) in the DS group versus 17 incidents ( 0.89 incidents per person ) in the control group . At 18 months , 6.2 % in the DS were involved in accidents compared with 21.1 % in the control group ( p= 0.35 ) . Speeding infractions occurred at 18 months in 12.5 % in the DS group versus 26.3 % in the control group ( p = 0.4150 ) . CONCLUSION In this prospect i ve pilot evaluation of computerized driving simulation , adolescents subjected to structured simulator training showed trends toward committing fewer offences and accidents . Larger studies examining the practical potential of driving simulation in novice drivers are needed . LEVEL OF EVIDENCE Prognostic study , level III OBJECTIVES . The effects of a computer kiosk intervention on parents ' child safety seat , smoke alarm , and poison storage knowledge and behaviors were evaluated in a pediatric emergency department serving predominantly low-income , urban families . The effects of parent anxiety and the reason for the child 's emergency department visit also were examined . METHODS . A r and omized , controlled trial of a Safety in Seconds program with a 2- to 4-week follow-up interview was conducted with 759 parents of young children ( 4–66 months of age ) . The intervention group received a personalized report containing tailored , stage-based safety messages based on the pre caution adoption process model . The control group received a report on other child health topics . RESULTS . The intervention group had significantly higher smoke alarm , poison storage , and total safety knowledge scores . The intervention group was more likely to report correct child safety seat use . Neither parent anxiety nor the reason for the emergency department visit was related to the safety behaviors . Virtually all ( 93 % ) intervention parents read at least some of the report ; 57 % read it all , and 68 % discussed it with others . Lower-income intervention parents who read all of the report and discussed it with others were more likely than control parents to practice safe poison storage . Higher-income intervention parents were more likely than control parents to report correct child safety seat use . CONCLUSIONS . These results bode well for widespread applicability of computer technology to patient education in busy emergency departments and other child health care setting s. Reducing financial barriers to certain safety behaviors should continue to be a high priority Unintentional injuries are a leading cause of death and disability for children . Those with developmental disabilities , including children affected by prenatal alcohol exposure , are at highest risk for injuries . Although teaching safety skills is recommended to prevent injury , cognitive limitations and behavioral problems characteristic of children with fetal alcohol spectrum disorder make teaching these skills challenging for parents and teachers . In the current study , 32 children , ages 4 - 10 , diagnosed with fetal alcohol syndrome ( FAS ) and partial FAS , learned fire and street safety through computer games that employed " virtual worlds " to teach recommended safety skills . Children were pretested on verbal knowledge of four safety elements for both fire and street safety conditions and then r and omly assigned to one condition . After playing the game until mastery , children were retested verbally and asked to " generalize " their newly acquired skills in a behavioral context . They were retested after 1 week follow-up . Children showed significantly better knowledge of the game to which they were exposed , immediately and at follow-up , and the majority ( 72 % ) was able to generalize all four steps within a behavioral setting . Results suggested that this is a highly effective method for teaching safety skills to high-risk children who have learning difficulties Nursing facility administrators must find new and innovative ways to meet the training needs of their staff . The authors faced the challenge of teaching nursing facility staff about fire safety using computer-based training that had been adapted from a print-based/instructor-led ( IL ) program . This article discusses the effectiveness of the computer-based ( CB ) training as compared to the effectiveness of the traditional IL format . The CB and IL versions of a fire safety training program were presented to staff of a nursing facility . The 141 participants were r and omly assigned to the CB , IL , or control groups . The control group completed a pretest and posttest , but received no training until the study was completed . Both the CB and IL groups significantly increased their knowledge scores from pretest to posttest and both significantly outperformed the control group . How the participants responded to the CB training was also important . Staff reported they enjoyed the CB training and had no difficulty using the computers . Computer-based training can be an effective alternative training technique for this population BACKGROUND An emergency department ( ED ) visit may be an effective place to screen and educate families about injury prevention . The purpose of this study was to determine if a computerized kiosk in a pediatric ED can screen families for injury risk and encourage them to make more safety changes at follow-up survey compared with an injury prevention specialist ( IPS ) . METHODS A prospect i ve , r and omized controlled study was performed with families of children younger than 14 years in an ED lobby . Families were screened for injury risk by computerized kiosk based on child ’s age category at triage ( birth to 1 year , 1–4 years , 5–9 years , or 10–14 years ) . Families were r and omized to receive either injury behavior instructions by kiosk printout or by IPS when answers to specific practice s were deemed unsafe . Three weeks after intervention , families were telephoned to determine change in safety practice s. RESULTS Three hundred seventeen families completed ED kiosk screen at enrollment ( 172 kiosk , 145 IPS ) . On initial screen , kiosk families practice d 79.6 % of behaviors safely versus 75.9 % in the IPS group ( p = 0.011 ) . A total of 221 families ( 69.7 % ) were reached for follow-up ( 121 kiosk , 100 IPS ) . On average , IPS families improved their safe behavior responses by 8.3 % versus 1.0 % in the kiosk group ( p < 0.0001 ) . Significantly more families in the IPS group than in the kiosk group ( 36 % vs. 23 % , p < 0.03 ) used additional safety equipment after the intervention . CONCLUSION A computerized kiosk based in a pediatric ED can help screen families for their injury risk . However , to elicit significant behavior change , an IPS discussing safety changes may be more effective . LEVEL OF EVIDENCE Therapeutic study , level II Background Pedestrian injuries are among the leading causes of morbidity and mortality in middle childhood . One limitation to existing pedestrian safety interventions is that they do not provide children with repeated practice needed to develop the complex perceptual and cognitive skills required for safe street crossing . Virtual reality offers training through repeated unsupervised practice without risk , automated feedback on success of crossings , adjustment of traffic to match children 's skill and a fun , appealing environment for training . Objective To test the efficacy of virtual reality to train child pedestrians in safe street crossing . Setting Birmingham , Alabama , USA . Methods A r and omised controlled trial is underway with an expected sample of four groups of 60 children aged 7–8 years ( total N=240 ) . One group receives training in an interactive , immersive virtual pedestrian environment . A second receives pedestrian safety training via widely used video and computer strategies . The third group receives what is judged to be the most efficacious treatment currently available , individualised behavioural training at streetside locations . The fourth group serves as a no-contact control group . All participants are exposed to a range of field and laboratory-based measures of pedestrian skill during baseline and post-intervention visits , as well as during a 6-month follow-up assessment . Outcome Measures Primary analyses will be conducted through linear mixed models testing change over time in the four intervention groups . Three pedestrian safety measures will serve as primary outcomes : temporal gap before initiating crossing , temporal gap remaining after crossing and attention to traffic while waiting to cross . Clinical Trial Registration This study is registered at the US government website , www . clinical trials.gov , under the title ‘ Using virtual reality to train children in pedestrian safety ’ , registration number NCT00850759 Objective . To determine the effectiveness of an interactive Web-based module on knowledge acquisition , retention , and clinical practice by residents . Methods . Residents were r and omized to complete an interactive Web-based module on injury prevention or a noninteractive Web-based module of identical content . Acquisition and retention of medical knowledge were measured by pretest , posttest , and long-term test scores , and change in clinical practice was measured by videotaped clinical encounters . Results . Fifty-seven residents completed the modules . The control group had higher posttest scores than the intervention group ( P = .036 ) . Thirty-seven residents completed the long-term test with scores that were significantly higher than pretest scores ( P = .00 ) . Thirty-six residents had videotaped encounter scores ( 232 visits ) , with no difference in these scores after the intervention ( P = .432 ) . Conclusion . The noninteractive module was more effective in promoting knowledge acquisition . Residents successfully demonstrated knowledge retention with completion of either module . The modules were insufficient to change clinical practice OBJECTIVE Fire is a leading cause of unintentional injury and , although young children are at particularly increased risk , there are very few evidence -based re sources available to teach them fire safety knowledge and behaviors . Using a pre-post r and omized design , the current study evaluated the effectiveness of a computer game ( The Great Escape ) for teaching fire safety information to young children ( 3.5 - 6 years ) . METHOD Using behavioral enactment procedures , children 's knowledge and behaviors related to fire safety were compared to a control group of children before and after receiving the intervention . RESULTS The results indicated significant improvements in knowledge and fire safety behaviors in the intervention group but not the control . CONCLUSION Using computer games can be an effective way to promote young children 's underst and ing of safety and how to react in different hazardous situations BACKGROUND Injury is the number one cause of death and disability in children in the United States and an increasingly important public health problem globally . While prevention of injuries is an important goal , prevention efforts are currently fragmented , poorly funded , and rarely studied . Among school-aged children , pedestrian crashes are a major mechanism of injury . We hypothesized that we could develop a game-based educational tool that would be effective in teaching elementary school children the principles of pedestrian safety . METHODS Between November 2011 and June 2013 , second- and third- grade children in Los Angeles Unified School District were r and omly assigned to play a unique interactive video game ( Ace ’s Adventure ) about pedestrian safety or to a traditional didactic session about pedestrian safety . A pretest and posttest were administered to the study participants . Afterward , study participants were observed for appropriate pedestrian behavior on a simulated street set called Street Smarts . All statistical analyses were performed using SAS version 9.2 . RESULTS A total of 348 study participants took the pretest and posttest . There were 180 who were r and omized to the didactic and 168 who were r and omized to the video game . The didactic group demonstrated a higher mean score increase ( 1.01 , p < 0.0001 ) as compared with the video game group ( 0.44 , p < 0.0001 ) . However , observation of study participants revealed that participants who played the video game , as compared with the didactic group , more frequently exhibited appropriate behavior during the following : exiting a parked car ( p = 0.01 ) , signaling to a car that was backing up ( p = 0.01 ) , signaling to a stopped car ( p = 0.0002 ) , and crossing the street ( p = 0.01 ) . CONCLUSION Students who played the educational video game about pedestrian safety performed similarly to those who attended a more traditional and labor-intensive didactic learning . Innovative educational methods , such as game playing , could significantly change our approach to injury prevention and have the potential to decrease the burden of injury among children worldwide We tested a kiosk-based tailoring intervention with a sample of 144 parents of young children using a two-group r and omized controlled design to evaluate the kiosk . Intervention group parents ( n = 70 ) answered 50 questions at a practice -based kiosk and they and their child 's physician received immediate feedback reports of their injury prevention needs . Four weeks later , both control ( n = 74 ) and intervention parents completed a telephone interview . Safety knowledge , beliefs , and practice s were compared at follow-up . Compared to control group parents , intervention group parents were more knowledgeable about the inappropriateness of young children riding in the front seat of a car ( 16 % versus 5 % , p < 0.05 ) , less likely to believe that teaching a child to mind you is the best way to prevent injuries ( 64 % versus 86 % , p < 0.05 ) , and more likely to report that they " have syrup of ipecac " ( 34 % versus 9 % , p < 0.001 ) and " know how to use " it ( 24 % versus 4 % , p < 0.002 ) . This study provides further support for the use of tailored communication to address the prevention of injuries to young children but calls for continued investigation in the area OBJECTIVE This r and omized controlled trial examined one aspect of child pedestrian behavior , route selection across intersections , to evaluate whether a combination of widely-available videos and websites effectively train children in safe pedestrian route selection compared to active pedestrian safety control training and a no-contact control group . METHODS A sample of 231 seven- and eight-year-olds were r and omly assigned to one of four groups : training with videos and internet websites , active control groups of individualized streetside training or training within a virtual pedestrian environment , or a no-contact control group . All training groups received six 30-minute training sessions . Pedestrian route selection was assessed using two strategies , vignettes accompanied by illustrations and tabletop models of intersections , on three occasions : prior to intervention group assignment , immediately post-training , and six months after training . RESULTS Although there were differences in route selection over time , no time by condition interaction effects were significant ( ps > .05 ) , suggesting children in the video/internet training group did not learn pedestrian route selection skills at a rate different from those in the other training groups or those in the no-contact control group . CONCLUSION Safe route selection is a critical component of pedestrian safety . Our results suggest children may not learn route selection from widely-available videos or websites . Explanations for the null finding and implication s for both research and future practice are discussed Background Paediatric dog bites are a significant public health problem worldwide . Existing prevention programmes focused on altering children 's risky behaviour with pet dogs tend to be atheoretical and only moderately effective . Objective Test efficacy of a website to train young children in relevant cognitive skills to be safe with pet dogs in their home . Setting Birmingham , Alabama , USA . Methods A r and omised trial will be conducted with an expected sample of two groups of 34 children ( total N=68 ) ages 4–6 years . One group will engage in the newly design ed website at home for 2 weeks and the other group will engage in a control website on transportation safety for an equivalent amount of time . All participants will complete a battery of laboratory-based tests to assess safety with dogs and cognitive functioning at baseline and postintervention . Outcome measures Primary analyses will be conducted through linear mixed models testing change over time . Children 's cognitive functioning , knowledge about safety with dogs , and behaviour with dogs in simulation and in vivo will serve as the primary outcomes . Clinical trial registration This study is exempt from registry at the US government website , http://www . clinical trials.gov , based on being a behavioural trial in the early phases of testing |
13,664 | 30,653,708 | CONCLUSIONS SGLT2 inhibitors and GLP-1RAs reduced the three-point major adverse cardiovascular event risk compared to placebo , with no differences between them .
Compared with GLP-1RAs and placebo , SGLT2 inhibitors led to a larger reduction in hospital admission for heart failure risk | AIMS To compare the cardiovascular efficacy and safety of sodium-glucose co-transporter-2 ( SGLT2 ) inhibitors and glucagon-like peptide-1 receptor agonists ( GLP-1RAs ) in adults with Type 2 diabetes . | BACKGROUND The cardiovascular effects of adding once‐weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown . METHODS We r and omly assigned patients with type 2 diabetes , with or without previous cardiovascular disease , to receive subcutaneous injections of extended‐release exenatide at a dose of 2 mg or matching placebo once weekly . The primary composite outcome was the first occurrence of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke . The co primary hypotheses were that exenatide , administered once weekly , would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy . RESULTS In all , 14,752 patients ( of whom 10,782 [ 73.1 % ] had previous cardiovascular disease ) were followed for a median of 3.2 years ( interquartile range , 2.2 to 4.4 ) . A primary composite outcome event occurred in 839 of 7356 patients ( 11.4 % ; 3.7 events per 100 person‐years ) in the exenatide group and in 905 of 7396 patients ( 12.2 % ; 4.0 events per 100 person‐years ) in the placebo group ( hazard ratio , 0.91 ; 95 % confidence interval [ CI ] , 0.83 to 1.00 ) , with the intention‐to‐treat analysis indicating that exenatide , administered once weekly , was noninferior to placebo with respect to safety ( P<0.001 for noninferiority ) but was not superior to placebo with respect to efficacy ( P=0.06 for superiority ) . The rates of death from cardiovascular causes , fatal or nonfatal myocardial infa rct ion , fatal or nonfatal stroke , hospitalization for heart failure , and hospitalization for acute coronary syndrome , and the incidence of acute pancreatitis , pancreatic cancer , medullary thyroid carcinoma , and serious adverse events did not differ significantly between the two groups . CONCLUSIONS Among patients with type 2 diabetes with or without previous cardiovascular disease , the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo . ( Funded by Amylin Pharmaceuticals ; EXSCEL Clinical Trials.gov number , NCT01144338 . BACKGROUND R and omized trials demonstrated a lower risk of cardiovascular ( CV ) events with sodium-glucose cotransporter-2 inhibitors ( SGLT-2i ) in patients with type 2 diabetes ( T2D ) at high CV risk . Prior real-world data suggested similar SGLT-2i effects in T2D patients with a broader risk profile , but these studies focused on heart failure and death and were limited to the United States and Europe . OBJECTIVES The purpose of this study was to examine a broad range of CV outcomes in patients initiated on SGLT-2i versus other glucose-lowering drugs ( oGLDs ) across 6 countries in the Asia Pacific , the Middle East , and North American regions . METHODS New users of SGLT-2i and oGLDs were identified via cl aims , medical records , and national registries in South Korea , Japan , Singapore , Israel , Australia , and Canada . Propensity scores for SGLT-2i initiation were developed in each country , with 1:1 matching . Hazard ratios ( HRs ) for death , hospitalization for heart failure ( HHF ) , death or HHF , MI , and stroke were assessed by country and pooled using weighted meta- analysis . RESULTS After propensity-matching , there were 235,064 episodes of treatment initiation in each group ; ∼27 % had established CV disease . Patient characteristics were well-balanced between groups . Dapagliflozin , empagliflozin , ipragliflozin , canagliflozin , tofogliflozin , and luseogliflozin accounted for 75 % , 9 % , 8 % , 4 % , 3 % , and 1 % of exposure time in the SGLT-2i group , respectively . Use of SGLT-2i versus oGLDs was associated with a lower risk of death ( HR : 0.51 ; 95 % confidence interval [ CI ] : 0.37 to 0.70 ; p < 0.001 ) , HHF ( HR : 0.64 ; 95 % CI : 0.50 to 0.82 ; p = 0.001 ) , death or HHF ( HR : 0.60 ; 95 % CI : 0.47 to 0.76 ; p < 0.001 ) , MI ( HR : 0.81 ; 95 % CI : 0.74 to 0.88 ; p < 0.001 ) , and stroke ( HR : 0.68 ; 95 % CI : 0.55 to 0.84 ; p < 0.001 ) . Results were directionally consistent across both countries and patient subgroups , including those with and without CV disease . CONCLUSIONS In this large , international study of patients with T2D from the Asia Pacific , the Middle East , and North America , initiation of SGLT-2i was associated with a lower risk of CV events across a broad range of outcomes and patient characteristics . ( Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors [ CVD-REAL ] ; NCT02993614 ) ABSTRACT Review of : Neal B , Perkovic V , Mahaffey K , et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes . N Engl J Med . 2017;377:644–657 . The report combines the data from two trials , CANVAS and CANVAS-Renal , which were design ed to evaluate the safety and effect of canagliflozin , an SGLT-2 inhibitor , on the appearance of cardiovascular and renal events in patients with type 2 diabetes . Enrollees were patients with type 2 diabetes of at least 30 years of age , with a glycated hemoglobin of > or equal to 7.0 % and < or equal to 10.5 % . Patients either had to have preexisting cardiovascular disease or to be at elevated risk for cardiovascular disease , and to have an estimated glomerular filtration rate ( eGFR ) of > 30 ml/min . Patients were r and omized to canagliflozin at doses of either 100 mg or 300 mg or matching placebo in CANVAS , and to canagliflozin 100 mg with a possible increase to 300 mg , or placebo , in CANVAS-Renal . Physicians were instructed to continue appropriate diabetic management and other therapies in accordance with the best practice s in their community . There was a significant 14 % reduction in the combined endpoint of cardiovascular events of death from cardiovascular causes , nonfatal myocardial infa rct ion , or nonfatal stroke in the canagliflozin treated patients . There was also a pattern of improvement in markers of renal disease , including the change in the level and nature of albuminuria , a 40 % decrease in the glomerular filtration rate , the need for renal replacement therapy , or death from renal causes . This study exp and s the scope of SGLT-2 inhibitor therapy to prevent cardiovascular disease in diabetic patients beyond those with preexisting cardiovascular disease studied in the previous empagliflozin study , raising the question as to whether SGLT-2 inhibitor therapy should be considered appropriate for most , if not all , type 2 diabetes patients , not only to control hyperglycemia but also to reduce cardiovascular and renal events Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more CONTEXT Mortality from coronary heart disease has declined substantially in the United States during the past 30 years . However , it is unknown whether patients with diabetes have also experienced a decline in heart disease mortality . OBJECTIVE To compare adults with diabetes with those without diabetes for time trends in mortality from all causes , heart disease , and ischemic heart disease . DESIGN , SETTING , AND PARTICIPANTS Representative cohorts of subjects with and without diabetes were derived from the First National Health and Nutrition Examination Survey ( NHANES I ) conducted between 1971 and 1975 ( n = 9639 ) and the NHANES I Epidemiologic Follow-up Survey conducted between 1982 and 1984 ( n = 8463 ) . The cohorts were followed up prospect ively for mortality for an average of 8 to 9 years . MAIN OUTCOME MEASURE Changes in mortality rates per 1000 person-years for all causes , heart disease , and ischemic heart disease for the 1982 - 1984 cohort compared with the 1971 - 1975 cohort . RESULTS For the 2 periods , nondiabetic men experienced a 36.4 % decline in age-adjusted heart disease mortality compared with a 13.1 % decline for diabetic men . Age-adjusted heart disease mortality declined 27 % in nondiabetic women but increased 23 % in diabetic women . These patterns were also found for all-cause mortality and ischemic heart disease mortality . CONCLUSIONS The decline in heart disease mortality in the general US population has been attributed to reduction in cardiovascular risk factors and improvement in treatment of heart disease . The smaller declines in mortality for diabetic subjects in the present study indicate that these changes may have been less effective for people with diabetes , particularly women ABBREVIATIONS A1C = hemoglobin A1C ; AACE = American Association of Clinical Endocrinologists ; ACCORD = Action to Control Cardiovascular Risk in Diabetes ; ACCORD BP = Action to Control Cardiovascular Risk in Diabetes Blood Pressure ; ACEI = angiotensin-converting enzyme inhibitor ; ADVANCE = Action in Diabetes and Vascular Disease : Preterax and Diamicron MR Controlled Evaluation ; AGI = alpha-glucosidase inhibitor ; apo B = apolipoprotein B ; ASCVD = atherosclerotic cardiovascular disease ; BAS = bile acid sequestrant ; BCR-QR = bromocriptine quick release ; BMI = body mass index ; BP = blood pressure ; CCB = calcium channel blocker ; CHD = coronary heart disease ; CKD = chronic kidney disease ; CVD = cardiovascular disease ; DASH = Dietary Approaches to Stop Hypertension ; DPP4 = dipeptidyl peptidase 4 ; eGFR = estimated glomerular filtration rate ; ER = extended release ; FDA = Food and Drug Administration ; GLP1 = glucagon-like peptide 1 ; HDL-C = high-density lipoprotein cholesterol ; IMPROVE-IT = Improved Reduction of Outcomes : Vytorin Efficacy International Trial ; LDL-C = low-density lipoprotein cholesterol ; LDL-P = low-density lipoprotein particle ; Look AHEAD = Look Action for Health in Diabetes ; NPH = neutral protamine Hagedorn ; OSA = obstructive sleep apnea ; RCT = r and omized controlled trial ; SU = sulfonylurea ; SGLT2 = sodium glucose cotransporter-2 ; SMBG = self-monitoring of blood glucose ; T2D = type 2 diabetes ; TZD = thiazolidinedione ; VADT = Veterans Affairs Diabetes Trial BACKGROUND Glucagon-like peptide 1 receptor agonists differ in chemical structure , duration of action , and in their effects on clinical outcomes . The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown . We aim ed to determine the safety and efficacy of albiglutide in preventing cardiovascular death , myocardial infa rct ion , or stroke . METHODS We did a double-blind , r and omised , placebo-controlled trial in 610 sites across 28 countries . We r and omly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease ( at a 1:1 ratio ) to groups that either received a subcutaneous injection of albiglutide ( 30 - 50 mg , based on glycaemic response and tolerability ) or of a matched volume of placebo once a week , in addition to their st and ard care . Investigators used an interactive voice or web response system to obtain treatment assignment , and patients and all study investigators were masked to their treatment allocation . We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death , myocardial infa rct ion , or stroke , which was assessed in the intention-to-treat population . If non-inferiority was confirmed by an upper limit of the 95 % CI for a hazard ratio of less than 1·30 , closed testing for superiority was prespecified . This study is registered with Clinical Trials.gov , number NCT02465515 . FINDINGS Patients were screened between July 1 , 2015 , and Nov 24 , 2016 . 10 793 patients were screened and 9463 participants were enrolled and r and omly assigned to groups : 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo . On Nov 8 , 2017 , it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued , and participants returned for a final visit and discontinuation from study treatment ; the last patient visit was on March 12 , 2018 . These 9463 patients , the intention-to-treat population , were evaluated for a median duration of 1·6 years and were assessed for the primary outcome . The primary composite outcome occurred in 338 ( 7 % ) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 ( 9 % ) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group ( hazard ratio 0·78 , 95 % CI 0·68 - 0·90 ) , which indicated that albiglutide was superior to placebo ( p<0·0001 for non-inferiority ; p=0·0006 for superiority ) . The incidence of acute pancreatitis ( ten patients in the albiglutide group and seven patients in the placebo group ) , pancreatic cancer ( six patients in the albiglutide group and five patients in the placebo group ) , medullary thyroid carcinoma ( zero patients in both groups ) , and other serious adverse events did not differ between the two groups . There were three ( < 1 % ) deaths in the placebo group that were assessed by investigators , who were masked to study drug assignment , to be treatment-related and two ( < 1 % ) deaths in the albiglutide group . INTERPRETATION In patients with type 2 diabetes and cardiovascular disease , albiglutide was superior to placebo with respect to major adverse cardiovascular events . Evidence -based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes . FUNDING GlaxoSmithKline BACKGROUND Cardiovascular morbidity and mortality are higher among patients with type 2 diabetes , particularly those with concomitant cardiovascular diseases , than in most other population s. We assessed the effects of lixisenatide , a glucagon-like peptide 1-receptor agonist , on cardiovascular outcomes in patients with type 2 diabetes who had had a recent acute coronary event . METHODS We r and omly assigned patients with type 2 diabetes who had had a myocardial infa rct ion or who had been hospitalized for unstable angina within the previous 180 days to receive lixisenatide or placebo in addition to locally determined st and ards of care . The trial was design ed with adequate statistical power to assess whether lixisenatide was noninferior as well as superior to placebo , as defined by an upper boundary of the 95 % confidence interval for the hazard ratio of less than 1.3 and 1.0 , respectively , for the primary composite end point of cardiovascular death , myocardial infa rct ion , stroke , or hospitalization for unstable angina . RESULTS The 6068 patients who underwent r and omization were followed for a median of 25 months . A primary end-point event occurred in 406 patients ( 13.4 % ) in the lixisenatide group and in 399 ( 13.2 % ) in the placebo group ( hazard ratio , 1.02 ; 95 % confidence interval [ CI ] , 0.89 to 1.17 ) , which showed the noninferiority of lixisenatide to placebo ( P<0.001 ) but did not show superiority ( P=0.81 ) . There were no significant between-group differences in the rate of hospitalization for heart failure ( hazard ratio in the lixisenatide group , 0.96 ; 95 % CI , 0.75 to 1.23 ) or the rate of death ( hazard ratio , 0.94 ; 95 % CI , 0.78 to 1.13 ) . Lixisenatide was not associated with a higher rate of serious adverse events or severe hypoglycemia , pancreatitis , pancreatic neoplasms , or allergic reactions than was placebo . CONCLUSIONS In patients with type 2 diabetes and a recent acute coronary syndrome , the addition of lixisenatide to usual care did not significantly alter the rate of major cardiovascular events or other serious adverse events . ( Funded by Sanofi ; ELIXA Clinical Trials.gov number , NCT01147250 . ) Background : Reduction in cardiovascular death and hospitalization for heart failure ( HHF ) was recently reported with the sodium-glucose cotransporter-2 inhibitor ( SGLT-2i ) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease . We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class . Methods : Data were collected via medical cl aims , primary care/hospital records , and national registries from the United States , Norway , Denmark , Sweden , Germany , and the United Kingdom . Propensity score for SGLT-2i initiation was used to match treatment groups . Hazard ratios for HHF , death , and their combination were estimated by country and pooled to determine weighted effect size . Death data were not available for Germany . Results : After propensity matching , there were 309 056 patients newly initiated on either SGLT-2i or other glucose-lowering drugs ( 154 528 patients in each treatment group ) . Canagliflozin , dapagliflozin , and empagliflozin accounted for 53 % , 42 % , and 5 % of the total exposure time in the SGLT-2i class , respectively . Baseline characteristics were balanced between the 2 groups . There were 961 HHF cases during 190 164 person-years follow-up ( incidence rate , 0.51/100 person-years ) . Of 215 622 patients in the United States , Norway , Denmark , Sweden , and the United Kingdom , death occurred in 1334 ( incidence rate , 0.87/100 person-years ) , and HHF or death in 1983 ( incidence rate , 1.38/100 person-years ) . Use of SGLT-2i , versus other glucose-lowering drugs , was associated with lower rates of HHF ( hazard ratio , 0.61 ; 95 % confidence interval , 0.51–0.73 ; P<0.001 ) ; death ( hazard ratio , 0.49 ; 95 % confidence interval , 0.41–0.57 ; P<0.001 ) ; and HHF or death ( hazard ratio , 0.54 ; 95 % confidence interval , 0.48–0.60 ; P<0.001 ) with no significant heterogeneity by country . Conclusions : In this large multinational study , treatment with SGLT-2i versus other glucose-lowering drugs was associated with a lower risk of HHF and death , suggesting that the benefits seen with empagliflozin in a r and omized trial may be a class effect applicable to a broad population of patients with type 2 diabetes mellitus in real-world practice . Clinical Trial Registration : URL : http://www . clinical trials.gov . Unique identifier : NCT02993614 |
13,665 | 31,549,743 | Currently no evidence is available to show the benefits or harms of stem cell-based interventions for treatment or prevention of GM-IVH in preterm infants | BACKGROUND Germinal matrix-intraventricular haemorrhage ( GMH-IVH ) remains a substantial issue in neonatal intensive care units worldwide .
Current therapies to prevent or treat GMH-IVH are limited .
Stem cell-based therapies offer a potential therapeutic approach to repair , restore , and /or regenerate injured brain tissue .
These pre clinical findings have now culminated in ongoing human neonatal studies .
OBJECTIVES To determine the benefits and harms of stem cell-based interventions for prevention or treatment of germinal matrix-intraventricular haemorrhage ( GM-IVH ) in preterm infants . | CONTEXT Infants born prematurely are at risk for a perinatal encephalopathy characterized by white and gray matter injuries that affect subsequent cortical development and neural connectivity and potentially increase risk for later psychiatric disorder . OBJECTIVE To determine the relation of perinatal brain injury , as detected by neonatal head ultrasound , to psychiatric disorders in adolescents who were born prematurely . DESIGN Prospect i ve cohort . SETTING Community . PARTICIPANTS Adolescent survivors of a population -based low-birth-weight ( < 2000 g ; 96 % preterm ; born 1984 - 1987 ) cohort ( n = 1105 ) screened as neonates with serial head ultrasounds . Neonatal head ultrasound abnormalities were categorized as either ( 1 ) germinal matrix and /or intraventricular hemorrhage or ( 2 ) parenchymal lesions and /or ventricular enlargement . Of 862 eligible survivors , 628 ( 72.9 % ) were assessed at age 16 years . The sample consisted of 458 nondisabled survivors assessed in person . Main Outcome Measure Adolescent current and lifetime psychiatric disorders assessed with parent report on the Diagnostic Interview Schedule for Children-IV . RESULTS Compared with no abnormality , germinal matrix/intraventricular hemorrhage increased risk for current major depressive disorder ( odds ratio , 2.7 ; 95 % confidence interval , 1.0 - 6.8 ) and obsessive-compulsive disorder ( 9.5 ; 3.0 - 30.1 ) . Parenchymal lesions/ventricular enlargement increased risk for current attention-deficit/hyperactivity disorder-inattentive type ( odds ratio , 7.6 ; 95 % confidence interval , 2.0 - 26.5 ) , tic disorders ( 8.4 ; 2.4 - 29.6 ) , and obsessive-compulsive disorder ( 7.6 ; 1.39 - 42.0 ) . Parenchymal lesions/ventricular enlargement were not related to lifetime attention-deficit/hyperactivity disorder-inattentive type , but all other relations were similar for lifetime disorders . Control for other early risk factors did not alter these relations . Most of these relations persisted with control for concurrent cognitive or motor problems . CONCLUSION In preterm infants , 2 distinct types of perinatal brain injury detectable with neonatal head ultrasound selectively increase risk in adolescence for psychiatric disorders in which dysfunction of subcortical-cortical circuits has been implicated Umbilical cord blood ( UCB ) , rich in stem/progenitor cells , is partially eliminated from the bloodstream during childbirth because the cord is immediately clamped . We hypothesize that transfusion of autologous UCB to premature infants after delivery could serve as an adjuvant modality for preventing the development of prematurity-related complications . We r and omly enrolled 20 preterm infants born before 32 weeks of gestational age ( GA ) , all of whom developed anemia , necessitating transfusion of red blood cells ( RBCs ) . Two groups , matched for GA , were selected : ( 1 ) infants ( n = 5 ) who underwent UCB transfusion once within 5 days of birth ( mean ± st and ard deviation , 3.2 ± 1.9 days ) and ( 2 ) infants ( n = 15 ) from whom UCB was not collected ( e.g. , lack of consent ) . The latter served as controls and received allogeneic RBC transfusions ( 7.8 ± 3.9 days after birth ) . Selected prematurity-related complications were monitored . Two weeks after UCB/RBC transfusion , peripheral blood sample s were collected , and the concentrations of 41 selected growth factors and their receptors were analyzed using a multiplex protein array . UCB transfusions were found to be both feasible and tolerable . Intraventricular haemorrhage was diagnosed in two of five ( 40 % ) UCB recipients , but was found in thirteen of fifteen RBC recipients ( 86.7 % ) . Twenty-two plasma proteins ( e.g. , insulin-like growth factors , stem cell factor , epidermal growth factors ) were found with significantly different concentrations in UCB recipients compared to controls . Results demonstrate safety and feasibility of UCB transfusion in a small group of very premature neonates and should be interpreted as preliminary speculation . Transfusion of UCB could induce a specific humoral effects , and this could serve as an adjuvant modality for prevention of prematurity complications Background Little is known about the effects of induced pluripotent stem cell ( iPSC ) treatment on acute cerebral inflammation and injuries after intracerebral hemorrhage ( ICH ) , though they have shown promising therapeutic potentials in ischemic stoke . Methods An ICH model was established by stereotactic injection of collagenase VII into the left striatum of male Sprague-Dawley ( SD ) rats . Six hours later , ICH rats were r and omly divided into two groups and received intracerebrally 10 μl of PBS with or without 1 × 106 of iPSCs . Subsequently , neural function of all ICH rats was assessed at days 1 , 3 , 7 , 14 , 28 and 42 after ICH . Inflammatory cells , cytokines and neural apoptosis in the rats ’ perihematomal regions , and brain water content were determined on day 2 or 3 post ICH . iPSC differentiation was determined on day 28 post ICH . Nissl+ cells and glial fibrillary acidic protein (GFAP)+ cells in the perihematoma and the survival rates of rats in two groups were determined on post-ICH day 42 . Results Compared with control animals , iPSCs treatment not only improved neurological function and survival rate , but also result ed in fewer intracephalic infiltrations of neutrophils and microglia , along with decreased interleukin (IL)-1β , IL-6 and tumour necrosis factor-alpha ( TNF-α ) , and increased IL-10 in the perihematomal tissues of ICH rats . Furthermore , brain oedema formation , apoptosis , injured neurons and glial scar formation were decreased in iPSCs-transplanted rats . Conclusions Our findings indicate that iPSCs transplantation attenuate cerebral inflammatory reactions and neural injuries after ICH , and suggests that multiple mechanisms including inflammation modulation , neuroprotection and functional recovery might be involved simultaneously in the therapeutic benefit of iPSC treatment against hemorrhagic stroke OBJECTIVE To assess the safety and feasibility of allogeneic human umbilical cord blood (hUCB)-derived mesenchymal stem cell ( MSC ) transplantation in preterm infants . STUDY DESIGN In a phase I dose-escalation trial , we assessed the safety and feasibility of a single , intratracheal transplantation of hUCB-derived MSCs in preterm infants at high risk for bronchopulmonary dysplasia ( BPD ) . The first 3 patients were given a low dose ( 1 × 10(7 ) cells/kg ) of cells , and the next 6 patients were given a high dose ( 2 × 10(7 ) cells/kg ) . We compared their adverse outcomes , including BPD severity , with those of historical case-matched comparison group . RESULTS Intratracheal MSC transplantation was performed in 9 preterm infants , with a mean gestational age of 25.3 ± 0.9 weeks and a mean birth weight of 793 ± 127 g , at a mean of 10.4 ± 2.6 days after birth . The treatments were well tolerated , without serious adverse effects or dose-limiting toxicity attributable to the transplantation . Levels of interleukin-6 , interleukin-8 , matrix metalloproteinase-9 , tumor necrosis factor α , and transforming growth factor β1 in tracheal aspirates at day 7 were significantly reduced compared with those at baseline or at day 3 posttransplantation . BPD severity was lower in the transplant recipients , and rates of other adverse outcomes did not differ between the comparison group and transplant recipients . CONCLUSION Intratracheal transplantation of allogeneic hUCB-derived MSCs in preterm infants is safe and feasible , and warrants a larger and controlled phase II study In a previous study of preterm infants requiring mechanical ventilation for the respiratory distress syndrome , we demonstrated a striking association of fluctuating cerebral blood-flow velocity in the first day of life with the subsequent occurrence of intraventricular hemorrhage . Because this fluctuating pattern could be eliminated by muscle paralysis , we conducted a prospect i ve study of preterm infants receiving mechanical ventilation for the respiratory distress syndrome in which we evaluated the effect of paralysis and this flow-velocity pattern on the incidence and severity of intraventricular hemorrhage . Twenty-four infants with the fluctuating pattern in the first hours of life were identified and r and omly selected to serve as controls ( 10 ) or to be subjected to muscle paralysis ( 14 ) . Intraventricular hemorrhage developed in all 10 control infants but in only 5 of the 14 infants subjected to muscle paralysis . Moreover , in 4 of the 5 paralyzed infants in whom hemorrhage developed , it did so after cessation of the paralysis . Seven of the 10 control infants had Grade III hemorrhage , the most severe variety of intraventricular hemorrhage , whereas none of the paralyzed infants had Grade III hemorrhage . We conclude that elimination of fluctuating cerebral blood-flow velocity in preterm infants with respiratory distress syndrome markedly reduces the incidence and severity of intraventricular hemorrhage Objective . Bronchopulmonary dysplasia ( BPD ) is the endpoint of many intervention trials in neonatology , yet the outcome measure when based solely on oxygen administration may be confounded by differing criteria for oxygen administration between physicians . We previously reported a technique to st and ardize the definition of BPD between sites by using a timed room-air challenge in selected infants . We hypothesized that a physiologic definition of BPD would reduce the variation in observed rates of BPD among different neonatal centers . Methodology . A total of 1598 consecutive inborn premature infants ( 501–1249 g birth weight ) who remained hospitalized at 36 weeks ' postmenstrual age were prospect ively assessed and assigned an outcome with both a clinical definition and physiologic definition of BPD . The clinical definition of BPD was oxygen supplementation at exactly 36 weeks ' postmenstrual age . The physiologic definition of BPD was assigned at 36 ± 1 weeks ' postmenstrual age and included 2 distinct sub population s. First , neonates on positive pressure support or receiving > 30 % supplemental oxygen with saturations between 90 % and 96 % were assigned the outcome BPD and not tested further . Second , those receiving ≤30 % oxygen or effective oxygen > 30 % with saturations > 96 % underwent a room-air challenge with continuous observation and oxygen-saturation monitoring . Outcomes of the room-air challenge were “ no BPD ” ( saturations ≥90 % during weaning and in room air for 30 minutes ) or “ BPD ” ( saturation < 90 % ) . At the conclusion of the room-air challenge , all infants were returned to their baseline oxygen levels . Safety ( apnea , bradycardia , increased oxygen use ) and outcomes of the physiologic definition versus the clinical definition were assessed . Results . A total of 560 ( 35.0 % ) neonates were diagnosed with BPD by the clinical definition of oxygen use at 36 weeks ' postmenstrual age . The physiologic definition diagnosed BPD in 398 ( 25.0 % ) neonates in the cohort . All infants were safely studied . There were marked differences in the impact of the definition on BPD rates between centers ( mean reduction : 10 % ; range : 0–44 % ) . Sixteen centers had a decrease in their BPD rate , and 1 center had no change in their rate . Conclusions . The physiologic definition of BPD reduced the overall rate of BPD and reduced the variation among centers . Significant center differences in the impact of the physiologic definition were seen , and differences remained even with the use of this st and ardized definition . The magnitude of the change in BPD rate is comparable to the magnitude of treatment effects seen in some clinical trials in BPD . The physiologic definition of BPD facilitates the measurement of BPD as an outcome in clinical trials and the comparison between and within centers over time Individuals born very preterm ( VPT ) are at increased risk of perinatal brain injury and long-term cognitive and behavioral problems . Executive functioning , in particular , has been shown to be impaired in VPT children and adolescents . This study prospect ively assessed executive function in young adults who were born VPT ( <33 weeks of gestation ) [ n = 61 ; mean age , 22.25 ( + /-1.07 ) years ; range , 20.62 - 24.78 years ] and controls [ n = 64 ; mean age , 23.20 ( + /-1.48 ) years ; range , 19.97 - 25.46 years ] . Tests used comprised the Wechsler Abbreviated Scale of Intelligence ( WASI ) , the Hayling Sentence Completion Test ( HSCT ) , the Controlled Oral Word Association Test ( COWAT ) , the Animal and Object test , the Trail-Making Test ( TMT ) , and the Test of Attentional Performance ( TAP ) . VPT participants showed specific executive function impairments in tasks involving response inhibition and mental flexibility , even when adjusting for IQ , gender , and age . No significant associations were observed between executive function test scores and perinatal variables or neonatal ultrasound classification . The results suggest that , although free from major physical disability , VPT young adults perform worse than controls on tasks involving selective aspects of executive processing , such as mental flexibility and response inhibition OBJECTIVE To assess feasibility and safety of providing autologous umbilical cord blood ( UCB ) cells to neonates with hypoxic-ischemic encephalopathy ( HIE ) . STUDY DESIGN We enrolled infants in the intensive care nursery who were cooled for HIE and had available UCB in an open-label study of non-cyropreserved autologous volume- and red blood cell-reduced UCB cells ( up to 4 doses adjusted for volume and red blood cell content , 1 - 5 × 10(7 ) cells/dose ) . We recorded UCB collection and cell infusion characteristics , and pre- and post-infusion vital signs . As exploratory analyses , we compared cell recipients ' hospital outcomes ( mortality , oral feeds at discharge ) and 1-year survival with Bayley Scales of Infant and Toddler Development , 3rd edition scores ≥85 in 3 domains ( cognitive , language , and motor development ) with cooled infants who did not have available cells . RESULTS Twenty-three infants were cooled and received cells . Median collection and infusion volumes were 36 and 4.3 mL. Vital signs including oxygen saturation were similar before and after infusions in the first 48 postnatal hours . Cell recipients and concurrent cooled infants had similar hospital outcomes . Thirteen of 18 ( 74 % ) cell recipients and 19 of 46 ( 41 % ) concurrent cooled infants with known 1-year outcomes survived with scores > 85 . CONCLUSIONS Collection , preparation , and infusion of fresh autologous UCB cells for use in infants with HIE is feasible . A r and omized double-blind study is needed Background . Advances in perinatal care have result ed in increased survival rates for extremely low birth weight children . We sought to examine the relative changes in rates of survival and neurodevelopmental impairment at 20 months of corrected age among 500- to 999-g birth weight infants born at our perinatal center during 2 periods , before and after the introduction of surfactant therapy in 1990 . Methods . Four hundred ninety-six infants with birth weights of 500 to 999 g were born at our perinatal center during period I ( 1982–1989 ) ( mean body weight : 762 g ; mean gestational age : 25.8 weeks ) and 682 during period II ( 1990–1998 ) ( mean body weight : 756 g ; mean gestational age : 25.5 weeks ) . Rates of death and survival with and without neurodevelopmental impairment at 20 months of corrected age for the 2 periods were compared with logistic regression analyses , with adjustment for gestational age . Results . Survival rates increased from 49 % during period I to 67 % during period II . Neonatal morbidity rates also increased during period II , including rates of sepsis ( from 37 % to 51 % ) , periventricular leukomalacia ( from 2 % to 7 % ) , and chronic lung disease , defined as oxygen dependence at 36 weeks of corrected age ( from 32 % to 43 % ) . Rates of severe cranial ultrasound abnormalities were similar ( 22 % vs 22 % ) . Among children monitored , the rate of neurologic abnormalities , including cerebral palsy , increased from 16 % during period I to 25 % during period II and the rate of deafness increased from 3 % to 7 % . The overall rate of neurodevelopmental impairment ( major neurosensory abnormality and /or Bayley Mental Developmental Index score of < 70 ) increased from 26 % to 36 % . Compared with period I , in period II there were decreased rates of death ( odds ratio [ OR ] : 0.3 ; 95 % confidence interval [ CI ] : 0.2–0.4 ) and increased rates of survival with impairment ( OR : 2.3 ; 95 % CI : 1.7–3.3 ) but also increased rates of survival without impairment ( OR : 1.7 ; 95 % CI : 1.3–2.2 ) . Compared with period I , for every 100 infants with birth weights of 500 to 999 g born in period II , 18 additional infants survived , of whom 7 were unimpaired and 11 were impaired . Conclusions . The improved survival rates in the 1990s occurred with an increased risk of significant neurodevelopmental impairment . Prospect i ve parents of extremely low birth weight infants should be advised of this substantial risk , to facilitate decision-making in the delivery room Background Preterm birth complications are one of the leading causes of death among children under 5 years of age . Despite advances in medical care , many survivors face a lifetime of disability , including mental and physical retardation , and chronic lung disease . More recently , both allogenic and autogenic cord blood cells have been applied in the treatment of neonatal conditions such as hypoxic-ischemic encephalopathy ( HIE ) and bronchopulmonary dysplasia ( BPD ) . Objective To assess the safety of autologous , volume- and red blood cell- ( RBC- ) reduced , noncryopreserved umbilical cord blood ( UCB ) cell infusion to preterm infants . Method This study was a phase I , open-label , single-arm , single-center trial to evaluate the safety of autologous , volume- and RBC-reduced , noncryopreserved UCB cell ( 5 × 107cells/kg ) infusion for preterm infants < 37 weeks gestational age . UCB cell characteristics , pre- and postinfusion vital signs , and laboratory investigations were recorded . Clinical data including mortality rates and preterm complications were recorded . Results After processing , ( 22.67 ± 4.05 ) ml UCB cells in volume , ( 2.67 ± 2.00 ) × 108 cells in number , with ( 22.67 ± 4.05 ) × 106 CD34 + , ( 3.72 ± 3.25 ) × 105 colony forming cells ( CFU-GM ) , and ( 99.7 ± 0.17 % ) vitality were infused to 15 preterm infants within 8 hours after birth . No adverse effects were noticed during treatment . All fifteen patients who received UCB infusion survived . The duration of hospitalization ranged from 4 to 65 ( 30 ± 23.6 ) days . Regarding preterm complications , no BPD , necrotizing enterocolitis ( NEC ) , retinopathy of prematurity ( ROP ) was observed . There were 1/15 ( 7 % ) infant with intraventricular hemorrhage ( IVH ) , 5/15 ( 33.3 % ) infants with ventilation-associated pneumonia , and 10/15 ( 66.67 % ) with anemia , respectively . Conclusions Collection , preparation , and infusion of fresh autologous UCB cells to preterm infants is feasible and safe . Adequately powered r and omized controlled studies are needed CONTEXT Up-to- date information on infant survival after extremely preterm birth is needed for assessing perinatal care services , clinical guidelines , and parental counseling . OBJECTIVE To determine the 1-year survival in all infants born before 27 gestational weeks in Sweden during 2004 - 2007 . DESIGN , SETTING , AND PATIENTS Population -based prospect i ve observational study of extremely preterm infants ( 707 live-born and 304 stillbirths ) born to 887 mothers in 904 deliveries ( 102 multiple births ) in all obstetric and neonatal units in Sweden from April 1 , 2004 , to March 31 , 2007 . MAIN OUTCOME MEASURES Infant survival to 365 days and survival without major neonatal morbidity ( intraventricular hemorrhage grade > 2 , retinopathy of prematurity stage > 2 , periventricular leukomalacia , necrotizing enterocolitis , severe bronchopulmonary dysplasia ) . Associations between perinatal interventions and survival . RESULTS The incidence of extreme prematurity was 3.3 per 1000 infants . Overall perinatal mortality was 45 % ( from 93 % at 22 weeks to 24 % at 26 weeks ) , with 30 % stillbirths , including 6.5 % intrapartum deaths . Of live-born infants , 91 % were admitted to neonatal intensive care and 70 % survived to 1 year of age ( 95 % confidence interval [ CI ] , 67%-73 % ) . The Kaplan-Meier survival estimates for 22 , 23 , 24 , 25 , and 26 weeks were 9.8 % ( 95 % CI , 4%-23 % ) , 53 % ( 95 % CI , 44%-63 % ) , 67 % ( 95 % CI , 59%-75 % ) , 82 % ( 95 % CI , 76%-87 % ) , and 85 % ( 95 % CI , 81%-90 % ) , respectively . Lower risk of infant death was associated with tocolytic treatment ( adjusted for gestational age odds ratio [ OR ] , 0.43 ; 95 % CI , 0.36 - 0.52 ) , antenatal corticosteroids ( OR , 0.44 ; 95 % CI , 0.24 - 0.81 ) , surfactant treatment within 2 hours after birth ( OR , 0.47 ; 95 % CI , 0.32 - 0.71 ) , and birth at a level III hospital ( OR , 0.49 ; 95 % CI , 0.32 - 0.75 ) . Among 1-year survivors , 45 % had no major neonatal morbidity . CONCLUSION During 2004 to 2007 , 1-year survival of infants born alive at 22 to 26 weeks of gestation in Sweden was 70 % and ranged from 9.8 % at 22 weeks to 85 % at 26 weeks |
13,666 | 28,901,007 | Induction of labour in outpatient setting s appears feasible and important adverse events seem rare , however , in general there is insufficient evidence to detect differences .
There was no strong evidence that agents used to induce labour in outpatient setting s had an impact ( positive or negative ) on maternal or neonatal health .
There was some evidence that compared to placebo or no treatment , induction agents administered on an outpatient basis reduced the need for further interventions to induce labour , and shortened the interval from intervention to birth . | BACKGROUND Induction of labour is carried out for a variety of indications and using a range of methods .
For women at low risk of pregnancy complications , some methods of induction of labour or cervical ripening may be suitable for use in outpatient setting s. OBJECTIVES To examine pharmacological and mechanical interventions to induce labour or ripen the cervix in outpatient setting s in terms of effectiveness , maternal satisfaction , healthcare costs and , where information is available , safety . | OBJECTIVE To assess the ability of mifepristone to prime the cervix adequately and induce labor in pregnant women at term ; and when mifepristone alone proves insufficient , to determine whether oral misoprostol taken 48 h following mifepristone administration is effective in inducing labor . METHODS In this prospect i ve study 50 pregnant women at term with an unfavorable cervix were given 400 mg of mifepristone orally and allowed to return home . If labor did not start within 48 h , the women were admitted and induction was continued with 50 mug of misoprostol , a prostagl and in ( PG ) E1 analogue , taken orally every 4 h. The 50 controls , who were matched prospect ively for parity and pregnancy duration , underwent labor induction according to the routine administration of 3-mg tablets of PGE2 vaginally . RESULTS In the study group , 66 % of the women entered labor spontaneously or had a sufficiently ripened cervix within 48 h of taking mifepristone . However , there was no difference in time between prostagl and in administration and delivery between the control group and the 34 % of women who required misoprostol in the study group . In the study group , the cesarean section rate was significantly lower among the women whose labor was induced with mifepristone alone than among those who required misoprostol . There were no differences overall in obstetric or neonatal outcomes between the study and control groups . CONCLUSIONS In this pilot sample , 400 mg of mifepristone was effective in inducing cervical changes and labor . Although there were no adverse effects using oral misoprostol in combination with mifepristone , labor was more difficult to induce in the women who did not respond to mifepristone alone , and these women had a higher operative delivery rate The value of gentle , unilateral breast stimulation in the ripening of cervix and induction of labour was studied . Three hundred patients with uncomplicated term pregnancies , ( 38 - 42 weeks ) were recruited into the study , consisting of three separate r and omised double blind prospect i ve trials . The first trial was to evaluate the effectiveness of breast stimulation in ripening the cervices of 200 term primigravid patients . There was a mean change of 3.90 + /- 2.39 points in cervical score among the study group compared to 0.50 + /- 0.67 among the control group . Thirty-three per cent of the study group went into labour when compared with 4 % among the control group . In a second study of cross-over trial involving 78 of the original 200 patients , the study ( ex-control ) group had a mean change in cervical score of 3.84 + /- 2.24 when compared with the control ( ex- study ) group , ( 1.43 + /- 1.08 ) . In a third study involving 100 multiparous patients , a mean change in cervical score of 2.74 + /- 1.16 was observed in the study group when compared with the control group , 0.92 + /- 1.07 . Forty-six per cent of the patients went into labour compared with 12 % in the control group . All findings were highly significant and there were no maternal or fetal side-effects . The study confirmed the efficacy of breast stimulation in cervical ripening and induction of labour OBJECTIVE To determine the safety and effectiveness of self-administered treatment with isosorbide mononitrate ( IMN ) for cervical ripening in Indian women with post date d pregnancies . METHODS A r and omized , placebo-controlled study was conducted with 200 women with post date d pregnancies and unfavorable cervices who self-administered vaginally either 2 40-mg tablets of IMN or 2 40-mg tablets of pyridoxine as placebo prior to admission for induction of labor . The main outcome variables were change in Bishop score , time from admission to delivery , and presence or absence of fetal and maternal morbidity . RESULTS The Bishop score was significantly improved 24 hours after initiation of the outpatient IMN treatment ( P<0.001 ) and the needs for further cervical ripening and oxytocin infusion were less in the study than in the control group ( P<0.001 and P=0.008 ) . The time from admission to delivery was also less ( P<0.001 ) . Moreover , the IMN treatment had no major adverse maternal or fetal effects . The vast majority of women in both groups were either satisfied or very satisfied with the outpatient treatment . CONCLUSION The self-administration , at home , of isosorbide mononitrate leads to a safe and effective cervical ripening prior to labor induction in women with post date d pregnancies . CTRI Registration No.:CTRI/2011/091/000121 Two hundred consecutive women with uncomplicated pregnancies , at or within 4 days of their expected date of confinement , were prospect ively r and omized into 2 groups . One group had expectant management , with twice weekly surveillance tests , while the other group had 3 mg of vaginal prostagl and in E2 as outpatient treatment . There were 104 women in the expectant group and 70 in the induction group ( 26 women allocated to induction preferred no treatment ) . The average number of days to delivery was 1.6 in the induction group and 5.2 in the expectant group ( p < 0.001 ) . While meconium was much less frequent in the induction group ( p < 0.002 ) , all other outcome measures , including cesarean section rates , incidence of macrosomia , and Apgar scores , were similar in the two groups In a prospect i ve r and omized study , pregnancies with unfavorable cervix and well established gestational age of at least 42 weeks were selected for management by either antepartum fetal testing or prostagl and in gel induction of labor . Of the 108 pregnancies studied , 57 ( 53 % ) had labor induced and 51 ( 47 % ) continued without intervention . Comparison of the two groups showed no difference in meconium staining , fetal distress , length of first stage of labor , the need for intervention , or the mode of delivery . In terms of Apgar score the neonatal outcome was not significantly different but a greater proportion of the babies ( 7.8 % versus 1.8 % ) in the noninduced group required intubation . Our data show that there is no particular advantage in letting the pregnancy go beyond 42 completed weeks of gestation especially if prostagl and in is available for induction of labor OBJECTIVE To determine whether outpatient administration of intracervical prostagl and in ( PG ) E2 gel decreases the interval to delivery and duration of labor . METHODS A r and omized , double-blind , placebo-controlled trial compared the intracervical placement of 0.5 mg PGE2 gel with placebo in 61 pregnant women at 38 weeks ' or greater gestation with Bishop scores less than 9 . Transvaginal cervical length , fetal fibronectin , and Bishop score were assessed before gel placement . Subjects were then allowed to go into spontaneous labor unless an indication for induction developed . RESULTS Thirty women were assigned to PGE2 and 31 to placebo . There were no significant demographic differences between the groups and there were no differences in cervical length , fetal fibronectin status , or Bishop scores . Fifteen women in the PGE2 group and five in the placebo group went into labor and delivered within the first 2 days after gel placement ( P = .007 ) . The median interval to delivery was significantly shorter in the PGE2 group , at 2.5 days , compared with placebo , at 7 days ( P = .02 ) . Nulliparas in the PGE2 group had a median interval to delivery of 2 days , compared with 7 days for nulliparas receiving placebo ( P = .03 ) . Active phases of labor were significantly shorter in the PGE2 group and for women with a negative fetal fibronectin test who received PGE2 . CONCLUSION Outpatient administration of intracervical PGE2 gel shortened intervals to delivery and shortened labor Objective To compare the effects of 50 mg or 200 mg of oral mifepristone with placebo on cervical ripening and induction of labor in primigravid women at term with unfavorable cervices . Methods This was a double-blind study in which 80 primigravidae at term with a modified Bishop score of 4 or less were r and omly assigned to one of three treatment groups . They were assessed at 24-hour intervals for 72 hours , after which labor was induced if it had not occurred spon-taneously . Results Two hundred milligrams of mifepristone result ed in a favorable cervix ( with a Bishop score greater than 6 or in spontaneous labor ) in significantly more women than placebo ( P = .01 ) . An improvement in cervical ripening was seen in the group given 50 mg of mifepristone , but this was not statistically significant . There were more cesarean deliveries performed for fetal distress in the group treated with 200 mg of mifepristone than placebo , but this was not statistically significant and was not associated with any differences between groups in terms of neonatal outcome . Conclusion Mifepristone , a progesterone antagonist , is known to cause softening and dilation of the human early pregnant cervix and an increase in uterine activity . It is theoretically attractive for use as an adjunct in cervical priming and labor induction . In this study , 200 mg of mifepristone was significantly more likely to result in a favorable cervix than placebo Background There is increasing interest in carrying out pre-induction cervical ripening on an outpatient basis . However , there are concerns about the use of prostagl and ins , the agents commonly used in hospital setting s for this indication , because prostagl and ins induce uterine contractions that may lead to fetal hypoxia . Indeed , in a recent study we demonstrated abnormalities in 9 % of fetal heart rate tracings performed following prostagl and in induced cervical ripening at term . In contrast , we confirmed in the same study that isosorbide mononitrate ( IMN ) ( administered on an inpatient basis ) was both effective in inducing cervical ripening at term , and was associated with no associated fetal heart rate abnormalities . Methods / design The aim of this study is to determine whether IMN self administered by women on an outpatient basis improves the process of induction of labour . Specifically , we hypothesise that the use of outpatient IMN will result in a shorter inpatient stay before delivery , decreased costs to the health service and greater maternal satisfaction with ripening and induction of labour , compared with placebo treatment . In the study described here ( the " IMOP " study ) , women scheduled for induction of labour at term , and who require pre-induction cervical ripening will be r and omised to self-administer at home either IMN 40 mg , or a placebo , each vaginally , at 48 hours , 32 hours and 16 hours before scheduled hospital admission . After admission to hospital , treatment will revert to the usual induction of labour protocol . We will compare the primary outcomes of the elapsed time interval from hospital admission to vaginal delivery , the costs to the health service of induction of labour , and women 's experience of induction of labour in the two groups . Discussion This trial will provide evidence on the efficacy of outpatient IMN for pre-induction cervical ripening at term . We will study a formulation of IMN which is cheap and widely available . If the treatment is effective , acceptable to women , and cost effective , it could be implemented into obstetric practice worldwide . Trial registration The trial has been registered on the International St and ard R and omised Controlled Trial Number Register ( IS RCT N ) and given the registration number ISRTN39772441 OBJECTIVE Our purpose was to determine whether a protocol for outpatient induction is safe and effective for initiating labor . STUDY DESIGN A r and omized , double-blind , placebo-controlled trial was performed with 100 low-risk patients having well- date d pregnancies . Women with a Bishop score < or = 6 at 38 to 40 weeks ' gestation were administered either 2 mg of intravaginal prostagl and in E2 gel or placebo for 5 consecutive days as out patients while undergoing fetal monitoring . RESULTS The median interval from r and omization to delivery was 4 days in the prostagl and in E2 group ( range 0 to 28 days ) versus 10 days in the placebo group ( range 0 to 26 days , p = 0.002 ) . Twenty-seven of 50 patients ( 54 % ) in the prostagl and in E2 group were admitted for labor during the dosing interval compared with 10 placebo-treated patients ( 20 % , p = 0.001 ) . The mean gestational age at delivery was significantly reduced in the treatment group ( 39.9 + /- 1.0 weeks vs 40.5 + /- 0.99 weeks , p = 0.003 ) as was the incidence of post date s pregnancy ( 40 % vs 66 % , p = 0.016 ) . Hyperstimulation was observed in one prostagl and in E2-treated patient , but no intervention was required . CONCLUSIONS Outpatient low-dose prostagl and in E2 gel administration is effective for initiating labor in patients with an unfavorable cervix and appears safe if performed with adequate monitoring CONTEXT Despite wide use of castor oil to initiate labor , the obstetric literature contains few references to this botanical laxative . Derived from the castor plant Ricinus communis , castor oil may possess properties that are useful in post-term pregnancies . OBJECTIVE To evaluate the relationship between the use of castor oil and the onset of labor . DESIGN Prospect i ve evaluation . SETTING A community hospital in Brooklyn , NY . PATIENTS A total of 103 singleton pregnancies with intact membranes at 40 to 42 weeks referred for antepartum testing . Inclusion criteria included cervical examination , Bishop score of 4 or less , and no evidence of regular uterine contractions . INTERVENTION Patients were alternately assigned to 1 of 2 study groups : a single oral dose of castor oil ( 60 mL ) or no treatment . MAIN OUTCOME MEASURES Castor oil was considered successful if labor began within 24 hours after dosing . Groups were compared for onset of labor in 24 hours , method of delivery , presence of meconium-stained amniotic fluid , Apgar score , and birth weight . RESULTS Fifty-two women received castor oil and 48 were assigned no treatment . Following administration of castor oil , 30 of 52 women ( 57.7 % ) began active labor compared to 2 of 48 ( 4.2 % ) receiving no treatment . When castor oil was successful , 83.3 % ( 25/30 ) of the women delivered vaginally . CONCLUSIONS Women who receive castor oil have an increased likelihood of initiation of labor within 24 hours compared to women who receive no treatment . Castor oil use in pregnancy is underreported worldwide . This small series represents the first attempt to evaluate the medication OBJECTIVE Within the obstetric community , several studies suggest that cervical ripening and labor induction after 40 weeks ' gestation leads to improved maternal and neonatal outcomes . The most effective drug regimen to safely promote labor has not been determined . METHOD Forty-nine subjects followed in an outpatient obstetrical clinic with pregnancies of at least 40 weeks ' gestation , and an unfavorable Bishop score were assigned r and omly to receive oral misoprostol 50 or 25 microg every 3 days for a maximum of three doses . RESULTS Twenty-three subjects received misoprostol 25 microg and 26 received 50 microg . The mean interval ( + /-st and ard deviation ) from start of cervical ripening to delivery was 2.4 days + /-0.3 vs. 3.9 days + /-0.7 for the 50 and 25 microg groups ( P<0.05 ) . No adverse events were noted . However , due to small sample size , less frequent adverse events may be missed . Type II errors can not be excluded . CONCLUSION In the prevention of post date pregnancy , out patients use of oral misoprostol 50 microg appears to result in earlier delivery , as compared to 25 microg Abstract Our purpose was to examine the hypothesis that corticosteroids , when administered intramuscularly , can enhance the labor process and reduce the time interval between the induction and the active phase . A r and omized , controlled study was conducted on 66 women with gestational age of 41 weeks and over and favorable cervix ( bishop score ≥ 7 ) . The study group ( n = 32 ) received 10 mg of dexamethasone phosphate intramuscularly in two doses at an interval of 12 hours , and the day after the enrolling administration intravenous oxytocin was given . The control group ( n = 33 ) received only intravenous oxytocin 24 hours after enrolling . The number of patients to enter the active phase of labor was significantly higher in the study group than in the control group ( n = 33 [ 100 % ] vs n = 29 [ 87.9 % ] , p < 0.039 ) . The mean time interval between induction of labor and the active phase was significantly shorter in the study group than in the control group ( 1.7±1.5 hours vs 4±1.7 , P < 0.0001 ) , and the mean of oxytocin dose was significantly lower in the study group ( 1.15±1.5u vs 4.16±2.5u , P < 0.0001 ) . Induction of labor with the use of intramuscularly injected dexamethasone phosphate reduced the time interval between the induction of labor and the active phase A double-blind , placebo-controlled , prospect i ve investigation was undertaken to determine whether the outpatient administration of prostagl and in E2 gel was helpful for ripening the cervix in post date pregnancies . One hundred eighteen women with an uncomplicated pregnancy at or beyond 42 weeks ' gestation with an unripe cervix ( Bishop score less than or equal to 5 ) were r and omly administered a single dose of gel containing either 2.5 mg prostagl and in E2 ( n = 55 ) or a placebo ( n = 63 ) before induction of labor with Pitocin . No side effects were detected in these healthy mothers and fetuses . A distinct change in Bishop score after 12 hours occurred more often in the prostagl and in E2 than in the placebo group ( 42 % versus 6 % , p less than 0.0001 ) . Forty-four women ( 80 % ) who had received prostagl and in E2 were admitted in early labor ; they required little or no oxytocin for augmentation . The duration of labor and maximum dose of oxytocin infused were significantly decreased in the prostagl and in E2 group , and forceps delivery or primary cesarean sections were performed less often when prostagl and in E2 was used ( 24 % versus 44 % , p less than 0.05 ) . The outpatient administration of a single dose of prostagl and in E2 gel is safe in the uncomplicated post date pregnancy and was found to significantly change the unripe cervix , enhance the onset of labor , minimize the need for oxytocin administration , and encourage a spontaneous vaginal delivery Induction of labor is frequently a matter of medical or obstetric necessity . Patients with worsening maternal or fetal problems often have an unfavorable cervix which may preclude successful induction of labor . In a blind , r and omized , controlled trial of breast stimulation to ripen the cervix at term , it was found that breast stimulation was associated with a 45 % incidence of spontaneous labor . When the patient did not go into labor , there was a mean change of 2.4 points in the Bishop score . Both findings are highly significant when compared with the control group Objective To evaluate the efficacy and tolerance of mifepristone in women undergoing induction of labour at term after previous caesarean section Objective : To determine whether weekly outpatient administration of prostagl and in gel or estrogen cream initiated labor in women with an unfavorable cervix . Methods : All uncomplicated pregnancies at term gestation who were c and i date s for a vaginal delivery with a Bishop score of ≤ 6 were r and omly assigned to receive on a weekly basis : prostagl and in E2 gel ( n = 41 ) ; estrogen cream ( n = 44 ) ; or inert lubricant jelly ( n = 43 ) . Results : In the three groups no differences were observed among 128 subjects in the weekly Bishop scores , cervical dilatation or gestational age upon admission to the labor and delivery suite , the percentage of patients presenting with spontaneous labor or ruptured membranes , the number of post- date inductions or neonatal outcome . Conclusions : Weekly out-patient cervical ripening using either prostagl and in gel or estrogen in women with an unfavorable cervix at 37 weeks ' gestation was no more effective than a placebo in Bishop score improvement or in preventing post- date inductions Recent experience has suggested that porcine ovarian relaxin may promote cervical changes . We have performed two double-blind r and omized studies : ( 1 ) comparing cervical changes with relaxin versus placebo during oxytocic labor induction and ( 2 ) as out patients in post date s pregnancies . In the induction study , cervical changes were speeded up by both 2 and 4 mg doses of relaxin , and times to delivery were decreased . In the outpatient study , 2 mg doses of relaxin produced greater cervical changes than did control or 4 mg doses . We conclude that relaxin may have benefit in ripening of the cervix . Since relaxin works directly on the cervix and not through uterine contractions , relaxin may have advantages in cervical ripening of pregnancies in which stress to the fetus is an issue The aim of this study was to evaluate whether sweeping of the membranes at term could shorten the length of pregnancy and reduce the incidence of postterm pregnancies . We r and omly selected 104 nulliparas with uncomplicated pregnancy and gestational age between 281 and 287 days . Our patients were divided into three groups . Group A consisted of 34 women who were subjected to sweeping of the membranes . Uterine stimulation with oxytocin was applied in 35 women ( group B ) , and 35 women ( group C ) were used as a control group . We had no significant reduction of the time interval from sweeping of the membranes until delivery ( 1.9 ± 1.2 days ) , compared to that of group B ( 2.1 ± 0.8 days ) as well as that of the control group ( 2.5 ± 0.9 days ) . The incidence of spontaneous labor in patients after sweeping of the membranes was greater ( 67.6 % ) when compared with oxytocin-stimulated patients and the control group ( p < 0.05 ) . Furthermore , a better Bishop score was noted in patients of group A. No statistically significant difference was noted in the mode of delivery between the groups , but sweeping of the membranes significantly decreased the incidence of postterm pregnancies ( p < 0.05 ) . We concluded that sweeping of the membranes is an effective method for initiating labor in women with a gestational age between 40 and 41 weeks , thus reducing the need for induction OBJECTIVE Our purpose was to determine the optimal management of pregnancies beyond 41 weeks ' gestation with a cervix unfavorable for induction . STUDY DESIGN All uncomplicated pregnancies that reached 41 weeks ' gestation with a Bishop score of < or = 4 were r and omly assigned to one of three groups : ( 1 ) daily cervical examinations , ( 2 ) daily membrane stripping , or ( 3 ) daily placement of prostagl and in gel until 42 weeks . RESULTS In 105 pregnancies the Bishop score on admission to labor and delivery was significantly greater in the groups receiving prostagl and in or stripping of the membranes versus the control group , whereas the converse was time of gestational age at delivery ( p = 0.0001 ) . Fewer patients required induction in the two treatment groups ( 20 % , 17 % ) versus the control ( 69 % ) patients ( p < 0.0001 ) . CONCLUSIONS Daily membrane stripping or daily placement of prostagl and in gel is successful in reducing the number of inductions at 42 weeks for postdatism To evaluate the efficacy and safety of three concentrations of prostagl and in E2 ( PGE2 ) gel for preinduction cervical ripening . Two hundred ninety-one patients with an unfavorable cervix scheduled for induction of labor were eligible to participate in a prospect i ve , r and omized , double-blind study of one or two doses of intracervical PGE2 gel . Group 1 received a dose of 0.125 mg/2 ml ; group 2 received 0.25 mg/2 ml ; and group 3 received 0.5 mg/2 ml . Outcome variables included change in Bishop score , uterine tachysystole , oxytocin use , route of delivery , and maternal and neonatal complications . Two hundred twenty-nine patients were included in the study , 79 in group 1 , 70 in group 2 , and 80 in group 3 . Among the three groups , no statistically significant differences were noted for change in Bishop score , uterine tachysystole , oxytocin use , route of delivery , or incidence of maternal or neonatal complications , Subsequent labors were frequently complicated by fetal heart rate abnormalities ( 24.3 % ) and uterine tachysystole ( 9.6 % ) ; 84 ( 38.9 % ) patients were delivered by cesarean section . A dose-dependent influence on outcome variables was not identified . Complications from PGE2-ripening within 4 hours of gel application were not dose dependent and occurred infrequently . This study demonstrates that there is no dose in the range tested that assures an absences of tachysystole , limiting the role of outpatient cervical ripening without some period of observation Objective : To shorten post- date pregnancies in a safe , effective manner by outpatient acceleration of cervical ripening . Methods : Eighty patients with uncomplicated pregnancies at or beyond 41 weeks ' gestation and a cervical Bishop score less than 9 were r and omized to daily self-administered , 2-mg intravaginal prostagl and in E2 ( PGE2 ) or placebo suppositories . Each followed a st and ard post- date antepartum surveillance protocol . Patients were admitted for spontaneous labor or for induction if the Bishop score reached 9 , antepartum testing was nonreassuring , exclusion criteria were fulfilled , or if the gestational age reached 44 weeks . Results : Fewer suppositories were used in the PGE2 group ( four versus seven ; P=.006 ) , result ing in earlier gestational age on admission ( 295 versus 297 days ; P=.021 ) and lower antepartum testing charges ( $ 476.97 versus $ 647.29 ; P=.001 ) . Labor and delivery time was significantly decreased in nulliparas ( 10.7 ± 5.1 versus 15.3 ± 7.6 hours ; P=.035 ) . Conclusions : Daily low-dose , patient-administered PGE2 vaginal suppositories can decrease the gestational length and cost of uncomplicated post- date pregnancies by reducing the time to achieve a favorable cervix , the need for antepartum testing , and , potentially , post- date -related complications OBJECTIVE To evaluate the efficacy of mifepristone in inducing labor in women with an unripe cervix , its effect on the cervix and on the status of the newborn . METHODS In a prospect i ve double-blind study , 36 post-term pregnant women with a Bishop score of 5 or less received either 400 mg mifepristone ( n=24 ) or placebo ( n=12 ) . If , 48 hours after the treatment was started , labor had not begun or the Bishop score was 5 or less , the women were given 0.5 mg prostagl and in E2 intracervically , a treatment which was repeated 12 hours later , if necessary . RESULTS During the first 48 hours following treatment , 19 ( 79.2 % ) of the women treated with mifepristone and two of the women ( 16.7 % ) treated with placebo went into labor . In addition , one and three women , respectively , had a ripe cervix at the end of the 48h period . The overall success rate was thus 83.3 % for mifepristone and 41.7 % for placebo ( p=0.008 ; OR 14.8 ; 95 % CI 2.1 - 107.6 ) . The median time from the start of treatment to delivery was also shorter ( mifepristone 36h23 ' and placebo 53h17 ' ) . Treatment with intracervical PGE2 was needed more often after the placebo . The duration of labor , however , tended to be shorter after placebo than after mifepristone in the women who delivered vaginally . The frequencies of instrumental delivery were similar in both treatment groups . The median Apgar score was slightly lower at 1 minute ( p<0.05 ) following mifepristone treatment , but did not differ at 5 and 10 minutes . There was no difference between the two treatment groups in the umbilical pH at delivery . CONCLUSION The results of the present study show that mifepristone is a simple and effective treatment for inducing labor in post-term women with an unripe cervix Objective . To evaluate the utility of outpatient acupuncture for labor stimulation . Methods . Nulliparous women at 39 4/7 weeks or greater with a singleton gestation and Bishop score of less than 7 were r and omized to usual medical care ( control group ) versus usual care and three outpatient acupuncture treatments ( acupuncture group ) . Each treatment consisted of eight needles applied to bilateral points LI4 , SP6 , UB31 , and UB32 . The primary outcome was time elapsed from the time of r and omization to delivery . Secondary outcomes included rates of cesarean section and induction of labor . Medical records were abstract ed for maternal demographic , medical , and delivery outcome data . A priori sample size calculation revealed that 56 women were required to detect a 72-hour difference in delivery time with a power of 83 % and an alpha of 0.05 . Student 's t-test , Chi-square , and Kaplan – Meier statistics were used to compare groups . Results . Fifty-six women were r and omized and completed the study procedures . Race , age , gestational age , and cervical Bishop score were similar in both groups . Mean time to delivery occurred 21 hours sooner in the acupuncture group , but this difference did not reach statistical significance ( p = 0.36 ) . Compared to controls , women in the acupuncture group tended to be more likely to labor spontaneously ( 70 % vs. 50 % , p = 0.12 ) and less likely to deliver by cesarean section ( 39 % vs. 17 % , p = 0.07 ) . Of women who were not induced , those in the acupuncture group were more likely to be delivered than the controls at any point after enrollment ( p = 0.05 ) . Conclusion . Acupuncture is well tolerated among term nulliparous women and holds promise in reducing interventions that occur in post-term pregnancies Background . Interventions that may help shorten the duration of pregnancy in an African setting where facilities for fetal monitoring in post‐term pregnancy are limited , and induction is not without its hazards , are needed OBJECTIVE To compare the clinical effectiveness and safety of outpatient administration of intracervical prostagl and in ( PG ) E2 gel with expectant treatment for women desiring vaginal births after cesareans . METHODS This was a r and omized , multicenter investigation involving term pregnant women who each had one previous low-transverse cesarean and an unfavorable cervix ( Bishop score no more than 6 ) , and who was a c and i date for vaginal delivery . They were assigned to receive 0.5 mg of PGE2 , ( Prepidil ; Pharmacia-Upjohn , Kalamazoo , MI ) intracervically at 39 weeks ' gestation , repeated at weekly office visits for up to three doses , or expectant treatment . The main outcome variable was vaginal birth . RESULTS Of 294 cases , 143 received gel and 151 were treated expectantly . No differences between groups were found for maternal age , race , or Bishop score . Compared with the expectant treatment group , the PGE2 gel group was not more likely to deliver sooner or vaginally ( 57 % versus 55 % , P = .68 ) . The onset of labor , duration of labor among those delivering vaginally , and 1- and 5-minute Apgar scores were not different between groups . No uterine ruptures occurred , and adverse effects were equally likely in both groups . CONCLUSION Although its safety was confirmed for outpatient use , weekly doses of intracervical PGE2 did not improve the likelihood of vaginal births after cesareans Objective To determine if outpatient cervical ripening using misoprostol can initiate labor within 48 hours of medication administration and to determine if time from medication administration to time of delivery is decreased using outpatient cervical ripening . Methods Uncomplicated singleton , vertex pregnancies at 41 weeks ' gestation or later with Bishop score of 4 or less were eligible for enrollment . Other inclusion criteria included intact membranes , less than eight uterine contractions per hour , a reactive nonstress test , and amniotic fluid index ( AFI ) over 5 cm . After r and omization , 25 μcg of misoprostol or placebo was placed within the posterior vaginal fornix . Patients were continuously monitored for 4 hours , then discharged if not in active labor . Patients returned in 24 hours for a repeat administration of the respective medication . Patients not delivered within 48 hours were admitted for inpatient induction of labor . Statistical analysis was performed with the Fisher , Student t , χ2 , and Mann-Whitney U tests , with P < .05 considered statistically significant . Results Among the 60 patients enrolled , 27 ( 45 % ) received misoprostol and 33 ( 55 % ) received placebo . The majority ( 24 of 27 , 88.9 % ) of study group patients entered active labor within 48 hours after dosing , compared with 16.7 % ( five of 33 ) of placebo group patients ( P < .001 ) . The time from initial dose to delivery was significantly shorter in the misoprostol group ( 36.9 ± 3.8 compared with 61.3 ± 3.8 hours , P < .001 ) . Conclusion Intravaginal misoprostol is effective for outpatient cervical ripening . No adverse effects were encountered , although further study is required to determine the safety of this treatment regimen Objective : To compare the clinical effectiveness and safety of outpatient administration of an intracervical prostagl and in ( PG ) E(2 ) gel with expectant management for women with an unfavorable cervix who wish to attempt a vaginal birth after cesarean section . Study Design : This outpatient study was a r and omized , multicenter investigation involving pregnant women at term with one previous low transverse cesarean section . Each had an unfavorable cervix ( Bishop score < /=4 ) and was a c and i date for vaginal delivery . Those r and omly assigned to receive the gel , rather than expectant management , were given a 0.5 mg dose of PGE(2 ) ( Prepidil ) intracervically at 39 weeks gestation . This cervical ripening treatment was repeated at weekly office visits for up to 3 doses . Results : Of the 294 cases , 143 received the gel while 151 underwent expectant management . No differences between the two groups were found for maternal demographics , race , parity , or predose Bishop score . The rates of repeat cesarean section did not differ ( P = .68 ) with use of the gel ( 61 , 42 % ) or with expectant therapy ( 48 , 45 % ) . The onset of active labor , the duration of labor among those delivering vaginally , and the 1-minute and 5-minute Apgar scores were not different between the two groups . No uterine rupture was apparent , and adverse effects during labor were as likely to occur in the two groups . Conclusions : Although its safety was confirmed for outpatient use and for persons with a prior cesarean delivery , intracervical prostagl and in E(2 ) gel did not improve the chance of a vaginal birth after a cesarean delivery OBJECTIVE Our aim was to examine the efficacy , safety , and acceptability of isosorbide mononitrate for cervical ripening and labor induction in women in an outpatient setting . STUDY DESIGN Two hundred pregnant women of at least 42 weeks ' gestation with an unripe cervix were r and omly selected to receive vaginally either 40 mg isosorbide mononitrate or placebo tablets . RESULTS Twenty-two women treated with isosorbide mononitrate went into labor within 24 hours compared to 8 women in the placebo group ( P < .05 ) . In women who did not go into labor , cervical status was similar in the 2 groups the next day . Headache was a common side effect . No maternal or fetal side effects of clinical importance were registered . CONCLUSION Outpatient cervical ripening and labor induction with isosorbide mononitrate seems to be an effective , safe , and well tolerated procedure . The definitive clinical efficacy and safety needs to be evaluated in larger series of patients OBJECTIVE To investigate the action of intracervical administration of hyaluronidase ( HAase ) as an inductor of cervical ripening on an outpatient basis . METHODS A r and omized double-blind trial was conducted with 168 pregnant women at term , Bishop score (BS)<5 , normal fetal vitality and no uterine contractions . An evaluation was performed at the first visit , when either 20,000 UI of lyophilized HAase ( 5 ml ) or placebo was administered via cervical injection . After 48 h , if the BS remained<5 , a second dose was administered . The primary outcome was the BS after 48 h or 96 h. The outcome was considered positive when BS>/=5 . RESULTS The results indicate that the proportion of positive response for the HAase group ( 55 % ) after 48 h is significantly higher ( p<0.0001 ) than the corresponding proportion for the placebo group ( 7 % ) with an absolute risk reduction ( ARR ) of 48%=55 - 7 % ( 95%CI=40 - 56 % ) . After 96 h , these proportions are 93 % in the Haase group and 22 % in the placebo group ( p<0.0001 , ARR=71 % , 95%CI=61 - 81 % ) . The average duration of labour for the nulliparae in the HAase group ( 6.5h ) is significantly smaller ( p<0.0001 ) than for those under placebo ( 12.0 h ) with an absolute difference of 5.5h ( 95%CI=4.6 - 6.4h ) . For the multiparae , the results are 4.3h for the HAase patients versus 9.5h for the placebo patients ( p<0.0001 ) with an absolute difference of 5.2h ( 95%CI=4.1 - 6.3h ) . The proportion of vaginal deliveries for women who received HAase was 82 % versus 51 % for the placebo group ( p=0.0007 , ARR=31 % , 95%CI=19 - 44 % ) . The proportion of vaginal deliveries for patients with prior cesareans in the HAase group ( 69 % ) was also significantly higher ( p<0.0001 ) than that corresponding to the placebo group ( 13 % ) with ARR=56 % ( 95%CI=26 - 86 % ) . No uterine hyper stimulation occurred in the study . CONCLUSION We detected significant associations between intracervical injection of HAase and ripening of the cervix , as well as with shorter duration of labour and larger chance of vaginal delivery , suggesting that this is a simple , effective and safe method even for women with prior cesarean A r and omized blinded investigation was undertaken to determine the efficacy and safety of sequentially applied intravaginal prostagl and in E2 ( PGE2 ) gel for accelerating cervical ripening in an outpatient setting in low-risk prolonged pregnancies . Fifty women with uncomplicated pregnancies at or beyond 41 weeks ' gestation and Bishop scores below 9 received twice-weekly outpatient administration of gel containing 2.0 mg of PGE2 or placebo . Thirty nulliparas and 20 multiparas were enrolled . The PGE2 gel failed to improve cervical ripening over placebo , as judged by Bishop scores . There was no difference between the groups in gestational age on admission to the labor and delivery suite , number of gel applications , requirement for oxytocin , incidence of cesarean delivery , or neonatal outcome . Only two patients ( 4 % ) experienced regular uterine contractions after gel insertion ; these subsided spontaneously in both . None of the subjects experienced labor , tetanic contractions , evidence of fetal distress , or any other side effects related to gel insertion . We conclude that PGE2 gel in this dosage may be used safely in an outpatient setting , but more frequent application or earlier initiation may be required to produce a clinical The influence of nipple stimulation ( NS ) at term on the duration of pregnancy was investigated among low-risk gravidas in a r and omized prospect i ve study . A significant inverse relationship was found between the duration of pregnancy and both gestational age at recruitment and cervical ( Bishop ) score , although the influence of cervical score was quantitatively small . Nipple stimulation did not influence either the duration of pregnancy or the probability of having a cesarean section or an instrumental delivery . Patient compliance was , however , poor , which may in part account for these findings , as there was an inverse trend between the daily average duration of NS and the duration of pregnancy OBJECTIVE : To determine the best method of cervical ripening to prevent post date inductions in women with an unfavorable cervix at 41 weeks ’ gestation . STUDY DESIGN : Women presenting at 41 weeks ’ gestation with a Bishop score of ≤4 received daily dinoprostone ( Cervidil ) vaginal inserts ( group I ) or daily membrane sweeping ( group II ) . RESULTS : One-hundred and eighty-two women were prospect ively r and omized with 91 women in each arm . The women in group II , membrane sweeping , had Bishop scores significantly greater on admission for delivery ( p < 0.001 ) , had less time elapsed from admission to delivery ( p = 0.018 ) , and had fewer labor inductions at 42 weeks ( p = 0.04 ) than the women in group I , the dinoprostone group . In addition , a greater number of women in group II were admitted in spontaneous labor ( p = 0.006 ) than in group I. Total antenatal costs for the membrane sweeping group was $ 15,120 versus $ 59,540 for the dinoprostone group . CONCLUSION : Daily membrane sweeping was more effective than dinoprostone administration with fewer post date inductions at one-fourth the cost OBJECTIVE : To determine whether a single outpatient dose of intravaginal misoprostol ( versus intracervical dinoprostone gel ) reduces the oxytocin use for induction . Despite the numerous trials examining misoprostol for induction , the efficacy of a single outpatient dose of misoprostol followed by oxytocin induction is unknown . METHODS : Patients with a term , vertex , singleton pregnancy and a Bishop score of 6 or less were r and omly assigned to receive misoprostol ( n = 42 , 0.25 μg intravaginally ) or dinoprostone gel ( n = 42 , 0.5 mg intracervically ) the evening before oxytocin induction . Patients were monitored for 3 hours after administration and discharged to home if fetal assessment was reassuring , for readmission the next morning for oxytocin . Primary outcomes were oxytocin dose , time , and dose intensity ( dose divided by duration ) . Secondary outcomes were incidence of labor , uterine hyperstimulation , cesarean delivery , Apgar score . Statistics used were χ2 , Student t test , Mann-Whitney rank sum test , and Fisher exact test . P < .05 was accepted as statistically significant . RESULTS : A single dose of misoprostol significantly decreased the cumulative dose of oxytocin , the cumulative time of oxytocin administration , and the dose intensity of oxytocin ( dose divided by time ) . Data are as follows ( mean ± st and ard error of the mean ) : oxytocin dose — dinoprostone 10,929 ± 219 mU , misoprostol 6,081 ± 170 mU , P = .008 ; oxytocin time — dinoprostone 798 ± 11 minutes , misoprostol 531 ± 11 minutes , P = .009 ; dose intensity — dinoprostone 11.3 ± 0.1 mU/min , misoprostol 7.4 ± 0.2 mU/min , P = .003 . Misoprostol induced labor during the ripening period in 19 of 41 of patients , compared with 6 of 42 after dinoprostone ( P = .002 ) . There was no difference in cesarean delivery ( dinoprostone , 8/42 ; misoprostol , 9/42 ; P = 1.00 ) . There was no difference in short-term neonatal outcome . No patient had hyperstimulation or required cesarean delivery for nonreassuring fetal assessment during the ripening period . CONCLUSION : A single dose of misoprostol administered in the outpatient setting significantly decreases oxytocin use , largely due to labor within the ripening period . LEVEL OF EVIDENCE : A prospect i ve double-blind r and omized study was undertaken to evaluate the use of RU-486 for induction of labor at term with living infants . 120 patients at 37 weeks of pregnancy or over were included . 60 were given 200 mg RU-486 per day for 48 hours and the others were given placebos . The 120 women all had a medical indication for induction of labor . In the RU-486 and placebo groups respectively , 27 and 28 were past term , 10 and 13 had preeclampsia , and 6 and 4 showed signs of intrauterine growth retardation . 75 were primiparas . Pregnancy ages ranged from 37.5 weeks to 41.4 and averaged 39.8 . The uterus was scarred in 30 cases . The 2 groups were homogeneous in maternal age , pregnancy age , average parity , number of primiparas and number of scarred uterus , and average Bishop scores indicating cervical status . 3 patients in the RU-486 and 5 in the placebo group were excluded from the analysis because of deteriorating obstetrical status in the 12 hours after administration of the 1st pill . For all vaginal deliveries , the total dose in international units of oxytocin was lower in the RU-486 group : 2.41 + or- 2.4 international units , vs. 4.48 + or- 2.66 in the placebo group . The difference was also found in women undergoing caesareans , 2.97 + or- 1.82 vs 4.94 + or- 2.41 in the controls . 31 women in the RU-486 group but only 10 in the placebo group underwent spontaneous labor . It was possible to induce labor on the 4th day following administration of the 1st dose of RU-486 or placebo using prostagl and in ( PG ) E1 in 13 patients in each group . 13 patients in the RU-486 group and 32 in the placebo group still had Bishop scores under 4 on the 4th day . For this subgroup of 45 patients , there was no significant difference between the 2 groups in the average dose of PG E2 . Indication of labor with RU-486 alone was especially successful after 40 weeks of gestation . In this series , RU-486 was successful in spontaneously inducing labor in over 80 % of pregnancies around 41 weeks of gestation . There were no significant differences in the RU-486 and placebo groups in the type of delivery , average duration of labor , use of anesthetic , or neonatal condition . Maternal tolerance of RU-486 was good . There were no cases of metrorrhagia . RU-486 was shown to be useful for women with scarred uteri , in whom the use of oxytocin and prostagl and ins for induction of labor remains relatively contraindicated Objective To determine the efficacy and safety of mifepristone for cervical ripening in post-term pregnancies . Methods Women with post-term pregnancies and Bishop scores less than 6 were assigned r and omly to mifepristone ( 41 patients ) or placebo ( 42 patients ) . Mifepristone was given orally in a dose of 400 mg . Efficacy was assessed by change in the Bishop score within 48 hours after treatment ; a score of 6 or greater was considered a “ strict ” success . An “ extended ” success rate was defined , including all patients with scores of at least 6 or those who delivered within 48 hours of treatment . Antenatal safety was assessed by fetal heart rate testing before and throughout labor . Neonatal safety was assessed by Apgar score , arterial or venous pH of cord blood , and blood glucose level during the first 48 hours . Analysis used Student t test for continuous variables , Kruskal-Wallis test for ordinal data , and χ2 for categoric variables . Results Strict success was achieved in 10 of 18 mifepristone patients ( 55 % ) evaluated for Bishop score on day 2 versus 8 of 29 placebo patients ( 27.5 % ) ( P = .004 ) . Extended success was achieved in 33 mifepristone patients ( 80.5 % ) and 21 placebo patients ( 50.0 % ) ( P = .004 ) . There were no statistical differences with regard to number of cesareans or fetal and neonatal safety . Conclusion Mifepristone proved effective for cervical ripening and reduced the time to delivery compared with placebo , but it did not improve the rate of cesarean . Our study did not include enough pregnancies to reach conclusions about fetal or neonatal safety OBJECTIVE The purpose of this study was to compare the efficacy and safety profile of prostagl and in E2 with isosorbide mononitrate for cervical ripening before the induction of labor at term . STUDY DESIGN Primigravid women were assigned r and omly to receive either 40 mg of isosorbide mononitrate or 2 mg of prostagl and in E2 . Efficacy outcomes were the cervical ripening effect of each agent and the time from treatment initiation to delivery . Safety outcomes were the incidence and frequency of maternal side effects and events that would be potentially hazardous for mother and baby during outpatient cervical ripening . RESULTS Prostagl and in E2 was more effective than isosorbide mononitrate in inducing a change in modified Bishop score . Mean duration from treatment initiation to delivery was greater for isosorbide mononitrate than prostagl and in E2 . There were no adverse events in the isosorbide mononitrate group that would contraindicate outpatient treatment . However , in the prostagl and in E2 group , 7 % of the pregnancies had abnormal fetal heart rate patterns ( P = .0002 ) . Maternal satisfaction was significantly higher in the isosorbide mononitrate group . CONCLUSION Although isosorbide mononitrate was less effective , maternal satisfaction was significantly greater . The safety profile of each agent was such that it would be reasonable to give isosorbide mononitrate , but not prostagl and in E2 , on an outpatient basis OBJECTIVE To examine the effectiveness and safety of outpatient vaginal administration of isosorbide mononitrate ( IMN ) to induce cervical ripening . METHODS A prospect i ve , double-blind , placebo-controlled , r and omized clinical trial was conducted on 102 singleton term pregnant women with unfavorable cervices who were r and omly assigned to receive outpatient intravaginal IMN or placebo before admission for induction of labor . The main outcome variable was time from hospital admission to delivery . Secondary outcomes included fetal and maternal morbidity , labor characteristics , and incidence of cesarean delivery . RESULTS The admission-delivery interval was 13.45+/-6.63 and 20.12+/-8.19 h ( P=0.0001 ) for the IMN and placebo groups , respectively . Of the IMN patients 62.75 % needed prostagl and ins for cervical ripening versus 90.2 % with placebo ( P=0.002 ) . The incidence of tachysystole was significantly lower in the IMN group ( P<0.05 ) but there were no significant differences in cesarean delivery rate , neonatal outcomes , and incidence of hyperstimulation . CONCLUSIONS Outpatient use of IMN result ed in shorter admission to delivery interval , and was associated with less prostagl and in use and lower incidence of uterine tachysystole The study evaluates breast stimulation and oxytocin infusion as methods for cervical ripening in patients where an obstetric indication for induction of labour exists . Forty patients with a Bishop score of 5 or 6 were r and omly selected for either breast stimulation or oxytocin infusion . In a similar group of 20 cases , no method was employed . The Bishop score improved in 41.2 % of cases where breast stimulation was used as compared to 75 % where an oxytocin infusion was given . Three foetal deaths in the breast stimulation group brought the study to a stop after 17 cases . Cervical ripening with an oxytocin infusion drip appears to be a better method since infusion dosage can be precisely controlled making the technique more predictable and reliable . Though breast stimulation is effective in ripening the cervix , it may be used only in cases of intrauterine foetal death as it may otherwise adversely affect foetal outcome The purpose of the study was to determine the safety and efficacy of outpatient intravaginal prostagl and in E2 ( PGE2 ) and membrane stripping in promoting labor in the uncomplicated post date pregnancy . In a double-blind placebo-controlled study , 150 enrollees were r and omized to one of four treatment groups ; group I , no membrane stripping and placebo gel ; group II , no membrane stripping and PGE2 gel ; group III , membrane stripping and placebo gel ; and group IV , membrane stripping and PGE2 gel . The treatments were administered at 287 days ( 41 weeks ) and 294 days ( 42 weeks ) of gestation , then every 3 - 4 days until 307 days ( 43 completed weeks ) of gestation . The patients in group IV had the shortest interval to delivery with a median of 1 day , P = .001 , and the fewest antenatal surveillance visits with only 21 % requiring more than one visit , P = .02 . Group I patients in comparison , had a 7-day median to delivery , and 61 % required more than one visit . The time spent in labor and delivery and the need for oxytocin augmentation was not significantly reduced in groups II , III , and IV . No adverse side effects to either mother or neonate could be directly attributed to this outpatient treatment combination . We conclude that intravaginal PGE2 gel combined with membrane stripping reduces postterm pregnancies and antenatal visits in our patients OBJECTIVE : To assess whether outpatient cervical ripening at 41 0/7 weeks of gestation with the nitric oxide donor isosorbide mononitrate reduces cesarean delivery rates in nulliparous women with an unfavorable cervix . METHODS : We recruited nulliparous pregnant women with a Bishop score less than 6 in a r and omized , multicenter , double-blind , placebo-controlled trial . Women received 40 mg vaginal isosorbide mononitrate or a placebo at 41 0/7 , 41 2/7 , and 41 4/7 weeks of gestation . They returned home between visits . At 41 5/7 weeks of gestation , for women who had not yet given birth , labor was induced with oxytocin or prostagl and ins , depending on cervical status . We needed 685 women per group to detect a 25 % reduction in the cesarean delivery rate , the primary outcome measure , from 25 % in the placebo group to 18.75 % in the isosorbide mononitrate group ( 1-&bgr;=0.8 , & agr;=0.05 , two-sided ) . RESULTS : The NOCETER ( NO donors for reduction of CEsareans at TERm ) trial was a negative study . The cesarean delivery rate was 27.3 % ( 185/678 ) in the isosorbide mononitrate group and 27.2 % ( 186/684 ) in the placebo group ( relative risk 1.00 , 95 % confidence interval [ CI ] 0.84–1.19 ) . None of the maternal secondary efficacy outcomes differed between groups . Side effects were more common among women receiving isosorbide mononitrate than in the placebo group ( 78.8 % [ 534/678 ] compared with 27.9 % [ 191/684 ] , relative risk 2.82 , 95 % CI 2.49–3.20 ) . Composite perinatal morbidity did not differ between groups . CONCLUSION : Outpatient cervical ripening with vaginal isosorbide mononitrate for prolonged pregnancy in nulliparous women does not reduce cesarean delivery rate . CLINICAL TRIAL REGISTRATION : Clinical Trials.gov , www . clinical trials.gov , NCT00930618 . LEVEL OF EVIDENCE : OBJECTIVE To compare the use of vaginally administered misoprostol to placebo for outpatient labor induction in patients with diabetes . STUDY DESIGN In this double-masked , controlled clinical trial , pregnant women with diabetes and gestational age of > 38(1/2 ) weeks were r and omized to receive 25 microg misoprostol or placebo vaginally on days 1 and 4 of a 7-day outpatient cervical ripening period . If necessary , inpatient labor induction was managed by using a st and ard protocol . RESULTS Of 120 women included in the study , 57 received misoprostol and 63 received placebo . Most of the women had been diagnosed with gestational ( Class A ) diabetes . Similar numbers of misoprostol and placebo-treated women delivered within 7 days of the first dose ( 31/57 [ 54 % ] vs 36/63 [ 57 % ] , P = .63 ) . The mean ( + /-SEM ) interval from induction to delivery was similar ( 8530.5 minutes + /-1439.7 minutes vs 6712.5 minutes + /-606.4 minutes , P = .23 ) . CONCLUSION Vaginally administered misoprostol was no more effective than placebo in reducing the need for inpatient labor induction or the induction-delivery interval . Outpatient cervical ripening with use of vaginally administered misoprostol was well tolerated Objective : To determine the efficacy and safety of mifepristone as an induction agent for the initiation of labor or as a cervical ripening agent in women at term . Methods : Our study group contained 120 women at term ( after 37.5 weeks ' amenorrhea ) who had clear clinical indications for labor induction . They were r and omized to receive either 200 mg of mifepristone or placebo on days 1 and 2 of a 4-day observation period , with labor induction planned for day 4 . Eight patients , three treated with mifepristone and five receiving placebo , had to be excluded from the survey because they required cesareans for medical reasons ( fetal distress or maternal complications ) less than 12 hours after taking the first tablet . Results : Forty-one subjects entered spontaneous labor , 31 treated with mifepristone and ten in the control group ( P<.001 ) . Forty-five needed cervical maturation with prostagl and ins on day 4,13 of whom had received mifepristone and 32 of whom had been given placebo ( P<.001 ) . Thirteen women treated with mifepristone and 13 who had taken placebo had mature cervices sufficient for classic labor induction with oxytocin and amniotomy . Patients who delivered vaginally needed a much lower amount of oxytocin when mifepristone had been given , and the mean time interval between day 1 of the survey and the onset of labor was also significantly shorter in this group . Conclusion : Although more studies are needed , we have found mifepristone to be a safe , efficient , and suitable induction agent for initiation of labor in women at term . ( Obstet Gynecol 1992;80:972 - 5 Bishop score changes , by a cross-over , r and omized study , were evaluated in 60 primigravidas at term , not yet in labour , who performed nipple stimulation for 45 minutes three times a day for three days . Results showed that changes of Bishop score in the treated groups were statistically highly significant , in comparison to control groups . A greater frequency in the onset of labour was also remarked OBJECTIVE Our purpose was to evaluate whether inserting prostagl and in E2 gel at the time of scheduled nonstress tests in patients with post date pregnancies can decrease rates of intervention . STUDY DESIGN A multicenter pilot study enrolled women with post date pregnancies with Bishop score < or = 6 who were undergoing antepartum fetal heart rate testing . Patients were r and omized in a double-blind fashion to receive either a prostagl and in E2 intracervical gel ( Prepidil ) or a placebo gel after each of their scheduled nonstress tests . RESULTS There were no significant differences in the number of antepartum tests , labor inductions , or cesarean sections , the maximum oxytocin dosage , or the interval from admission to delivery in the prostagl and in E2 gel and placebo gel groups ( n = 90 ) . In the subset of patients with a Bishop score between 3 and 6 ( 63 patients ) , there were fewer inductions in the prostagl and in E2 group ( 30 % vs 55 % , P < .05 ) . CONCLUSION Application of prostagl and in E2 gel at the time of scheduled antepartum testing in patients with post date pregnancies with unfavorable cervices decreased the induction rate only among patients with intermediate Bishop scores Post date pregnancy is estimated to occur in 3 % to 12 % of all gestations . Morbidity and mortality rates associated with this common obstetric problem are higher than those with term gestation . The incidence of fetal distress , birth injury , meconium aspiration , congenital malformations , macrosomia , and oligohydramnios is also greater in post date pregnancy . We prospect ively evaluated breast self-stimulation to determine its effect on the incidence of post date pregnancy . Two hundred low-risk patients at 39 weeks ' gestation were r and omly assigned to either a control group or a breast-stimulation group . Results showed that breast stimulation reduced the number of pregnancies managed as post date s from 17 per 100 ( 17 % ) to five per 100 ( 5 % ) ( p less than 0.01 ) , a 70 % reduction . It is concluded that breast stimulation in post date s pregnancies can decrease significantly the number of patients that must be monitored by biochemical or biophysical means OBJECTIVE : To estimate the effect of outpatient administration of a single dose of vaginal misoprostol at term on the interval to delivery in women with unfavorable cervices . METHODS : R and omized , double blind , placebo-controlled trial comparing a single 25-μg outpatient intravaginal dose of misoprostol to placebo in pregnant women with Bishop scores less than 9 at 40 weeks or greater . After placement of the study medication , subjects were permitted to go into spontaneous labor unless an indication for induction developed . Analysis was by intent to treat . The interval to delivery , defined as the time from medication placement to delivery , was compared by Student t test and by survival analysis with the log-rank test . RESULTS : Thirty-three women were r and omly assigned to receive misoprostol , and 35 were assigned to receive placebo . The mean interval to delivery was significantly less in the misoprostol group , 4.2 ± 4.1 compared with 6.1 ± 3.6 days , P = .04 . The interval to delivery for only the nulliparous patients was significantly less in the misoprostol group , 4.2 ± 4.0 compared with 7.2 ± 3.7 days , P = .02 . The survival curves for the interval to delivery were significantly different ( P = .04 by log-rank test ) with 4.1 days median interval to delivery for misoprostol compared with 9.2 days for placebo . There were no adverse outcomes in either group . CONCLUSION : A single 25-μg outpatient intravaginal dose of misoprostol is effective in decreasing the interval to delivery in women with unfavorable cervices at term . LEVEL OF EVIDENCE : OBJECTIVES to explore women 's experiences of cervical ripening using isosorbide mononitrate ( IMN ) in the home as part of the main r and omised controlled trial . DESIGN qualitative study with semi-structured interviews carried out at three weeks post partum . Interview transcripts were analysed to identify recurrent themes , focusing on why women became involved in the study , their views about both the self-medication and the home setting , and whether they would repeat the experience . SETTING the home . PARTICIPANTS twenty women enrolled in the main r and omised controlled trial . INTERVENTION the study is part of a double-blind r and omised controlled trial with 350 patients investigating whether a nitric oxide donor ( IMN ) used in cervical ripening improves the process of induction of labour . FINDINGS women liked the opportunity to remain at home during the cervical ripening process . Timing and setting were central issues ; women hoped that it would hasten labour , while the home was seen as a setting offering freedom , security and reassurance , as opposed to the hospital , seen as constraining . Two women reported problems with IMN but the remainder reported that they would repeat the experience . IMPLICATION S FOR PRACTICE women were very positive about the opportunity to undertake cervical ripening at home . It is important to explore this setting further for appropriate interventions OBJECTIVE : To characterize the frequency and timing of cardiotocographic abnormalities associated with the use of 3 commercially available prostagl and in analogues , misoprostol , dinoprostone gel , and dinoprostone pessary , as labor preinduction agents . METHODS : One-hundred and eleven women undergoing induction of labor with an unfavorable cervix were r and omized to receive either misoprostol 50 μg every 6 hours × 2 doses , dinoprostone gel 0.5 mg every 6 hours × 2 doses , or dinoprostone pessary 10 mg × 1 dose for 12 hours intravaginally . Oxytocin induction was initiated per st and ardized protocol . Cardiotocographic tracings were blindly review ed , with abnormalities coded using established definitions . RESULTS : Fifty-five percent of women treated with misoprostol demonstrated an abnormal tracing event within the initial 24 hours of induction , compared with 21.1 % with dinoprostone pessary and 31.4 % with the dinoprostone gel . The mean ( ± st and ard deviation ) number of abnormal events was significantly greater in women treated with misoprostol ( 5.0 ± 5.9 ) versus the dinoprostone pessary ( 1.6 ± 2.5 ) and gel ( 2.2 ± 3.1 ) ( P < .05 ) . In addition , these events occurred earlier after initial misoprostol dosing ( 5.0 ± 4.0 hours ) , compared with the dinoprostone pessary ( 9.4 ± 5.6 hours ) and gel ( 7.7 ± 6.6 ) . Thirty-nine percent of the misoprostol-treated women had abnormal patterns within 6 hours of initial dosing , compared with those treated with the dinoprostone pessary ( 7.9 % ) and gel ( 17.1 % ) . CONCLUSION : Cardiotocographic abnormalities are more frequent after misoprostol administration compared with the dinoprostone analogues . The early onset and frequent nature of the tracing abnormalities associated with misoprostol raises concern for the potential use of misoprostol for outpatient cervical ripening . LEVEL OF EVIDENCE : UNLABELLED We evaluated the effectiveness of oral misoprostol for outpatient cervical ripening and labor induction in prolonged pregnancies . We performed a r and omized , double-blind , placebo-controlled study of women at 40 to 42 weeks ' gestation with well- date d pregnancies , singleton gestations , Bishop scores less than 6 , vertex presentations , and intact membranes . Subjects received either oral misoprostol 100 microg or placebo daily for 3 days unless the subject developed significant cervical change or began labor spontaneously . Study drug was repeated every 24 hours for a maximum of three doses if subjects did not develop significant cervical change or enter labor . Induction of labor was not allowed while the subject was enrolled in the study . Forty-three subjects were r and omized to receive misoprostol and 44 r and omized to receive placebo . A significant difference was noted in reduction of time from study entry to both active phase ( p < 0.001 ) and delivery ( p < 0.001 ) in the misoprostol group . Fewer women remained undelivered after the 72-hour study period in the misoprostol group . There were no differences in route of delivery or neonatal outcomes between groups . CONCLUSION Daily administration of oral misoprostol over 3 days to women with prolonged pregnancies shortened time intervals from dosing to entry into active labor and delivery compared with placebo |
13,667 | 28,141,913 | The composite outcomes of death or BPD and death or abnormal neurodevelopmental outcome showed similar results although the former only reached borderline significance .There were no differences in outcomes between a moderate- and a low-dosage regimen . | BACKGROUND Cochrane systematic review s show that systemic postnatal corticosteroids reduce the risk of bronchopulmonary dysplasia ( BPD ) in preterm infants .
However , corticosteroids have also been associated with an increased risk of neurodevelopmental impairment .
It is unknown whether these beneficial and adverse effects are modulated by differences in corticosteroid treatment regimens .
OBJECTIVES To assess the effects of different corticosteroid treatment regimens on mortality , pulmonary morbidity , and neurodevelopmental outcome in very low birth weight ( VLBW ) infants . | Objective To determine survival and neonatal morbidity for babies born between 22 and 26 weeks ’ gestation in Engl and during 2006 , and to evaluate changes in outcome since 1995 for babies born between 22 and 25 weeks ’ gestation . Design Prospect i ve national cohort studies . Setting Maternity and neonatal units in Engl and . Participants 3133 births between 22 and 26 weeks ’ gestation in 2006 ; 666 admissions to neonatal units in 1995 and 1115 in 2006 of babies born between 22 and 25 weeks ’ gestation . Main outcome measures Survival to discharge from hospital , pregnancy and delivery outcomes , infant morbidity until discharge . Results In 2006 , survival of live born babies was 2 % ( n=3 ) for those born at 22 weeks ’ gestation , 19 % ( n=66 ) at 23 weeks , 40 % ( n=178 ) at 24 weeks , 66 % ( n=346 ) at 25 weeks , and 77 % ( n=448 ) at 26 weeks ( P<0.001 ) . At discharge from hospital , 68 % ( n=705 ) of survivors had bronchopulmonary dysplasia ( receiving supplemental oxygen at 36 weeks postmenstrual age ) , 13 % ( n=135 ) had evidence of serious abnormality on cerebral ultrasonography , and 16 % ( n=166 ) had laser treatment for retinopathy of prematurity . For babies born between 22 and 25 weeks ’ gestation from March to December , the number of admissions for neonatal care increased by 44 % , from 666 in 1995 to 959 in 2006 . By 2006 adherence to evidence based practice associated with improved outcome had significantly increased . Survival increased from 40 % to 53 % ( P<0.001 ) overall and at each week of gestation : by 9.5 % ( confidence interval −0.1 % to 19 % ) at 23 weeks , 12 % ( 4 % to 20 % ) at 24 weeks , and 16 % ( 9 % to 23 % ) at 25 weeks . The proportions of babies surviving in 2006 with bronchopulmonary dysplasia , major cerebral scan abnormality , or weight and /or head circumference < −2 SD were similar to those in 1995 , but the proportion treated for retinopathy of prematurity had increased from 13 % to 22 % ( P=0.006 ) . Predictors of mortality and morbidity were similar in both cohorts . Conclusion Survival of babies born between 22 and 25 weeks ’ gestation has increased since 1995 but the pattern of major neonatal morbidity and the proportion of survivors affected are unchanged . These observations reflect an important increase in the number of preterm survivors at risk of later health problems OBJECTIVE : To assess dexamethasone ( DEX ) and hydrocortisone ( HC ) use in premature infants over time and the association of steroid use with the incidence of bronchopulmonary dysplasia ( BPD ) at 36 weeks ' postmenstrual age . METHODS : We analyzed data from the Pediatrix data base for neonates of 23 to 32 weeks ' gestation managed during 1997–2006 ( N = 77520 ) . We compared the use of DEX , HC and BPD ( defined by oxygen use at 36 weeks ' postmenstrual age ) according to year and estimated gestational age . Mantel-Haenszel χ2 was used to compare the trends in steroid use and BPD rates according to year . RESULTS : There were no differences by year in the proportion of births at each gestation or in early or late neonatal death . DEX use decreased from a peak of 25.0 % in 1998 to 6.8 % in 2006 , but HC use increased from 1.1 % in 1997 to a peak of 6.5 % in 2006 . The median age at initiation of DEX use increased > 2 weeks from 1997 to 2006 . BPD rates increased from 19 % in 1997 to 25 % by 2006 . Rates for severe BPD ( defined by positive pressure support ) also increased significantly over time . Between 23 and 28 weeks , there was a significant increase in BPD rates associated with the decrease in DEX over time . CONCLUSIONS : Steroid use and preference have changed significantly over the past decade . Decreased use of DEX was associated with increased rates of BPD , any or severe , among very preterm infants . Well- design ed , r and omized , noncrossover trials with long-term outcome analysis of high-risk infants are needed We previously reported on a 7-day course of dexamethasone starting at 0.5 mg/kg/day in intubated very low birth weight ( VLBW ) infants , 7 - 14 days of age , with increased dynamic pulmonary compliance and decreased bronchopulmonary dysplasia ( BPD ) . The effect of low-dose dexamethasone on functional residual capacity ( FRC ) in VLBW infants is unknown . The objective of this study was to compare the effect of two regimens of moderately early dexamethasone on FRC and passive respiratory compliance ( Crs ) in VLBW infants at risk for BPD . Sixty-two intubated VLBW infants were r and omized ( double-blinded ) at 7 - 21 days of age ; 29 patients ( mean birth weight , 839 g ) received " high " dose dexamethasone ( 0.5 mg/kg/day for 3 days , 0.25 mg/kg/day for 3 days , and 0.1 mg/kg/day on day 7 , total dose of 2.35 mg/kg ) , and 33 infants ( mean birth weight , 830 g ) received " low-dose " dexamethasone ( 0.2 mg/kg/day for 3 days and 0.1 mg/kg/day for 4 days , total dose of 1 mg/kg ) . FRC and Crs were measured with the nitrogen washout technique and single breath occlusion technique , before and on days 2 , 5 , and 7 of therapy . Clinical outcome and early neurodevelopmental follow-up were evaluated . FRC significantly increased in the high-dose ( 19.3 ml/kg at baseline to 34 ml/kg on day 7 ; P < 0.001 ) and low-dose ( 18.1 ml/kg at baseline to 30.3 ml/kg on day 7 ; P < 0.001 ) dexamethasone groups when compared to baseline . There was a significant increase in Crs and a decrease in FiO2 within each group . The improvements in FRC and Crs were comparable between groups , and specific compliances ( Crs/FRC ) were not different . There were no significant differences in other clinical outcome parameters , including BPD and neurodevelopmental outcome . In conclusion , there are significant increases in FRC during a 7-day course of moderately early dexamethasone in VLBW infants . The lower total dose ( 1 mg/kg ) appears as effective as the higher total dose of dexamethasone ( 2.35 mg/kg ) in increasing FRC . Comparable significant increases in Crs were observed in both groups of infants . Additional long-term follow-up is underway OBJECTIVES To study whether early postnatal ( < 12 hours ) dexamethasone therapy reduces the incidence of chronic lung disease in preterm infants with respiratory distress syndrome . MATERIAL S AND METHODS A multicenter r and omized , double-blind clinical trial was undertaken on 262 ( saline placebo , 130 ; dexamethasone , 132 ) preterm infants ( < 2000 g ) who had respiratory distress syndrome and required mechanical ventilation shortly after birth . The sample size was calculated based on the 50 % reduction in the incidence of chronic lung disease when early dexamethasone is used , allowing a 5 % chance of a type I error and a 10 % chance of a type II error . For infants who received dexamethasone , the dosing schedules were : 0.25 mg/kg/dose every 12 hours intravenously on days 1 through 7 ; 0.12 mg/kg/dose every 12 hours intravenously on days 8 through 14 ; 0.05 mg/kg/dose every 12 hours intravenously on days 15 through 21 ; and 0 . 02 mg/kg/dose every 12 hours intravenously on days 22 through 28 . A st and ard protocol for respiratory care was followed by the participating hospitals . The protocol emphasized the criteria of initiation and weaning from mechanical ventilation . The diagnosis of chronic lung disease based on oxygen dependence and abnormal chest roentgenogram was made at 28 days of age . To assess the effect of dexamethasone on pulmonary inflammatory response , serial tracheal aspirates were assayed for cell counts , protein , leukotriene B4 , and 6-keto prostagl and in F1alpha . All infants were observed for possible side effects , including hypertension , hyperglycemia , sepsis , intraventricular hemorrhage , retinopathy of prematurity , cardiomyopathy , and alterations in calcium homeostasis , protein metabolism , and somatic growth . RESULTS Infants in the dexamethasone group had a significantly lower incidence of chronic lung disease than infants in the placebo group either judged at 28 postnatal days ( 21/132 vs 40/130 ) or at 36 postconceptional weeks ( 20/132 vs 37/130 ) . More infants in the dexamethasone group than in the placebo group were extubated during the study . There was no difference between the groups in mortality ( 39/130 vs 44/132 ) ; however , a higher proportion of infants in the dexamethasone group died in the late study period , probably attributable to infection or sepsis . There was no difference between the groups in duration of oxygen therapy and hospitalization . Early postnatal use of dexamethasone was associated with a significant decrease in tracheal aspirate cell counts , protein , leukotriene B4 , and 6-keto prostagl and in F1alpha , suggesting a suppression of pulmonary inflammatory response . Significantly more infants in the dexamethasone group than in the placebo group had either bacteremia or clinical sepsis ( 43/132 vs 27/130 ) . Other immediate , but transient , side effects observed in the dexamethasone group are : an increase in blood glucose and blood pressure , cardiac hypertrophy , hyperparathyroidism , and a transient delay in the rate of growth . CONCLUSIONS In preterm infants with severe respiratory distress syndrome requiring assisted ventilation shortly after birth , early postnatal dexamethasone therapy reduces the incidence of chronic lung disease , probably on the basis of decreasing the pulmonary inflammatory process during the early neonatal period . Infection or sepsis is the major side effect that may affect the immediate outcome . Other observable side effects are transient . In view of the significant side effects and the lack of overall improvement in outcome and mortality , and the lack of long term follow-up data , the routine use of early dexamethasone therapy is not yet recommended OBJECTIVE We hypothesized that a pulsed course of dexamethasone would result in better linear growth than a 42-day reducing course in preterm infants at risk for chronic lung disease of prematurity . STUDY DESIGN Forty infants with a birth weight of < or = 1,250 g who required mechanical ventilation at 7 days of age were r and omly assigned to a repeatable 3-day pulse course of dexamethasone commencing immediately or a 42-day ( long ) course commencing at 14 days of age if they still required mechanical ventilation and supplemental oxygen . The primary outcome measure was linear growth at 36 weeks ' postmenstrual age measured by knemometry . RESULTS There was no difference in lower leg length at 36 weeks ' postmenstrual age . Infants receiving the pulse course had lower rises in blood pressure , less myocardial hypertrophy , and less adrenal suppression . However , more infants required supplemental oxygen at 28 days ' postnatal age ( 14/18 vs 8/21 , P < .05 ) and 36 weeks ' PMA ( 8/16 vs 5/20 , P = .12 ) . CONCLUSION In preterm infants at risk for chronic lung disease , a pulsed course of dexamethasone has fewer side effects than a long course but may be less effective at preventing chronic lung disease AIM To compare early ( <3 days ) with late ( > 15 days ) steroid therapy and dexamethasone with inhaled budesonide in very preterm infants at risk of developing chronic lung disease . METHODS Five hundred seventy infants from 47 neonatal intensive care units were enrolled . Criteria for enrollment included gestational age < 30 weeks , postnatal age < 72 hours , and need for mechanical ventilation and inspired oxygen concentration > 30 % . Infants were r and omly allocated to 1 of 4 treatment groups in a factorial design : early ( < 72 hours ) dexamethasone , early budesonide , delayed selective ( > 15 days ) dexamethasone , and delayed selective budesonide . Dexamethasone was given in a tapering course beginning with 0.50 mg/kg/day in 2 divided doses for 3 days reducing by half until 12 days of therapy had elapsed . Budesonide was administered by metered dose inhaler and a spacing chamber in a dose of 400 microg/kg twice daily for 12 days . Delayed selective treatment was started if infants needed mechanical ventilation and > 30 % oxygen for > 15 days . The factorial design allowed 2 major comparisons : early versus late treatment and systemic dexamethasone versus inhaled budesonide . The primary outcome was death or oxygen dependency at 36 weeks and analysis was on an intention-to-treat basis . Secondary outcome measures included death or major cerebral abnormality , duration of oxygen treatment , and complications of prematurity . Adverse effects were also monitored daily . RESULTS There were no significant differences among the groups for the primary outcome . Early steroid treatment was associated with a lower primary outcome rate ( odds ratio [ OR ] : 0.85 ; 95 % confidence interval [ CI ] : 0.61,1.18 ) but even after adjustment for confounding variables the difference remained nonsignificant . Dexamethasone-treated infants also had a lower primary outcome rate ( OR : 0.86 ; 95 % CI : 0.62,1.20 ) but again this difference remained not significant after adjustment . For death before discharge , dexamethasone and early treatment had worse outcomes than budesonide and delayed selective treatment ( OR : 1.42 ; 95 % CI : 0.93,2.16 ; OR : 1.51 ; 95 % CI : 0.99,2.30 after adjustment , respectively ) with the results not quite reaching significance . Duration of supplementary oxygen was shorter in the early dexamethasone group ( median : 31 days vs 40 - 44 days ) . Early dexamethasone was also associated with increased weight loss during the first 12 days of treatment ( 52 g vs 3 g ) compared with early budesonide , but over 30 days there was no difference . In the early dexamethasone group , there was a reduced incidence of persistent ductus arteriosus ( 34 % vs 52%-59 % ) and an increased risk of hyperglycemia ( 55 % vs 29%-34 % ) compared with the other 3 groups . Dexamethasone was associated with an increased risk of hypertension and gastrointestinal problems compared with budesonide but only the former attained significance . CONCLUSIONS Infants given early treatment and dexamethasone therapy had improved survival without chronic lung disease at 36 weeks compared with those given delayed selective treatment and inhaled budesonide , respectively , but results for survival to discharge were in the opposite direction ; however , none of these findings attained statistical significance . Early dexamethasone treatment reduced the risk of persistent ductus arteriosus . Inhaled budesonide may be safer than dexamethasone , but there is no clear evidence that it is more or less effective OBJECTIVE To compare duration of ventilation to mortality and adverse neurodevelopmental outcomes among extremely low birth weight ( ELBW ; 501 - 1000 g ) infants . STUDY DESIGN Retrospective analysis of prospect ively collected data from 5364 infants with a birthweight of 501 to 1000 g born at National Institute of Child Health and Human Development ( NICHD ) Neonatal Research Network centers from 1995 to 1998 . The main outcome measures were : survival , duration of mechanical ventilation , and neurodevelopmental outcome . RESULTS Overall survival was 71 % . The median duration of ventilation for survivors was 23 days ; 75 % were free of mechanical ventilation by 39 days , and 7 % were ventilated for > or = 60 days . Of those ventilated for > or = 60 days , 24 % survived without impairment . Of those ventilated for > or = 90 days , only 7 % survived without impairment . Of those ventilated > or = 120 days , all survivors were impaired . CONCLUSIONS The prognosis for ELBW with protracted ventilation remains grim . The cohort who remain intubated have diminished survival and high rates of impairment . Parents of these infants should be informed of changes in prognosis as the time of ventilation increases Two historical cohorts ( 1993–1994 and 2001 ) of preterm infants ventilated for respiratory distress syndrome were compared . Dexamethasone administration fell from 22 % to 6 % . Chronic lung disease in survivors rose slightly from 13 % to 17 % , and mortality fell from 21 % to 15 % ( other causes ) . The effect of restriction of dexamethasone use on chronic lung disease and mortality remains to be seen ABSTRACT : A number of studies have shown that increased numbers of neutrophils and macrophages are recruited into the airways during the development of chronic lung disease ( CLD ) in preterm infants . The objective of this study was to determine whether the anaphylatoxin C5a is detectable in tracheobronchial aspirate fluid of infants at risk for CLD and to evaluate the possible effects of dexamethasonc ( Dxm ) treatment . C5a/C5a(des Arg ) levels were determined by a sensitive ELISA based on a neoepitope-specific MAb . In a prospect i ve study , 27 infants ( birth weight 881 ± 169 g , mean ± SD ) still on mechanical ventilation at d 10 postnatal age with fraction of inspired oxygen ≥0.3 and /or peak inspiratory pressure ≥16 cm H2O were r and omly assigned to Dxm treatment at d 10 ( n = 14 ) or d 16 ( n = 13 ) . Ten mechanically ventilated infants with no respiratory disease or who had recovered from respiratory distress syndrome did not meet these criteria on d 10 and served as a control group ( birth weight 928 ± 126 g ) . For the evaluation of Dxm therapy , the late treatment group was used as a control group for the early regimen . Compared with controls , C5a concentrations were higher in infants at risk for CLD on d 10 [ median ( 25th-75th percentile ) : 2.40 ( 1.13–3.38 ) versus 0.82 ( 0.55–1.78 ) μg/L , p < 0.05 ] . After Dxm , C5a concentrations decreased significantly in the early treatment group compared with pretreatment values in the late treatment group [ d 15 , pre Dxm 2.22 ( 0.98–3.92 ) , post Dxm 0.57 ( 0.18–1.02 ) μg/L , p < 0.01 ] . C5a levels in plasma of eight infants were not affected by Dxm treatment . Our results show that increased levels of complement anaphylatoxin C5a are present in lung effluent fluid of infants at risk for CLD , and that local but not systemic levels are affected by Dxm . These findings indicate a role of C5a in the recruitment of inflammatory cells into the airways of infants with CLD OBJECTIVE To investigate the effects of postnatal dexamethasone treatment on aerobic fitness and physical activity levels in school-aged children born with very low birth weight ( VLBW ) . STUDY DESIGN This was a follow-up study of 65 VLBW infants who participated in a r and omized controlled trial of dexamethasone ( DEX ) to reduce ventilator dependency . Aerobic fitness was determined from peak oxygen uptake ( VO(2peak ) ) with a cycle ergometer . Habitual physical activity was assessed by question naire . RESULTS A trend for a treatment with an interaction between treatment and of diagnosis of chronic lung disease ( CLD ) was found , with the children in the placebo group with CLD having the lowest VO(2peak ) ( P = .09 ) . Reduced fitness was seen in 53 % of the group treated with DEX and 48 % of the group given placebo . No between-group differences in physical activity were seen . Parental reports suggested that nearly two-thirds of the children participated in < 1 hour per week of vigorous physical activity , which was explained in part by decreased large airway function ( r = 0.30 ; P = .03 ) . CONCLUSIONS We found no adverse effect of postnatal DEX on aerobic fitness or habitual physical activity at school age . However , the reduced fitness and physical activity levels emphasize the need for closer follow-up and early interventions promoting physical activity to reduce the risk of chronic disease in this at-risk population Background . Infection is a major complication of preterm infants , result ing in increased morbidity and mortality . We recently reported the results of a multicenter trial of dexamethasone initiated at 14 or 28 days in very low birth weight ( VLBW ) infants who were at risk for chronic lung disease ; the results showed an increase in nosocomial bacteremia in the group receiving dexamethasone . This study is an in-depth analysis of bacteremia/sepsis and meningitis among infants enrolled in the trial . Methods . Data on cultures performed and antibiotic therapy were collected prospect ively . Infections were classified as definite or possible/ clinical . Results . A total of 371 infants were enrolled in the trial . There were no baseline differences in risk factors for infection . For the first 14 days of study , infants received either dexamethasone ( group I , 182 ) or placebo ( group II , 189 ) . During this period , infants in group I were significantly more likely than those in group II to have a positive blood culture result ( 48 % vs 30 % ) and definite bacteremia/sepsis/meningitis ( 22 % vs 14 % ) . Over the 6-week study period , 47 % of those cultured had at least one positive blood culture result ( 53 % in group I vs 41 % in group II ) and 25 % of the infants had at least one episode of definite bacteremia/sepsis/meningitis ( 29 % in group I vs 21 % in group II ) . Among infants with definite infections , 46.8 % were attributable to Gram-positive organisms , 26.6 % to Gram-negative organisms and 26.6 % to fungi . The factors present at r and omization were evaluated for their association with infection . Group I assignment and H2blocker therapy ( before study entry ) were associated with increased risk of definite infection , whereas cesarean section delivery and increasing birth weight were associated with decreased risk . Conclusions . Infants who received a 14-day course of dexamethasone initiated at 2 weeks of age were more likely to develop a bloodstream or cerebrospinal fluid infection while on dexamethasone therapy than were those who received placebo . Physicians must consider this increased risk of infection when deciding whether to treat VLBW infants with dexamethasone OBJECTIVE To investigate the relationship between the severity-based definition of bronchopulmonary dysplasia ( BPD ) , choice of treatment , and neurocognitive outcomes at age 3 and 8 years . DESIGN This is a secondary analysis of data collected from a prospect i ve , longitudinal sample of 99 children with a history of BPD . SETTING Children born with BPD admitted to 3 hospitals from February 1 , 1989 , to November 31 , 1991 . PARTICIPANTS Ninety-nine children with BPD were longitudinally assessed at age 3 and 8 years . Three severity groups ( mild , moderate , and severe ) were formed based on gestational age and need for supplemental oxygen therapy . MAIN EXPOSURES Supplemental oxygen therapy for 28 days or longer , birth weight less than 1500 g , and radiographic evidence of lung disease . MAIN OUTCOME MEASURES Neurologic and medical outcomes ; type of medical management ; and language , achievement , and cognitive functioning were compared among the 3 severity groups . RESULTS Severity classification of BPD was associated with poorer outcomes . Compared with children with mild or moderate BPD , children with severe BPD performed more poorly on IQ tests ( Mental Development Index , 90 vs 76.4 ; and Psychomotor Development Index , 92.5 vs 73.9 ) and language measures ( total , 95 vs 82 ) at age 3 years and performance IQ ( 86 vs 75 ) and perceptual organization ( 86 vs 76 ) at age 8 years . Severity of BPD was not associated with choice of medical management but was related to educational interventions . Children with severe BPD received more special education services ( 69 % vs 44 % ) than did children with mild BPD . CONCLUSIONS The severity-based classification clarifies the relationship between BPD and developmental sequelae . Children with severe BPD required more interventions at age 8 years than did children with mild or moderate BPD To evaluate the effects of dexamethasone on pulmonary inflammation and permeability in preterm infants at high risk for chronic lung disease ( birth weight < 1200 gm ) , we assessed tracheobronchial aspirate fluid for chemotactic activity and concentrations of mediators of inflammation . In a prospect i ve study , 21 infants still undergoing mechanical ventilation at day 10 of postnatal age who required a fraction of inspired oxygen > or = 0.3 , a peak inspiratory pressure > or = 16 cm H2O , or both were r and omly assigned to treatment with dexamethasone at day 10 ( early treatment group , n = 10 ) or day 16 ( late treatment group , n = 11 ) . The groups were compared with respect to all measurements on day 15 ; the late treatment group served as a control group . Additionally , the effects of dexamethasone within both groups were evaluated . In the early treatment group , the chemotactic response of peripheral blood neutrophils exposed to tracheobronchial aspirate fluid was significantly reduced 5 days after initiation of dexamethasone treatment compared with pretreatment values of the late treatment group ( median ( 25th to 75th percentile ) : migratory distance before dexamethasone , 149 microns ( 140 to 173 microns ) ; after dexamethasone , 81 microns ( 68 to 114 microns ) ; p < 0.01 ) . In addition , the following values were decreased after dexamethasone therapy in the early treatment group : number of neutrophils in tracheobronchial aspirate fluid ( p < 0.05 ) , and concentrations of leukotriene B4 ( p < 0.01 ) , interleukin-1 ( p < 0.01 ) , elastase-alpha 1-proteinase inhibitor ( p < 0.01 ) , and albumin ( p < 0.01 ) . Free elastase activity was found in only two infants ; detectable activity of protective alpha 1-proteinase inhibitor was present in the others . Analysis of dexamethasone effects within the groups showed that all measurements were significantly decreased after both the early and the late treatment regimens , with the exception of leukotriene B4 and interleukin-1 , which declined only after early dexamethasone treatment . Our results indicate that the pulmonary inflammatory response and microvascular permeability are decreased by dexamethasone , which affects the release of inflammatory mediators and neutrophil influx into the airways of preterm infants who require mechanical ventilation OBJECTIVE To determine the changes in pulmonary mechanics before and during early dexamethasone therapy , and to evaluate the effect of dexamethasone on the duration of mechanical ventilation in very low birth weight ( VLBW ) ventilator-dependent infants at risk for chronic lung disease ( CLD ) . METHODS A prospect i ve r and omized trial was conducted . Forty-three patients ( birth weight 600 to 1500 g , gestational age 24 to 32 weeks ) who failed to be weaned from the respirator at 7 to 14 days of age were enrolled ; 23 infants received a 7-day course of dexamethasone ( 0.5 mg/kg/day intravenously for 3 days , 0.25 mg/kg/day for 3 days , and 0.1 mg/kg/day for 1 day ) , and 20 patients were in the control group . At similar mean airway pressure ( MAP ) and fractional inspired oxygen concentration ( FiO2 ) , respiratory system mechanics were measured before and on days 2 , 5 , and 7 of the study . Airway pressure , flow and tidal volume ( VT ) were recorded and only mechanical breaths were analyzed . Respiratory compliance ( Crs ) and respiratory resistance ( Rrs ) were calculated by two factor least mean square analysis . RESULTS Eighty-three percent of infants in the dexamethasone group and 90 % in the control group received surfactant in the first 24 hours of life . There was a significant increase in Crs and VT in the dexamethasone group as compared with the control group ( P < .001 ) . No major changes in Rrs were observed . Dexamethasone therapy significantly decreased FiO2 and MAP P < .001 ) and facilitated successful weaning from mechanical ventilation . In addition to a shorter duration of mechanical ventilation ( P < .01 ) , the occurrence of CLD ( FiO2 > 0.21 at 36 weeks of corrected gestational age , chest radiograph changes ) was significantly decreased in the dexamethasone group ( P < .01 ) . Except for a transient increase in blood pressure and serum glucose , there were no significant differences in infection rates , intraventricular hemorrhage , or retinopathy of prematurity . Thirteen patients in the control group received dexamethasone at a later age . CONCLUSIONS Our findings indicate that : 1 ) early dexamethasone therapy in VLBW infants markedly improves respiratory compliance and tidal volume , reduces FiO2 and MAP requirements , and facilitates extubation in these infants ; 2 ) early dexamethasone therapy reduces the duration of mechanical ventilation and decreases CLD ( at 28 days and 36 weeks ) in a population of VLBW infants largely treated with surfactant OBJECTIVE To investigate neurodevelopment at school age in preterm infants treated with hydrocortisone for bronchopulmonary dysplasia ( BPD ) in the neonatal period . STUDY DESIGN Preterm infants ( n = 226 ; gestational age < or = 32 weeks and /or body weight < or = 1500 grams ) performed subtests of the Wechsler Intelligence Scale for Children-Revised , the Visual Motor Integration test , a 15-Word Memory Test and the Movement Assessment Battery for Children at school age . Conventional MRI of the brain was obtained . Sixty-two children who received hydrocortisone for BPD ( starting dose , 5 mg/kg/day ; median duration , 27.5 days ) were compared with 164 nontreated neonates . RESULTS Hydrocortisone-treated infants were younger , lighter , and sicker than their non-steroid-treated counterparts . Adjustments for gestational age , body weight , sex , mechanical ventilation , and small for gestational age were made . Adjusted mean Intelligence Quotient , Visual Motor Integration test , and memory test results were the same in the hydrocortisone-treated group and the non-steroid-treated group ( 99 versus 101 , P = .62 ; 97 versus 99 , P = .49 , 7.9 versus 7.5 , P = .42 , respectively ) . Motor function and incidence of cerebral palsy in both groups was not different ( 11 % versus 7 % , P = .97 ) . Occurrence of brain lesions on MRI was similar for the two groups . CONCLUSIONS Neonatal hydrocortisone treatment for BPD had no long-term effects on neurodevelopment OBJECTIVE Dexamethasone is used in very low birth weight ( VLBW ) ventilator-dependent infants to prevent or decrease the severity of chronic lung disease . We reported a significant increase in respiratory compliance during a 7-day weaning course of moderately early dexamethasone therapy ( 0.5 mg/kg/d ) in VLBW infants , along with a shorter duration of mechanical ventilation and O2 supplementation . Although 0.5 mg/kg/d has been the most commonly used dose in preterm infants , the use of a lower dose of dexamethasone may reduce potential adverse effects of steroid therapy . Quantification of dynamic pulmonary mechanics in VLBW infants who receive low-dose dexamethasone has not been reported . The objective of this study was to compare the effect of 2 dose regimens of dexamethasone on dynamic pulmonary mechanics , mean airway pressure ( MAP ) , and fractional inspired oxygen concentration ( Fio2 ) in intubated VLBW infants who were at risk for chronic lung disease . METHODS We studied 47 VLBW ( birth weight : 550 - 1290 g ; gestational age : 24 - 30 weeks ) ventilator-dependent infants at 7 to 14 days of age . Twenty-three infants were r and omized to receive dexamethasone at 0.5 mg/kg/d intravenously for 3 days ( high dose ) , 0.25 mg/kg/d for 3 days , and 0.1 mg/kg/d during the 7th day ; 24 infants received low-dose dexamethasone as 0.2 mg/kg/d for 3 days and 0.1 mg/kg/d for 4 days . Respiratory compliance ( Crs ) and resistance were measured before and on days 2 , 5 , and 7 of dexamethasone therapy . We recorded airway pressure , flow , and tidal volume , and mechanical breaths were analyzed . RESULTS Crs significantly increased during dexamethasone therapy in both groups of infants when compared with baseline ( 74 % increase in the high-dose group and 66 % increase in the low-dose group ) . Dexamethasone increased tidal volume and significantly reduced Fio2 and MAP in both groups of infants . A transient increase in blood pressure was noted in both groups . CONCLUSIONS Our findings indicate that 1 ) comparable significant increases in Crs are present in the low-dose dexamethasone as well as the high-dose dexamethasone groups on days 2 , 5 , and 7 of steroid therapy ; and 2 ) MAP and Fio2 are significantly decreased during dexamethasone therapy in both groups of infants . We conclude that low-dose and high-dose dexamethasone , as used in this study , have comparable beneficial effects on dynamic pulmonary mechanics and subsequently on oxygen requirement and applied ventilatory support in VLBW infants Objectives : To report 18 month outcome of a r and omised trial of two courses of dexamethasone to prevent chronic lung disease of prematurity . Study design : Babies of birth weight 1250 g or less ventilated at 7 days of age were r and omised to a 42 day reducing course ( long ) or a 3 day pulsed ( pulse ) course of dexamethasone . Growth , cardiovascular status , and respiratory and neurodevelopmental outcomes were assessed at 18 months . Results : Seventy six babies were enrolled . Nine died and three were lost to follow up . Babies receiving the long course were weaned off oxygen more quickly than those receiving the pulse course ( 47 % v 69 % on oxygen at 28 days ; p = 0.01 ) , but there were no differences in 18 month outcomes . However , children averaged −1 SD for growth parameters , half had moderate or severe disability , and 35 % and 19 % respectively required oxygen at 36 weeks and discharge . Conclusions : The dexamethasone course used did not influence long term outcome . However , entry criteria for this study selected a group of babies at high risk of poor long term outcome Abstract The purpose of this controlled , prospect i ve pilot study was to compare the short- and long-term efficacy of early versus late treatment with dexamethasone ( Dex ) in preterm infants at risk for chronic lung disease ( CLD ) . Thirty ventilated premature infants with a birth weight ≤ 1250 g were r and omized to receive Dex either from day 7 or from day 14 . Dex was administered over 16 days tapering from 0.5 mg/kg per day to 0.1 mg/kg per day . The infants of the early treatment group could be weaned significantly earlier from the ventilator – after 14 days ( median ; range 9–24 ) versus 24 days ( median ; range 8–44 ) in the late treatment group . The need for supplemental oxygen was shorter if Dex was started early – 24 days ( median ; range 10–57 ) versus 40 days ( median ; range 10–74 ) . Oxygen dependency at 28 days of age was similar between the groups – 6 out of 14 infants ( 42.9 % ) versus 10 out of 16 patients (62.5%).The long-term efficacy of the two Dex regimens on lung function was evaluated by body plethysmographic measurements made at the age of 3 months . Thoracic gas volume and airway resistance were measured and specific airway conductance calculated . No statistically significant differences between the groups were demonstrated . Conclusion Early dexamethasone treatment led to earlier extubation in our study population , but was not associated with significant advantages regarding oxygen dependency at 28 days of life and pulmonary function test at 3 months of age OBJECTIVE Dexamethasone has been widely used to reduce the incidence of chronic lung disease in preterm infants . However side-effects are common , and the ideal dose of dexamethasone has not been identified . We aim ed to determine whether an individualized course of dexamethasone given to preterm babies at risk of chronic lung disease reduced the total dose of dexamethasone administered and reduced side-effects compared with a st and ard 42-day course . METHODS Thirty-three infants in a regional neonatal unit with a birthweight of < or = 1250 g who required mechanical ventilation at 7 days of age were r and omly assigned to a 42-day course of dexamethasone or an individualized course tailored to their respiratory status . The primary outcome was linear growth at 36 weeks corrected gestational age . RESULTS Infants in the individualized course received a 40 % lower total dose of dexamethasone . However , there was no difference between the two groups in linear growth or in the incidence of any other side-effects of treatment . There was also no difference in respiratory status or neurodevelopmental outcome . CONCLUSION The individualized course of dexamethasone used in this study reduced the total dose of dexamethasone administered but did not significantly reduce side-effects of treatment or alter outcome in infants at risk of chronic lung disease Background The use of postnatal corticosteroids to treat or prevent chronic lung disease is common in very preterm infants . Medullary nephrocalcinosis has been noted as a possible side effect . Objective This prospect i ve study was design ed to assess the incidence of nephrocalcinosis in extremely preterm infants exposed to dexamethasone . Patients and methods A prospect i ve study of extremely preterm infants , recruited to a r and omized trial of dexamethasone treatment for chronic lung disease , was initiated . Infants had US of the renal tract scheduled on entry into the study , at day 28 and at discharge or at the corrected gestational age of 36 weeks . Results Thirty-three infants were enrolled in the study . Birth weight ranged between 440 and 990 g and gestation between 24 and 28 weeks . Nine infants died and six had incomplete data . Because there was no difference in incidence of calcification between those on the short course and those on the long course of dexamethasone , analysis was made on the entire cohort . One infant had nephrocalcinosis at the time of the initial US examination on day 26 of life . By day 28 , nephrocalcinosis was present in 31 % of those with complete data . By discharge , or corrected gestational age of 36 weeks , US evidence of nephrocalcinosis was present in 15 ( 83 % ) of 18 infants . All infants had at least one course of an aminoglycoside antibiotic during the study . All infants had parenteral nutrition . Only four infants received furosemide more regularly than single doses . The longest course was 10 days , received by an infant who did not develop nephrocalcinosis . Conclusion The incidence of nephrocalcinosis is high in this group of sick , extremely preterm infants . Dexamethasone may be a factor in the development of nephrocalcinosis . Future research should focus on the natural history of nephrocalcinosis in extremely preterm infants We evaluated the use of dexamethasone in preterm infants to decrease morbidity associated with bronchopulmonary dysplasia in a r and omized , double-blind , placebo-controlled trial . Thirty-six preterm infants ( birth weight , less than or equal to 1250 g and gestational age , less than or equal to 30 weeks ) who were dependent on oxygen and mechanical ventilation at two weeks of age received a 42-day course of dexamethasone ( n = 13 ) , an 18-day course of dexamethasone ( n = 12 ) , or saline placebo ( n = 11 ) . The starting dose of dexamethasone was 0.5 mg per kilogram of body weight per day , and it was progressively lowered during the period of administration . Infants in the 42-day dexamethasone group , but not those in the 18-day group , were weaned from mechanical ventilation significantly faster than control infants ( medians 29 , 73 , and 84 days , respectively ; P less than 0.05 ) , and from supplemental oxygen ( medians 65 , 190 , and 136 days , respectively ; P less than 0.05 ) . No clinical complications of steroid administration were noted . Follow-up of all 23 survivors at 6 and 15 months of age showed good outcome ( normal neurologic examinations and Bayley Developmental Indexes greater than or equal to 84 ) in 7 of the 9 infants in the 42-day dexamethasone group , but in only 2 of the 9 infants in the 18-day dexamethasone group and 2 of the 5 in the placebo group ( P less than 0.05 ) . We conclude that dexamethasone therapy for 42 days improves pulmonary and neurodevelopmental outcome in very-low-birth-weight infants at high risk for bronchopulmonary dysplasia We conducted a prospect i ve , r and omized , double-blind trial to assess the efficacy and safety of pulse doses of dexamethasone on survival without supplemental oxygen in very low birth weight infants at high risk of having chronic lung disease . Seventy-eight infants with birth weights < or = 1500 gm who were ventilator dependent at 7 days of postnatal age were r and omly assigned to receive pulse doses of dexamethasone , 0.5 mg/kg per day , divided twice daily ( n = 39 ) , or an equivalent volume of saline solution placebo ( n = 39 ) , for 3 days at 10-day intervals until they no longer required supplemental oxygen or assisted ventilation , or reached 36 weeks of postmenstrual age . At study entry , the groups did not differ by birth weight , gestational age , or severity of lung disease . At 36 weeks of postmenstrual age , there was both a significant increase in survival rates without oxygen supplementation ( p = 0.03 ) and a significant decrease in the incidence of chronic lung disease ( p = 0.047 ) in the group that received pulse therapy . Supplemental oxygen requirements were less throughout the study period in the group that received repeated pulse doses of dexamethasone ( p = 0.013 ) . The total numbers of deaths and the duration s of supplemental oxygen , ventilator support , and hospital stay did not differ between groups . Recorded side effects in the pulse therapy group were minimal and included an increase in the use of insulin therapy for hyperglycemia ( p < 0.05 ) . We conclude that in this population of very low birth weight infants , treatment with pulse doses of dexamethasone result ed in improvement in pulmonary outcome without clinical ly significant side effects BACKGROUND Ventilator-dependent premature infants are often treated with dexamethasone . However , the optimal timing of therapy is unknown . METHODS We compared the benefits and hazards of initiating dexamethasone therapy at two weeks of age and at four weeks of age in 371 ventilator-dependent very-low-birth-weight infants ( 501 to 1500 g ) who had respiratory index scores ( mean airway pressure x the fraction of inspired oxygen ) of 52.4 at two weeks of age . One hundred eighty-two infants received dexamethasone for two weeks followed by placebo for two weeks , and 189 infants received placebo for two weeks followed by either dexamethasone ( those with a respiratory-index score of > or = 2.4 on treatment day 14 ) or additional placebo for two weeks . Dexamethasone was given at a dose of 0.25 mg per kilogram of body weight twice daily intravenously or orally for five days , and the dose was then tapered . RESULTS The median time to ventilator independence was 36 days in the dexamethasone-placebo group and 37 days in the placebo-dexamethasone group . The incidences of chronic lung disease ( defined as the need for oxygen supplementation at 36 weeks ' postconceptional age ) were 66 percent and 67 percent , respectively . Dexamethasone was associated with an increased incidence of nosocomial bacteremia ( relative risk , 1.5 ; 95 percent confidence interval , 1.1 to 2.1 ) and hyperglycemia ( relative risk , 1.9 ; 95 percent confidence interval , 1.2 to 3.0 ) in the dexamethasone-placebo group , elevated blood pressure ( relative risk , 2.9 ; 95 percent confidence interval , 1.2 to 6.9 ) in the placebo-dexamethasone group , and diminished weight gain and head growth ( P < 0.001 ) in both groups . CONCLUSIONS Treatment of ventilator-dependent premature infants with dexamethasone at two weeks of age is more hazardous and no more beneficial than treatment at four weeks of ages The National Institute of Child Health and Human Development conducts and supports research on all stages of human development from preconception to adulthood in order to better underst and the health of children , youths , adults , families , and communities . Health and human development information is made easily available on the site with a simple A to Z list , along with clinical trials and health education campaign information . Links to clinical trials , news releases , publications , and related web sites are also available , as well as information on research being conducted at present and supported by the National Institute of Child Health and Human Development OBJECTIVES . The goals were to compare early school-age neurodevelopmental and respiratory outcomes for children who were treated with either early ( <3 days ) or delayed selective ( > 15 days ) postnatal corticosteroid therapy and to compare systemic dexamethasone treatment with inhaled budesonide treatment . METHODS . One hundred twenty-seven ( 84 % ) of 152 survivors from the United Kingdom and Irel and who were recruited to the Open Study of Early Corticosteroid Treatment , a r and omized trial of inhaled and systemic corticosteroid therapy to prevent chronic lung disease , were traced and assessed at a median age of 7 years . Outcome measures were level of disability , presence of cerebral palsy , cognitive ability , behavioral difficulties and competencies , growth , and respiratory symptoms . Results were adjusted for potential confounding variables ( gestational age , birth weight , gender , prenatal steroid therapy , method of delivery , Apgar score at 5 minutes , and Clinical Risk Index for Babies score ) . RESULTS . There were no significant differences among the treatment groups in cognitive ability , behavioral competencies or difficulties , overall disability rates , cerebral palsy , combined outcomes of death or cerebral palsy and death or moderate/severe disability , growth , respiratory morbidity , or diastolic blood pressure . Those assigned to dexamethasone were more likely to have high systolic blood pressure and to have a diagnosis of asthma than were those assigned to budesonide . CONCLUSIONS . Although postnatal steroid therapy has been associated with poor long-term outcomes , this study failed to show significant differences in cognitive function between dexamethasone- and budesonide-allocated groups . There may be increased systolic blood pressure and a greater likelihood of developing asthma in childhood after postnatal dexamethasone treatment Pretreatment with the synthetic glucocorticoid dexamethasone prevents hypoxic-ischemic brain damage in 7-day-old neonatal rats . We presently characterize the response further by examining the effect of varying the age , the glucocorticoid , and the time of injection and by examining whether fasting can influence the response . Rats ( n = 193 ) were r and omized to one of 16 different treatment groups and subjected to hypoxia-ischemia ( right carotid artery occlusion + 8 % O2 which was 3 h in duration for 7-day , 1 h for 2-week , and 30 min for 1-month-old animals ) . The brains were subsequently perfusion fixed and the area of infa rct ion was measured from hematoxylin- and eosin-stained sections . Time dependence studies demonstrated that treatment with 0.1 mg/kg intraperitoneal dexamethasone 4 h prior to hypoxia reduced infa rct size compared to vehicle-treated animals whereas pretreatment at either 48 h or 4 days was ineffective . Dexamethasone pretreatment ( 4 h ) also provided neuroprotection against 4 h of hypoxia-ischemia . Fasted animals which received dexamethasone had reduced blood glucose levels yet markedly less damage than controls . Another glucocorticoid , methylprednisolone ( 0.7 mg/kg ) , also reduced infa rct ion . In 2-week-old animals the area of infa rct ion was reduced by pretreatment with dexamethasone , whereas in 1-month-old animals dexamethasone was ineffective . The results suggest that a glucocorticoid-mediated response intervenes in events leading to neuronal death in young animals but not older animals once myelination and synaptogenesis are complete Objective . Ventilator-dependent preterm infants are often treated with a prolonged tapering course of dexamethasone to decrease the risk and severity of chronic lung disease . The objective of this study was to assess the effect of this therapy on developmental outcome at 1 year of age . Methods . Study participants were 118 very low birth weight infants who , at 15 to 25 days of life , were not weaning from assisted ventilation and were then enrolled in a r and omized , placebo-controlled , double-blind trial of a 42-day tapering course of dexamethasone . Infants were examined at 1 year of age , adjusted for prematurity , by a pediatrician and a child psychologist . A physical and neurologic examination was performed , and the Bayley Scales of Infant Development were administered . All examiners were blind to treatment group . Results . Groups were similar in terms of birth weight , gestational age , gender , and race . A higher percentage of dexamethasone recipients had major intracranial abnormalities diagnosed by ultrasonography ( 21 % vs 11 % ) . Group differences were not found for Bayley Mental Development Index ( median [ range ] for dexamethasone-treated group , 94 [ 50–123 ] ; for placebo group , 90 [ 28–117 ] ) or Psychomotor Development Index Index ( median [ range ] ) for dexamethasone-treated group , 78 ( 50–109 ) ; for placebo-treated group , 81 [ 28–117 ] ) . More dexamethasone-treated infants had cerebral palsy ( 25 % vs 7 % ) and abnormal neurologic examination findings ( 45 % vs 16 % ) . In stratified analyses , adjusted for major cranial ultrasound abnormalities , these associations persisted ( OR values for cerebral palsy , 5.3 ; 95 % CI : 1.3–21.4 ; OR values for neurologic abnormality 3.6 ; 95 % CI : 1.2–11.0 ) . Conclusions . A 42-day tapering course of dexamethasone was associated with an increased risk of cerebral palsy . Possible explanations include an adverse effect of this therapy on brain development and /or improved survival of infants who either already have neurologic injury or who are at increased risk for such injury Infants at higher risk of bronchopulmonary dysplasia had increased rates of survival free of cerebral palsy after postnatal corticosteroid treatment in a previous metaregression of data from 14 r and omized controlled trials . The relationship persists and is stronger in an up date d analysis with data from 20 r and omized controlled trials |
13,668 | 21,438,898 | Our review shows that there is insufficient evidence to conclude that gender per se is a major autonomous predictor for disparities in psychological distress and QoL in ICD patients . | A subset of patients with an implantable cardioverter defibrillator ( ICD ) reports psychological distress and poor quality of life ( QoL ) .
Gender is one of the factors that has been proposed to explain individual differences in these outcomes . | Background —Women have an unexplained worse outcome after myocardial infa rct ion ( MI ) compared with men in many studies . Depressive symptoms predict adverse post-MI outcomes and are more prevalent among women than men . We examined whether depressive symptoms contribute to women ’s worse outcomes after MI . Methods and Results —In a prospect i ve multicenter study ( PREMIER ) , 2411 ( 807 women ) MI patients were enrolled . Depressive symptoms were assessed with the Patient Health Question naire . Outcomes included 1-year rehospitalization , presence of angina using the Seattle Angina Question naire , and 2-year mortality . Multivariable analyses were used to evaluate the association between sex and these outcomes , adjusting for clinical characteristics . The depressive symptoms score was added to the models to evaluate whether it attenuated the association between sex and outcomes . Depressive symptoms were more prevalent in women compared with men ( 29 % versus 18.8 % , P<0.001 ) . After adjusting for demographic factors , comorbidities , and MI severity , women had a mildly higher risk of rehospitalization ( hazard ratio , 1.20 ; 95 % CI , 1.04 to 1.40 ) , angina ( odds ratio , 1.32 ; 95 % CI , 1.00 to 1.75 ) , and mortality ( hazard ratio , 1.27 ; 95 % CI , 0.98 to 1.64 ) . After adding depressive symptoms to the multivariable models , the relationship further declined toward the null , particularly for rehospitalization ( hazard ratio , 1.14 ; 95 % CI , 0.98 to 1.34 ) and angina ( odds ratio , 1.22 ; 95 % CI , 0.91 to 1.63 ) , whereas there was little change in the estimate for mortality ( hazard ratio , 1.24 ; 95 % CI , 0.95 to 1.62 ) . Depressive symptoms were significantly associated with each of the study outcomes with a similar magnitude of effect in both women and men . Conclusions —A higher prevalence of depressive symptoms in women modestly contributes to their higher rates of rehospitalization and angina compared with men but not mortality after MI . Our results support the recent recommendations of improving recognition of depressive symptoms after MI BACKGROUND Depression is known to co-occur with coronary heart disease ( CHD ) . Depression may also inhibit the effectiveness of cardiac rehabilitation ( CR ) programs by decreasing adherence . Higher prevalence of depression in women may place them at increased risk for non-adherence . OBJECTIVE To assess the impact of a modified , stage-of-change-matched , gender-tailored CR program for reducing depressive symptoms among women with CHD . METHODS A two-group r and omized clinical trial compared depressive symptoms of women in a traditional 12-week CR program to those completing a tailored program that included motivational interviewing guided by the Transtheoretical Model of behavior change . Women in the experimental group also participated in a gender-tailored exercise protocol that excluded men . The Center for Epidemiological Studies Depression ( CES-D ) Scale was administered to 225 women at baseline , post-intervention , and at 6-month follow-up . Analysis of Variance was used to compare changes in depression scores over time . RESULTS Baseline CES-D scores were 17.3 and 16.5 for the tailored and traditional groups , respectively . Post-intervention mean scores were 11.0 and 14.3 ; 6-month follow-up scores were 13.0 and 15.2 , respectively . A significant group by time interaction was found for CES-D scores ( F(2 , 446)=4.42 , p=.013 ) . Follow-up tests revealed that the CES-D scores for the traditional group did not differ over time ( F(2 , 446)=2.00 , p=.137 ) . By contrast , the tailored group showed significantly decreased CES-D scores from baseline to post-test ( F(1 , 223)=50.34 , p<.001 ) ; despite the slight rise from post-test to 6-month follow-up , CES-D scores remained lower than baseline ( F(1 , 223)=19.25 , p<.001 ) . CONCLUSION This study demonstrated that a modified , gender-tailored CR program reduced depressive symptoms in women when compared to a traditional program . To the extent that depression hinders CR adherence , such tailored programs have potential to improve outcomes for women by maximizing adherence . Future studies should explore the mechanism by which such programs produce benefits BACKGROUND Psychosocial risk factors tend to cluster together within individuals , likely enhancing the risk of adverse health outcomes . We examined ( 1 ) the influence of clustering of poor device acceptance and Type D personality on anxiety and depressive symptoms , and ( 2 ) the demographic and clinical determinants of patients with clustering , in a large cohort of Danish implantable cardioverter defibrillator ( ICD ) patients . METHODS Patients ( N = 557 ; 81.9 % male ; mean age = 61.9 + /- 14.3 years ) implanted with an ICD between 1989 and 2006 were asked to complete a set of st and ardized and vali date d question naires and were divided into four risk groups : ( 1 ) No risk factors ( neither poor device acceptance nor Type D ) , ( 2 ) Poor device acceptance only , ( 3 ) Type D only , ( 4 ) Clustering ( both poor device acceptance and Type D ) . RESULTS The prevalence of anxiety was significantly higher in patients with clustering of risk factors ( 54.2 % ) compared to patients with poor device acceptance ( 30.0 % ) , Type D personality ( 26.5 % ) , or no risk factors ( 7.6 % ) ( chi(2)= 88.472 ; df = 3 ; P < 0.001 ) . Similarly , the prevalence of depression was higher in the clustering group ( 47.2 % ) compared to patients with poor device acceptance ( 19.1 % ) , Type D personality ( 23.5 % ) , or no risk factors ( 1.8 % ) ( Fisher 's exact = 112.874 ; df = 3 ; P < 0.001 ) . Patients with the clustering of poor device acceptance and Type D had the highest mean scores of anxiety ( P < 0.001 ) and depression ( < 0.001 ) , also when adjusting for demographic and clinical baseline characteristics including shocks . Shocks ( P = 0.006 ) were associated with increased anxiety but not with depression ( P = 0.31 ) . CONCLUSION Patients with poor device acceptance and Type D personality should be identified and monitored in clinical practice , as they may benefit from adjunctive intervention in order to experience the same quality of life benefits following implantation as other patients . Given the cross-sectional nature of the study , these findings should be confirmed using a prospect i ve study design BACKGROUND Significant rates of psychological distress occur in implantable cardioverter defibrillator ( ICD ) patients . Research has demonstrated that women are particularly at risk for developing distress and warrant psychosocial attention . The major objectives were to implement and test the effectiveness of a female-specific psychosocial group intervention on disease-specific quality of life outcomes in outpatient female ICD recipients versus a wait-list control group . METHOD Twenty-nine women were recruited for the study . Fourteen women were r and omized to the intervention group and participated in a psychosocial intervention focused on female-specific issues ; 15 were r and omized to the wait-list control group . All women completed individual psychological batteries at baseline and at 1-month follow-up measuring shock anxiety and device acceptance . RESULTS Pre-post measures of shock anxiety demonstrated a significant time by group interaction effect with the intervention group having a significantly greater decrease ( Pillai 's trace = 5.58 , P = 0.026 ) . A significant interaction effect ( Pillai 's trace = 5.05 , P = 0.046 ) was found , such that women under the age of 50 experienced greater reduction in shock anxiety than their middle-aged cohorts . Pre-post measures of device acceptance revealed a significant time by group interaction effect with the intervention group having significantly greater increases ( Pillai 's trace = 5.80 , P = 0.023 ) . CONCLUSIONS Structured interventions for female ICD patients involving ICD-specific education , cognitive behavioral therapy strategies , and group social support provide improvements in shock anxiety and device acceptance at 1-month re- assessment . Young women appear to be an at-risk subgroup of this population and may experience more benefit from psychosocial treatment targeting device-specific concerns OBJECTIVES We sought to examine the combination of adverse psychological factors ( anxiety , depression , and distressed or Type D personality ) as a predictor of ventricular arrhythmias in patients with implantable cardioverter-defibrillators ( ICDs ) . BACKGROUND Little is known about the role of psychological factors and their clustering in the occurrence of life-threatening arrhythmias . METHODS In this prospect i ve study , 391 patients with an ICD ( 81 % men , age 62.3 + /- 10.4 years ) completed anxiety , depression , and Type D personality scales at the time of implantation . The end point was occurrence of ventricular arrhythmia , defined as appropriate ICD therapies , in the first year after implantation . RESULTS Ventricular arrhythmias occurred in 19 % ( n = 75 ) of patients . Increased symptoms of depression ( p = 0.81 ) or anxiety ( p = 0.31 ) did not predict arrhythmias . However , anxious patients with a Type D personality had a significantly increased rate of ventricular arrhythmias ( 21 of 71 ; 29.6 % ) as compared with other ICD patients ( 54 of 320 ; 16.9 % ; hazard ratio [ HR ] : 1.89 ; 95 % confidence interval [ CI ] : 1.14 to 3.13 ; p = 0.013 ) . When controlled for the effects of sex , age , ischemic etiology , left ventricular dysfunction , prolonged QRS duration , and medication , anxious Type D patients ( HR : 1.72 ; 95 % CI : 1.03 to 2.89 ; p = 0.039 ) and secondary prevention patients ( HR : 1.91 ; 95 % CI : 1.14 to 3.20 ; p = 0.014 ) were at increased risk of ventricular arrhythmias . CONCLUSIONS Personality modulated the effect of emotional distress ; anxiety predicted a 70 % increase in risk of arrhythmia in Type D patients but not in other patients . Anxious Type D patients may be identified and offered additional behavioral support after ICD implantation BACKGROUND The Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation study demonstrated that implantable cardioverter defibrillators ( ICDs ) significantly reduce the risk of sudden cardiac death in patients with nonischemic cardiomyopathy and an ejection fraction of 35 % or less , with no statistically significant decrease in overall mortality . The impact of ICD placement and shock on health-related quality of life ( HRQL ) in this population is unknown . METHODS The 12-Item Medical Outcomes Short-Form Health Survey and the Minnesota Living with Heart Failure Question naire were administered to 458 patients with nonischemic cardiomyopathy , an ejection fraction of 35 % or less , and either nonsustained ventricular tachycardia or 10 or more premature ventricular depolarizations per hour at baseline , 1 month after r and omization , and every 3 months thereafter throughout the trial . The subjects were r and omized to an ICD or st and ard medical therapy . Outcomes were compared using hierarchical linear regression . RESULTS Overall , there were no significant differences in HRQL throughout the trial between patients r and omized to an ICD or st and ard medical therapy . However , in patients with 1 or more ICD shocks , HRQL declined 0.5 + /- 0.2 ( mean + /- SD ) points per shock on the emotional scale of the Minnesota Living with Heart Failure Question naire ( P = .04 ) and 1.0 + /- 0.5 points per shock on the mental component score of the 12-Item Medical Outcomes Short-Form Health Survey ( P = .04 ) . CONCLUSIONS Overall , HRQL was not affected by ICD implantation in patients in the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation study . Implantable cardioverter defibrillator shock was associated with a reduction in some measures of HRQL , but the effects were unlikely to result in a clinical ly observable alteration until 5 or more shocks were experienced Objective : To evaluate a minimal , easy , accessible intervention targeting anxiety and reduced quality of life in patients with an implantable cardioverter defibrillator ( ICD ) . An estimated 24 % to 87 % of patients experience anxiety , and 10 % to 15 % have reduced quality of life . Methods : A total of 119 ICD patients were assigned r and omly to usual medical aftercare ( n = 63 ) or additional psychological treatment ( n = 56 ) comprising of written information on medical and psychological consequences of an ICD plus 6 months of individual phone counseling . Treatment efficacy was evaluated by comparing T0 ( immediately after implantation ) and T1 ( 6 months later ) assessment s. Results : Although 75 % of patients considered the program helpful , age moderated treatment efficacy . As indicated by triple interactions , only in the treatment group , anxiety ( HADS-Anxiety , p < .01 ) , psychological distress ( SCL-K-9 , p < .02 ) , and somatic quality of life ( SF-36-PCS , p < .01 ) improved in ICD patients aged < 65 years but deteriorated in older patients ( age , 65–75 years ) . Frequency of ICD discharges was associated with a symptom increase from T0 to T1 in all patients ( HADS-Depression , CAQ-Avoidance , and ICD-Constraints ; all p < .05 ) . Conclusions : Our findings confirm that psychological treatments can not be expected to have uniformly positive effects in ICD patients . Our minimal intervention may have adequately addressed ICD-related concerns in younger patients but may have fostered problems in older patients with fewer concerns . Therefore , our findings warrant custom treatment with particular attention to the elderly as well as patients with frequent ICD discharges . ANOVA = analysis of variance ; ATP = antitachycardia pacing ; BMI = body mass index ; CAQ = Cardiac Anxiety Question naire ; HADS = Hospital Anxiety and Depression Scale ; ICD = implantable cardioverter defibrillator ; MI = myocardial infa rct ion ; MANOVA = multivariate analysis of variance ; QoL = quality of life ; SCL-K-9 = Symptom Checklist , 9-item short form ; SF-36-MCS = Medical Outcome Study Short Form-36 Health Survey : mental component summary ; SF-36-PCS = Medical Outcome Study Short Form-36 Health Survey : physical component summary ; T0 = assessment immediately after ICD implantation ; T1 = assessment at the end of the intervention ( i.e. , 6 months later ) BACKGROUND Life stresses and negative emotions , such as anxiety and depression , are associated with adverse cardiac events , including arrhythmia . Patients undergoing implantation of an automatic internal cardioverter defibrillator provide a unique opportunity to characterize these relationships since all tachyarrhythmia episodes are recorded by the device . OBJECTIVES The purpose of this study was to examine the association of emotional status after internal cardioverter defibrillator ( ICD ) implantation and subsequent arrhythmia events . METHODS An analysis of data obtained in a prospect i ve longitudinal study of responses to the ICD measured mood disturbance ( Profile of Mood States ; POMS ) before implant and at 1 , 3 , 6 , and 9 months postoperatively . Subjects included 144 men and 32 women with a mean age of 60 + /- 13 years and a mean left ventricular ejection fraction ( LVEF ) of 33 + /- 12 % . Arrhythmia events were measured by self-report of shocks and by ICD device interrogation to obtain the number and type ( defibrillation , cardioversion , and antitachycardia pacing ) of therapies delivered by the ICD . For each time point , POMS scores of subjects who had arrhythmia events were compared with those who did not . For subjects who had ICD shocks , pre-event and post-event POMS scores were also compared . Multiple logistic regression was used at each time point to determine if clinical , demographic and psychological data could predict arrhythmia events . RESULTS Patients with arrhythmia events had higher POMS scores throughout the 9 months of follow-up . Higher level of mood disturbance ( specifically anxiety , fatigue , and confusion ) at 1 and 3 months were independent predictors of subsequent arrhythmia events at 3 and 6 months after controlling for LVEF , the presence of coronary artery disease , pre-implant arrhythmia history , and the use of amiodarone and beta-blocking agents . There were no differences in POMS scores before and after ICD shocks , reinforcing the notion that negative emotions were a cause , rather than a consequence , of arrhythmia events . CONCLUSIONS Mood disturbances , such as anxiety , may increase the risk for arrhythmia events after ICD insertion Background —Observational studies have suggested that psychological stress increases the incidence of sudden cardiac death . Whether emotional or physical stressors can trigger spontaneous ventricular arrhythmias in patients at risk has not been systematic ally evaluated . Methods and Results — Patients with implantable cardioverter-defibrillators ( ICDs ) were given diaries to record levels of defined mood states and physical activity , using a 5-point intensity scale , during 2 periods preceding spontaneously occurring ICD shocks ( 0 to 15 minutes and 15 minutes to 2 hours ) and during control periods 1 week later . ICD-stored electrograms confirmed the rhythm at the time of shock . A total of 107 confirmed ventricular arrhythmias requiring shock were reported by 42 patients ( 33 men ; mean age , 65 years ; 78 % had coronary artery disease ) between August 1996 and September 1999 . In the 15 minutes preceding shock , an anger level ≥3 preceded 15 % of events compared with 3 % of control periods ( P < 0.04 ; odds ratio , 1.83 ; 95 % confidence intervals , 1.04 to 3.16 ) Other mood states ( anxiety , worry , sadness , happiness , challenge , feeling in control , or interest ) did not differ . Patients were more physically active preceding shock than in control periods . Anger and physical activity were independently associated with the preshock period . Conclusions —Anger and physical activity can trigger ventricular arrhythmias in patients with ICDs . Future investigations of therapies aim ed at blocking a response to these stressors may decrease ventricular arrhythmias and shocks in these patients CONTEXT Cardiac disease and treatment with an implantable cardioverter-defibrillator ( ICD ) may be psychologically traumatic . Posttraumatic stress disorder ( PTSD ) is generally overlooked in cardiac patients , and no study to date ( to our knowledge ) has evaluated the effect of PTSD symptoms on the prognosis in patients with ICDs . OBJECTIVE To test whether PTSD symptoms at baseline predict long-term mortality risk in patients with ICDs . DESIGN Prospect i ve cohort study with a mean follow-up period of 5.1 years , accounting for 743 person-years observed . SETTING Data were derived from the Living With an Implanted Cardioverter-Defibrillator- Study , which initially included 211 patients with ICDs routinely attending the German Heart Center Munich outpatient clinic . PARTICIPANTS The Impact of Event Scale-Revised was used in 147 patients ( 125 men and 22 women ) who qualified for the " A " criterion of PTSD ( survival of a life-threatening event ) . Thirty-eight patients scoring in the upper quartile of the scale constituted the PTSD index group . MAIN OUTCOME MEASURES Mortality risk per 1000 person-years as assessed by Cox proportional hazards regression analysis based on an appropriate model fit ( area under the curve , > 0.80 ) . RESULTS Index patients experienced more anxiety and depression , had more cardiac symptoms , but showed no differences in left ventricular ejection fraction status or extent of ICD discharges compared with non-index patients . Forty-five patients ( 30.6 % ) died during the follow-up period . The relative mortality risk ( multivariate adjusted for age , sex , diabetes mellitus , left ventricular ejection fraction , beta-blocker prescription , prior resuscitation , ICD shocks received , depression , and anxiety ) hazard ratio was 3.45 ( 95 % confidence interval , 1.57 - 7.60 ; P = .002 ) for the PTSD group . Compared with 55 fatal events per 1000 person-years in patients without PTSD , the long-term absolute mortality risk accounted for 80 fatal events per 1000 person-years in patients with PTSD . CONCLUSION The adverse effect of PTSD symptoms on the long-term mortality risk in ICD-treated cardiac event survivors , independent of disease severity , supports the need for routinely applied interdisciplinary psychosocial aftercare Objective : Higher anxiety is linked to poorer outcomes after acute myocardial infa rct ion ( AMI ) , including increased in‐hospital reinfa rct ion and potentially life‐threatening complications . If clinicians can identify patients at greatest risk for anxiety after AMI , they can institute early treatment . Previous research on the influence of gender on the incidence of anxiety post‐AMI reflects inconsistent findings , and differences across cultures have not been studied . Therefore , the purpose s of this study were to determine : 1 ) whether there are gender differences in anxiety in a diverse international sample of AMI patients , and 2 ) whether there was an interaction between gender and sociodemographic and clinical variables thought to influence anxiety . Methods : In this prospect i ve , comparative study , 912 AMI patients were enrolled from Australia , South Korea , Japan , Engl and , and the United States . Anxiety was assessed , using the Brief Symptom Inventory , within the first 72 hours of admission to the hospital for AMI symptoms . Results : Women had higher anxiety levels than men ( 0.76 ± 0.90 vs. 0.57 ± 0.70 , p = .005 ) , and this pattern of higher anxiety in women was seen in each country studied . Neither sociodemographic nor clinical variables interacted with gender to influence anxiety . Conclusion : Across a variety of cultures , women have higher anxiety than men after AMI and this relationship is independent of age , education level , marital status , or presence of comorbidities or severity of AMI BACKGROUND Little is known about the prevalence of chronic anxiety in patients with an implantable cardioverter defibrillator ( ICD ) . In a multi-center , prospect i ve study , we examined 1 ) the prevalence of chronic anxiety ( i.e. , patients anxious at implantation and 12 months ) , and 2 ) predictors of chronic anxiety . METHODS ICD patients ( N=284 ; 21.1 % women ) anxious ( cut-off ≥ 40 on the State Trait Anxiety Inventory ( STAI ) ) at the time of implantation qualified for inclusion in the current study . Patients completed the Type D Scale at baseline and the STAI ( state measure ) at baseline and 12 months . RESULTS Of 284 patients anxious at baseline , 53.9 % ( 153/284 ) remained anxious at 12-month follow-up . Diabetes ( OR:2.49 ; 95%CI:1.16 - 5.36 ) , cardiac resynchronization therapy ( CRT ) ( OR:2.03 ; 95%CI:1.02 - 4.05 ) , and Type D personality ( OR:1.87 ; 95%CI:1.09 - 3.19 ) were independent predictors of 12-month anxiety , adjusting for demographic and clinical variables including ICD therapy during follow-up . Shocks ( both appropriate and inappropriate during follow-up ) were not associated with chronic anxiety at 12 months ( OR:0.94 ; 95%CI:0.42 - 2.12 ) . The prevalence of chronic anxiety in the 96 patients with no risk factors was 34.4 % and 63.8 % in the 120 patients with either diabetes , CRT , or Type D personality . CONCLUSIONS More than 50 % of ICD patients anxious at the time of implantation were still anxious at 12 months , indicating a high level of chronicity . Diabetes , CRT , and Type D personality were independent predictors of chronic anxiety . ICD patients anxious at implantation should be closely monitored and offered adjunctive psychosocial intervention if symptoms do not remit spontaneously in order to prevent adverse health outcomes Purpose : The purpose of this article is to describe and evaluate a clinical nurse specialist (CNS)-facilitated support group for recipients of implantable cardioverter defibrillator . Specific evaluation aims were as follows : ( 1 ) How do demographic and clinical factors differ between those who attended the support group and those who did not ? ( 2 ) Is there a difference in the quality of life index ( QLI ) of individuals with an implantable cardioverter defibrillator who attended the CNS-facilitated support group and those who did not ? ( 3 ) What demographic and clinical factors are related to QLI ? Design and Method : Clinical project theory-based objectives were described . Implementation of the project was evaluated by retrospective survey of all implantable cardioverter defibrillator recipients during a 10-year time frame using the Ferrans and Powers ' Quality of Life Index : Cardiac Version and demographic question naire . Attendance sheets defined who attended so comparisons could be made . Evaluation Results : One hundred and twelve surveys were returned ( 34 % return rate ) . A positive relationship between CNS visit during hospitalization , number of and value of supports , years of education , and ejection fraction was noted with attendance at the support group . No between-group differences on total QLI , or on any subscales , were found . Comorbidity was the only clinical factor correlated with QLI . Conclusion : CNS-facilitated support groups can be offered as an additional support . Evaluation design issues limited the measuring outcomes of existing interventions . Future prospect i ve studies are recommended to determine the affect of the support group on quality of life Background and Research Objective : Although implantations of devices to support cardiovascular function are increasing , little is known about the factors involved in adjusting psychologically to having an implanted device . This study provides factor analysis of the Implanted Device Adjustment Scale ( IDAS ) and self-reported data on quality of life , mood states , and global adjustment . Subjects and Methods : This cross-sectional correlational design study included 174 subjects ( 46 women and 128 men ) . A convenience sample was recruited from electrophysiology practice s in 2 large Midwestern cities . Subjects completed the IDAS , the SF-36 quality -of-life measure , the Profile of Mood States , and a device adjustment visual analog scale . Results and Conclusions : The factor analysis produced 4 subscales for the IDAS : fear/anxiety , attitude , preparation , and body awareness . Perceived adjustment was " good " for 89 % of persons and was unrelated to age , sex , type of device , and whether a shock was received . All 4 subscales of the IDAS correlated negatively with adjustment ( higher IDAS score means poorer adjustment ) . The overall IDAS was internally consistent with a Cronbach α = .89 . Adjustment , as measured by the overall IDAS , had a weak but significant relationship with measures of quality of life including the mental component summary scale of the SF-36 ( r = 0.19 ) , but not the physical component summary scale of the SF-36 . All the Profile of Mood States subscales correlated positively with the IDAS subscale anxiety/fear with the exception of vigor/activity which had a negative correlation . No sex differences in total adjustment were seen in this group of patients , although there were differences in body awareness , physical functioning , and fatigue . Although patients with implanted cardioverter defibrillator were more fearful/anxious than patients with pacemaker only , no differences in total adjustment were seen between the 2 groups . A better underst and ing of the experience of adjusting to an implanted device is foundational to the development of appropriate interventions BACKGROUND Studies have examined the relationship between shocks and anxiety , but little is known about the role of personality . Our aim was to examine the determinants of self-reported and interviewer-rated anxiety following implantable cardioverter defibrillator ( ICD ) implantation . METHODS At baseline , that is , 0 - 3 weeks following ICD implantation , 308 ICD patients ( 82 % men , mean age = 62.6 years ) completed the DS14 ( Type D personality ) and ASI ( anxiety sensitivity ) . The STAI ( self-reported symptoms of state-anxiety ) was assessed at baseline and follow-up , which was 2 months following ICD implantation . At this follow-up , the HAM-A interview ( interviewer-rated anxiety ) was assessed in a sub sample ( 57 % ) ; the occurrence of ICD shocks was deduced from medical records . RESULTS Analysis of covariance ( ANCOVA ) for repeated measures showed a significant interaction effect between time and shocks ( F = 9.27 , P = 0.003 ) with patients who had experienced a shock experiencing higher levels of self-reported anxiety at follow-up . The main effects of Type D personality ( F = 33.42 , P < 0.0001 ) and anxiety sensitivity ( F = 66.31 , P < 0.0001 ) were significant , indicating that these patients scored higher on self-reported anxiety across time points . Multivariable linear regression analyses yielded Type D personality ( beta= 0.18 , P = 0.021 ) and anxiety sensitivity ( beta= 0.19 , P = 0.016 ) , but not shocks , as independent predictors of interviewer-rated anxiety . Covariates included gender , marital status , education , age , ICD indication , cardiac history , and comorbidity . CONCLUSIONS Type D personality and anxiety sensitivity were independent predictors of both self-reported and interviewer-rated anxiety outcomes while ICD shocks were related to an increase in levels of self-reported anxiety only . Identification and support of ICD patients with Type D personality , increased anxiety sensitivity , or shocks is important OBJECTIVE The purpose of this study was to assess gender differences in the impact of depression on 1-year cardiac mortality in patients hospitalized for an acute myocardial infa rct ion ( MI ) . METHODS Secondary analysis was performed on data from two studies that used the Beck Depression Inventory ( BDI ) to assess depression symptoms during hospitalization : a prospect i ve study of post-MI risk and a r and omized trial of psychosocial intervention ( control group only ) . The sample included 896 patients ( 283 women ) who survived to discharge and received usual posthospital care . Multivariate logistic regression analysis was used to assess the risk of 1-year cardiac mortality associated with baseline BDI scores . RESULTS There were 290 patients ( 133 women ) with BDI scores > or = 10 ( at least mild to moderate symptoms of depression ) ; 8.3 % of the depressed women died of cardiac causes in contrast to 2.7 % of the nondepressed . For depressed men , the rate of cardiac death was 7.0 % in contrast to 2.4 % of the nondepressed . Increased BDI scores were significantly related to cardiac mortality for both genders [ the odds ratio for women was 3.29 ( 95 % confidence interval ( CI ) = 1.02 - 10.59 ) ; for men , the odds ratio was 3.05 ( 95 % CI = 1.29 - 7.17 ) ] . Control for other multivariate predictors of mortality in the data set ( age , Killip class , the interactions of gender by non-Q wave MI , gender by left ventricular ejection fraction , and gender by smoking ) did not change the impact of the BDI for either gender . CONCLUSIONS Depression in hospital after MI is a significant predictor of 1-year cardiac mortality for women as well as for men , and its impact is largely independent of other post-MI risks Objective : Many patients treated with an implantable cardioverter defibrillator ( ICD ) experience clinical ly significant depression and anxiety after ICD implantation . As ICD use continues to evolve , it is important to underst and the correlates of depression and anxiety to identify patients at greatest risk of poor psychological functioning . Conservation of re sources theory , a general theory of stress , states that people experience greater stress if they perceive that they are losing personal , social , and material re sources . We hypothesized that perceptions of re source loss would be related to symptoms of depression and anxiety after controlling for other known predictors . Methods : One hundred patients treated with an ICD completed st and ardized depression and anxiety question naires along with question naires assessing social support , physical functioning , and re source loss . Clinical variables for patients were obtained from prospect ively obtained medical records . Results : Over 20 % of the sample exhibited elevated symptoms of depression and anxiety . Patients ' depression levels were associated with poor social support , poor physical functioning , a history of depression , and a greater length of time since ICD implantation . Having experienced one or more clinical ICD shocks was related to depression but not anxiety . Higher levels of perceived re source loss were associated with higher levels of both depression and anxiety after controlling for all other predictors . Conclusions : Re source loss may help to determine psychological distress after ICD implantation . Underst and ing how re source loss contributes to depression and anxiety may help to identify patients at greatest risk of poor psychological functioning and may suggest treatment strategies . ICD = implantable cardioverter defibrillator ; COR = conservation of re sources ; BDI = Beck Depression Inventory ; STAI = State-Trait Anxiety Inventory Few studies have prospect ively examined characteristics of implantable cardioverter defibrillator ( ICD ) patients as predictors of postimplant outcome . In this study the authors considered the association between preimplant psychological characteristics , ICD shocks , and postimplant quality of life at short- and long-term follow-ups , controlling for age and ejection fraction ( N=88 ) . Hierarchical regression analyses revealed that history of depression , trait anxiety , optimism , social support , and ICD shocks accounted for 41.8 % to 64.5 % of the variance in quality of life indices at 8- and 14-month follow-ups , depending on the outcome assessed . Further , psychological variables were as strong as , or stronger than , age , ejection fraction , and ICD shocks in predicting quality of life outcomes BACKGROUND Psychological responses have been reported for some patients after the insertion of an implantable cardioverter defibrillator ( ICD ) . This study tested the effects of a psychoeducational intervention on anxiety , depressive symptoms , functional status , and health re source use during the first year after ICD implantation . METHODS ICD patients ( n = 246 ) were r and omized to usual care ( UC ) , group ( GRP ) , or telephone counseling ( TC ) intervention that included education , symptom management , and coping skill training . Participants were 58 + /- 11 years , 73 % men , and 23 % minorities . Anxiety ( State-Trait Anxiety Inventory [ STAI ] ) , depressive symptoms ( Beck Depression Inventory II [ BDI-II ] ) , and functional status ( Duke Activity Status Inventory [ DASI ] ) were measured at baseline and after 1 , 3 , 6 , and 12 months . Health re source use and disability days were tracked . Analyses were repeated- measures analysis of covariance to assess Group x Time effects , chi(2)for percentage with clinical ly significant anxiety and depression at each time point , and logistic regression . RESULTS All groups experienced decreased anxiety and depressive symptoms over the 12 months ; GRP intervention had lower STAI ( P = 0.03 ) than UC at 3 months . Logistic regression revealed group differences for predicted probability of having depressive symptoms at 12 months ( UC = 0.31 , GRP = 0.17 , TC = 0.13 , P = 0.03 ) . UC had greater calls to providers at 1 and 6 months ( P < 0.05 ) and more sick/disability days at 12 months ( P = 0.01 ) than intervention groups . CONCLUSIONS A psychoeducational intervention reduced anxiety and depressive symptoms early after ICD implant , lowered probability of depressive symptoms at 1 year , and decreased disability days/calls to providers . These findings support further study and clinical use of both group and telephone interventions to yield better psychological outcomes after ICD implant Background While implantable cardioverter-defibrillators ( ICDs ) improve survival , their benefit in terms of health-related quality of life ( HRQOL ) is negligible . Objective To examine how shocks and congestive heart failure ( CHF ) mediate the effect of ICDs on HRQOL . Methods The US patients from the MADIT-II ( Multicenter Automatic Defibrillator Trial-II ) trial ( n = 983 ) were r and omized to receive an ICD or medical treatment only . HRQOL was assessed using the Health Utility Index 3 at baseline and 3 , 12 , 24 , and 36 months following r and omization . Logistic regressions were used to test for the effect of ICDs on the CHF indicator , and linear regressions were used to examine the effect of ICD shocks and CHF on HRQOL in living patients . We used a Monte Carlo simulation and a parametric Weibull distribution survival model to test for the effect of selective attrition . Observations were clustered by patients and robust st and ard errors ( RSEs ) were used to control for the non-independence of multiple observations provided by the same patient . Results Patients in the ICD arm had 41 % higher odds of experiencing CHF since their last assessment compared with those in the control arm ( RSE = 0.19 , p = 0.01 ) . Developing CHF reduced HRQOL at the subsequent visit by 0.07 ( p<0.01 ) . Having ICD shocks reduced overall HRQOL by 0.04 ( p = 0.04 ) at the subsequent assessment . The negative effect of ICD firing on HRQOL was an order of magnitude greater than the effect of CHF . Conclusions A higher prevalence of CHF and shocks among patients with ICDs and their negative effect on HRQOL may partially explain the lack of HRQOL benefit of ICD therapy Introduction Some patients with ICDs experience the sensation of a shock in the absence of true therapy ( phantom shock ) . We hypothesize that phantom shocks may be a manifestation of anxiety , depression or PTSD . Methods and results All patients over 18 years old with an ICD were eligible to enroll in the study . The first 75 subjects who agreed to participate were enrolled and divided into three groups : ICD patients with phantom shocks ( n = 19 ) ; ICD patients who had actual shocks ( n = 28 ) and ICD patients who had no shocks ( n = 28 ) . During a clinic visit a demographic question naire and three psychological rating scales were administered : the Spielberger State – Trait Anxiety Inventory ( STAI ) ; the Center for Epidemiologic Studies Depression Scale ( CES-D ) and the Posttraumatic Stress Checklist ( PCL-C ) . No significant differences between groups were found in gender , race , age , history of MI or cardiac surgery status . Data analysis of the psychological indices using one-way ANOVA showed that the group with phantom shocks had more depression ( CES-D p = 0.011 ) and more anxiety ( STAI p = 0.010 ) than the other groups . Multiple comparisons of group means showed a greater percentage of clinical ly depressed patients in the phantom shock group than in the other groups . Conclusion Patients with phantom shocks are more likely to be clinical ly depressed and have higher levels of anxiety than other ICD patients , regardless of history of actual shocks OBJECTIVES We sought to examine the relationship between symptoms of depression and shock-treated ventricular arrhythmias among implantable cardioverter-defibrillator ( ICD ) patients . BACKGROUND Depression predicts mortality in patients with coronary artery disease ( CAD ) , but whether this is via an increased risk of fatal ventricular arrhythmias is unclear . METHODS We prospect ively analyzed data on symptoms of depression and risk of ventricular arrhythmia ( ventricular tachycardia/ventricular fibrillation [ VT/VF ] ) result ing in ICD discharge in the Triggers of Ventricular Arrhythmias ( TOVA ) study . Symptoms were assessed by the Center for Epidemiologic Studies -Depression ( CES-D ) scale . Scores of 16 to 26 and > or = 27 represented mild and moderate/severe depression , respectively . The Cox and And erson-Gill proportional hazards models were used to test for associations among all patients and patients with CAD . RESULTS Among 645 patients with baseline assessment s , 90 ( 14 % ) were mildly depressed and 25 ( 3.9 % ) were moderately to severely depressed . Moderate/severe depression was associated with time to first shock for VT/VF ( hazard ratio [ HR ] 3.2 , 95 % confidence interval [ CI ] 1.1 to 9.9 ) and all shocks for VT/VF including recurrent episodes ( HR 3.2 , 95 % CI 1.2 to 8.6 ) . Among the 476 CAD patients , the association with time to first shock ( HR 6.4 , 95 % CI 1.9 to 21.1 ) and all shocks ( HR 8.3 , 95 % CI 2.9 to 23.3 ) remained . The risk of shock for VT/VF was associated with depression severity in the total population ( p for trend = 0.02 ) and among patients with CAD ( p < 0.01 ) , even after controlling for multiple confounders . CONCLUSIONS More severe symptoms of depression predict shocks for VT/VF among ICD patients . The elevated risk of VT/VF among patients with CAD and depression suggests that arrhythmia may contribute significantly to total mortality in this subgroup BACKGROUND Anxiety after acute myocardial infa rct ion influences both short- and long-term recovery . Therefore , determining specific subgroups of patients who have relatively higher anxiety levels is important . Published findings about gender differences in anxiety after acute myocardial infa rct ion are conflicting . OBJECTIVES To determine whether gender differences in anxiety after acute myocardial infa rct ion exist and whether any of the sociodemographic and clinical variables that often differ between men and women with acute myocardial infa rct ion interact with gender to influence anxiety . METHODS A total of 424 patients with confirmed acute myocardial infa rct ion were enrolled in this multicenter prospect i ve study . Patients ' anxiety level was measured within 72 hours of their arrival at the hospital by using the State Anxiety Inventory and the Brief Symptom Inventory . RESULTS Women had significantly higher anxiety than did men according to both the State Anxiety Inventory ( 42 + /- 12.9 vs 37.7 + /- 12.5 ; P = .001 ) and the Brief Symptom Inventory ( 0.83 + /- 0.97 vs 0.63 + /- 0.71 ; P = .02 ) . Of the sociodemographic and clinical variables examined , only marital status and income significantly interacted with gender to influence anxiety . Married women had higher anxiety than did single and widowed women , and married men had lower anxiety than did single men . Women with lower income had higher anxiety than did women with higher income ; income was not related to anxiety in men . CONCLUSION Women report significantly greater anxiety early after acute myocardial infa rct ion than men do . Women 's greater anxiety may be partially explained by marital status and lower income at the time of the infa rct ion |
13,669 | 32,146,139 | The studies examined PPE use in hospital ( n=7 ) , dental ( n=4 ) or laboratory ( n=2 ) setting s. Policies and practice s on PPE use were inconsistent .
Face masks and gloves were the most commonly used PPE to protect from respiratory and other infections .
PPE was not available in many facilities and its use was limited to high-risk situations .
Compliance with PPE use was low among healthcare workers , and reuse of PPE was reported . | Abstract Like other low-income countries , limited data are available on the use of personal protective equipment ( PPE ) in Pakistan .
We conducted a systematic review of studies on PPE use for respiratory infections in healthcare setting s in Pakistan . | Please cite this paper as : MacIntyre et al. ( 2011 ) A cluster r and omized clinical trial comparing fit‐tested and non‐fit‐tested N95 respirators to medical masks to prevent respiratory virus infection in health care workers . Influenza and Other Respiratory Viruses DOI : 10.1111/j.1750‐2659.2010.00198.x . Background We compared the efficacy of medical masks , N95 respirators ( fit tested and non fit tested ) , in health care workers ( HCWs ) . Methods A cluster r and omized clinical trial ( RCT ) of 1441 HCWs in 15 Beijing hospitals was performed during the 2008/2009 winter . Participants wore masks or respirators during the entire work shift for 4 weeks . Outcomes included clinical respiratory illness ( CRI ) , influenza‐like illness ( ILI ) , laboratory‐confirmed respiratory virus infection and influenza . A convenience no‐mask/respirator group of 481 health workers from nine hospitals was compared . Findings The rates of CRI ( 3·9 % versus 6·7 % ) , ILI ( 0·3 % versus 0·6 % ) , laboratory‐confirmed respiratory virus ( 1·4 % versus 2·6 % ) and influenza ( 0·3 % versus 1 % ) infection were consistently lower for the N95 group compared to medical masks . By intention‐to‐treat analysis , when P values were adjusted for clustering , non‐fit‐tested N95 respirators were significantly more protective than medical masks against CRI , but no other outcomes were significant . The rates of all outcomes were higher in the convenience no‐mask group compared to the intervention arms . There was no significant difference in outcomes between the N95 arms with and without fit testing . Rates of fit test failure were low . In a post hoc analysis adjusted for potential confounders , N95 masks and hospital level were significant , but medical masks , vaccination , h and washing and high‐risk procedures were not . Interpretation Rates of infection in the medical mask group were double that in the N95 group . A benefit of respirators is suggested but would need to be confirmed by a larger trial , as this study may have been underpowered . The finding on fit testing is specific to the type of respirator used in the study and can not be generalized to other respirators . Trial registration Australian New Zeal and Clinical Trials Registry ( ANZCTR ) , ACTRN : ACTRN12609000257268 ( http://www.anzctr.org.au ) BACKGROUND Certain emerging infections , such as severe acute respiratory syndrome and avian influenza , represent a great risk to healthcare workers ( HCWs ) . There are few data about the epidemiology of H1N1 influenza among HCWs . METHODS We conducted a prospect i ve surveillance study for all HCWs at King Abdulaziz Medical City ( Riyadh , Saudi Arabia ) who were confirmed positive for H1N1 influenza by polymerase chain reaction ( PCR ) from June 1 through November 30 , 2009 . RESULTS During 6 months of surveillance , 526 HCWs were confirmed positive for H1N1 influenza . The distribution of these cases showed 2 clear outbreaks : an initial outbreak ( peak at early August ) and a shorter second wave ( peak at end of October ) . Among all PCR-confirmed cases , the attack rate was significantly higher in clinical HCWs than in non clinical HCWs ( 6.0 % vs 4.3 % ; P < .001 ) and in HCWs in emergency departments than in HCWs in other hospital locations ( 17.4 % vs 5.0 % , P < .001 ) . The percentage of HCWs who received regular influenza vaccination was greater for clinical HCWs than for non clinical HCWs ( 46.2 % vs 24.6 % ; P < .001 ) . The majority of HCWs with confirmed H1N1 influenza were young ( mean age + or - st and ard deviation , 34.5 + or - 9.5 years ) , not Saudi ( 58.4 % ) , female ( 55.1 % ) , and nurses ( 36.1 % ) . Approximately 4 % of women who were less than 50 years old were pregnant . Reported exposures included contact with a case ( 41.0 % ) , contact with a sick household member ( 23.8 % ) , and recent travel history ( 13.3 % ) . Respiratory symptoms ( 98.0 % ) , including cough ( 90.1 % ) , were the most frequently reported symptoms , followed by muscle aches ( 66.2 % ) , fever ( 62.5 % ) , headache ( 57.9 % ) , diarrhea ( 16.5 % ) , and vomiting ( 9.8 % ) . None of these HCWs died , and all recovered fully without hospital admission . CONCLUSIONS The results confirm the vulnerability of HCWs , whether clinical or non clinical , to emerging H1N1 influenza Abstract Purpose To explore factors relating to the practice of habitual and volitional health behaviors against the severe acute respiratory syndrome ( SARS ) among Chinese adolescents in Hong Kong . Methods A community telephone survey was conducted with 230 Chinese adolescents . R and om-digit dialing of the local residential telephone directory was used to select respondents , who were asked to provide information on their practice of SARS preventive health behaviors and associated factors as specified by the Health Belief Model . These factors included perceived threat of SARS , perceived benefits and barriers in practicing SARS preventive health behaviors , cues to action , knowledge of SARS , and self-efficacy . Hierarchical regression analyses were conducted to determine salient correlates of habitual and volitional health behaviors against SARS . Results About 54.8 % of respondents reported practicing all three recommended habitual health behaviors . Another 47.8 % indicated consistent practice of volitional health behavior of facemask-wearing to prevent SARS . Results of hierarchical regression analyses showed that habitual health behaviors against SARS were related to perceived health threat and environmental cues . For facemask-wearing , salient correlates were environmental cues , rates of SARS habitual health behaviors , younger age , and perceived health threat . Conclusions The Health Belief Model is useful in underst and ing Chinese adolescents ’ practice of health behaviors , especially volitional health behaviors OBJECTIVE To evaluate healthcare worker ( HCW ) risk of self-contamination when donning and doffing personal protective equipment ( PPE ) using fluorescence and MS2 bacteriophage . DESIGN Prospect i ve pilot study . SETTING Tertiary-care hospital . PARTICIPANTS A total of 36 HCWs were included in this study : 18 donned/doffed contact pre caution ( CP ) PPE and 18 donned/doffed Ebola virus disease ( EVD ) PPE . INTERVENTIONS HCWs donned PPE according to st and ard protocol s. Fluorescent liquid and MS2 bacteriophage were applied to HCWs . HCWs then doffed their PPE . After doffing , HCWs were scanned for fluorescence and swabbed for MS2 . MS2 detection was performed using reverse transcriptase PCR . The donning and doffing processes were videotaped , and protocol deviations were recorded . RESULTS Overall , 27 % of EVD PPE HCWs and 50 % of CP PPE HCWs made ≥1 protocol deviation while donning , and 100 % of EVD PPE HCWs and 67 % of CP PPE HCWs made ≥1 protocol deviation while doffing ( P=.02 ) . The median number of doffing protocol deviations among EVD PPE HCWs was 4 , versus 1 among CP PPE HCWs . Also , 15 EVD PPE protocol deviations were committed by doffing assistants and /or trained observers . Fluorescence was detected on 8 EVD PPE HCWs ( 44 % ) and 5 CP PPE HCWs ( 28 % ) , most commonly on h and s. MS2 was recovered from 2 EVD PPE HCWs ( 11 % ) and 3 CP PPE HCWs ( 17 % ) . CONCLUSIONS Protocol deviations were common during both EVD and CP PPE doffing , and some deviations during EVD PPE doffing were committed by the HCW doffing assistant and /or the trained observer . Self-contamination was common . PPE donning/doffing are complex and deserve additional study . Infect Control Hosp Epidemiol 2017;38:1077 - 1083 BACKGROUND Masks are often worn in healthcare setting s to prevent the spread of infection from healthcare workers ( HCWs ) to patients . Masks are also used to protect the employee from patient-generated infectious organisms but poor compliance can reduce efficacy . The aim of this study was to examine the factors influencing compliance with the use of medical and cloth masks amongst hospital HCWs . METHODS HCWs compliance with the use of medical and cloth masks was measured over a 4-week period in a r and omized controlled trial in Vietnam . HCWs were instructed to record their daily activities in diary cards . Demographic , clinical , and diary card data were used to determine the predictors of compliance and the relationship of compliance with infection outcomes . RESULTS Compliance rates for both medical and cloth masks decreased during the 4 weeks : medical mask use decreased from 77 to 68 % ( P < 0.001 ) and cloth masks from 78 to 69 % ( P < 0.001 ) . The presence of adverse events ( adjusted RR 0.90 , 95 % CI 0.85 - 0.95 ) , and performing aerosol-generating procedures ( adjusted RR 0.78 , 95 % CI 0.73 - 0.82 ) were negatively associated with compliance , while contact with febrile respiratory illness patients was positively associated ( adjusted RR 1.14 , 95 % CI 1.07 - 1.20 ) . Being compliant with medical or cloth masks use ( average use ≥70 % of working time ) was not associated with clinical respiratory illness , influenza-like illness , and laboratory-confirmed viral infection . CONCLUSION Underst and ing the factors that affect compliance is important for the occupational health and safety of HCWs . New strategies and tools should be developed to increase compliance of HCWs . The presence of adverse events such as discomfort and breathing problems may be the main reasons for the low compliance with mask use and further studies should be conducted to improve the design / material of masks to improve comfort for the wearer This study investigated provincial and territorial differences in dentists ' compliance with recommended infection control practice s in Canada ( 1995 ) . Question naires were mailed to a stratified r and om sample of 6,444 dentists , of whom 66.4 % responded . Weighted analyses included Pearson 's chi-square test and multiple logistic regression . Significant provincial and territorial differences included testing for immune response after hepatitis B virus ( HBV ) vaccination , HBV vaccination for all clinical staff , use of infection control manuals and post-exposure protocol s , biological monitoring of heat sterilizers , h and washing before treating patients , using gloves and changing them after each patient , heat-sterilizing h and pieces between patients , and using masks and uniforms to protect against splatter of blood and saliva . Excellent compliance ( compliance with a combination of 18 recommended infection control procedures ) ranged from 0 % to 10 % ; the best predictors were more hours of continuing education on infection control in the last two years , practice location in larger cities ( > 500,000 ) and sex ( female ) . Clearly , improvements in infection control are desirable for dentists in all provinces and territories . Extending m and atory continuing education initiatives to include infection control may promote better compliance with current recommendations The nature of discomfort and level of exertion associated with wearing respiratory protection in the health care workplace are not well understood . Although a few studies have assessed these topics in a laboratory setting , little is known about the magnitude of discomfort and the level of exertion experienced by workers while they deliver health care to patients for prolonged periods . The purpose of this study was to determine the magnitude of discomfort and level of exertion experienced by health care workers while wearing respiratory protection for periods up to 8 hr when performing their typical occupational duties . This project was a multiple cross-over field trial of 27 health care workers , aged 24–65 , performing their typical , hospital-based occupational duties . Each participant served as his/her own control and wore one of seven respirators or a medical mask for 8 hr ( or as long as tolerable ) with interposed doffing periods every 2 hr . Self-perceived discomfort and exertion were quantified before each doffing : self-perceived level of discomfort using a visual analog scale , and self-perceived level of exertion using a Borg scale . Overall , and as would be expected , discomfort increased over time with continual respirator use over an 8-hr period . Interestingly , exertion increased only marginally over the same time period . The relatively low level of exertion associated with eight respiratory protective devices , including models commonly used in the U.S. health care workplace , is not likely to substantially influence workers ’ tolerability or occupational productivity . However , the magnitude of discomfort does appear to increase significantly over time with prolonged wear . These results suggest that respirator-related discomfort , but not exertion , negatively influences respirator tolerance over prolonged periods . Discomfort may also interfere with the occupational duties of workers Background : The aim of this study was to describe the risk of self‐contamination associated with doffing of personal protective equipment ( PPE ) and to compare self‐contamination with various PPE protocol s. Methods : We tested 10 different PPE donning and doffing protocol s , recommended by various health organizations for Ebola . Ten participants were recruited for this study and r and omly assigned to use 3 different PPE protocol s. After donning of PPE , fluorescent lotion and spray were applied on the external surface of the PPE to simulate contamination , and ultraviolet light was used to count fluorescent patches on the skin . Results : After testing 30 PPE sequences , large fluorescent patches were recorded after using “ WHO coverall and 95 ” and “ North Carolina coverall and N95 ” sequences , and small patches were recorded after using “ CDC coverall and N95 ” and “ Health Canada gown and N95 ” sequences . Commonly reported problems with PPE use were breathing difficulty , suffocation , heat stress , and fogging‐up glasses . Most participants rated PPE high ( 18/30 ) or medium ( 11/30 ) for ease of donning/doffing and comfort . PPE sequences with powered air‐purifying respirators ( PAPRs ) and assisted doffing were generally associated with fewer problems and were rated the highest . Conclusion : This study confirmed the risk of self‐contamination associated with the doffing of PPE . PAPR‐containing protocol s and assisted doffing should be preferred whenever possible during the outbreak of highly infectious pathogens |
13,670 | 24,990,591 | Conclusions The current evidence from the available clinical trials suggests that bevacizumab in combination with some other anticancer agents ( especially mTOR inhibitors and interferons ) could be a more effective and tolerable treatment for advanced GEP-NENs in the future . | Background Gastroenteropancreatic neuroendocrine neoplasms ( GEP-NENs ) consist of a large heterogeneous group of epithelial tumors with neuroendocrine differentiation that arises in gastrointestinal tract and pancreatic tissues .
Advanced GEP-NENs are considered distinct disease entity with limited approved treatment options and poor prognosis .
So , we will explore in this systematic review the value of using bevacizumab-based combination in this subset of NENs . | PURPOSE Effective systemic therapy for advanced carcinoid is lacking . The combination of bevacizumab ( BEV ) and pegylated ( PEG ) interferon alpha-2b was evaluated among patients with metastatic or unresectable carcinoid tumors . PATIENTS AND METHODS Forty-four patients on stable doses of octreotide were r and omly assigned to 18 weeks of treatment with bevacizumab or PEG interferon alpha-2b . At disease progression ( PD ) or at the end of 18 weeks ( whichever occurred earlier ) , patients received bevacizumab plus PEG interferon until progression . Functional computer tomography ( CT ) scans were performed to measure effect on tumor blood flow . RESULTS In the bevacizumab arm , four patients ( 18 % ) achieved confirmed partial response ( PR ) , 17 patients ( 77 % ) had stable disease ( SD ) , and one patient ( 5 % ) had PD . In the PEG interferon arm , 15 patients ( 68 % ) had SD and six patients ( 27 % ) had PD . Progression-free survival ( PFS ) rates after 18 weeks of monotherapy were 95 % in bevacizumab versus 68 % on the PEG interferon arm . The overall median PFS for all 44 patients is 63 weeks . Compared with paired baseline measurements on functional CT scans , we observed a 49 % ( P < .01 ) and 28 % ( P < .01 ) decrease in tumor blood flow at day 2 and week 18 among patients treated with bevacizumab . No significant changes in tumor blood flow were observed following PEG interferon . PEG interferon alpha-2b treatment was associated with decrease in plasma basic fibroblast growth factor ( bFGF ; P = .04 ) and increase in plasma interleukin-18 ( IL-18 ; P < .01 ) . No significant changes in bFGF or IL-18 following treatment with bevacizumab were observed . CONCLUSION Bevacizumab therapy result ed in objective responses , reduction of tumor blood flow , and longer PFS in patients with carcinoid than PEG interferon treatment Background Well-differentiated neuroendocrine carcinomas are highly vascularized and may be sensitive to drugs administered on a metronomic schedule that has shown antiangiogenic properties . A phase II study was design ed to test the activity of protracted 5-fluorouracil ( 5FU ) infusion plus long-acting release ( LAR ) octreotide in patients with neuroendocrine carcinoma . Methods Twenty-nine patients with metastatic or locally advanced well-differentiated neuroendocrine carcinoma were treated with protracted 5FU intravenous infusion ( 200 mg/m2 daily ) plus LAR octreotide ( 20 mg monthly ) . Patients were followed for toxicity , objective response , symptomatic and biochemical response , time to progression and survival . Results Assessment by Response Evaluation Criteria in Solid Tumors ( RECIST ) criteria showed partial response in 7 ( 24.1 % ) , stable disease in 20 ( 69.0 % ) , and disease progression in 2 patients . Response did not significantly differ when patients were stratified by primary tumor site and proliferative activity . A biochemical ( chromogranin A ) response was observed in 12/25 assessable patients ( 48.0 % ) ; symptom relief was obtained in 9/15 symptomatic patients ( 60.0 % ) . There was non significant decrease in circulating vascular epithelial growth factor ( VEGF ) over time . Median time to progression was 22.6 months ( range , 2.7 - 68.5 ) ; median overall survival was not reached yet . Toxicity was mild and manageable . Conclusion Continuous/metronomic 5FU infusion plus LAR octreotide is well tolerated and shows activity in patients with well-differentiated neuroendocrine carcinoma . The potential synergism between metronomic chemotherapy and antiangiogenic drugs provides a rationale for exploring this association in the future . Trial registration Purpose Sorafenib and everolimus are both active against neuroendocrine tumors ( NET ) . Because of potential synergy between VEGF pathway and mTOR inhibitors , we performed a phase I study to evaluate the safety and feasibility of combining sorafenib and everolimus in patients with advanced NET . Methods Patients were treated with everolimus 10 mg daily in combination with sorafenib ( dose level 1 : 200 mg twice daily ; dose level 2 : 200 mg per morning , 400 mg per evening ) using st and ard phase I dose escalation design . Dose-limiting toxicity ( DLT ) was defined within the first cycle ( 28 days ) of therapy . Treatment was continued until tumor progression , unacceptable toxicity , or withdrawal of consent . Twelve additional patients were treated at the maximum tolerated dose ( MTD ) level to further characterize safety and a preliminary assessment of activity . Results One patient in Cohort 1 experienced DLT ( grade 3 skin rash ) ; the cohort was exp and ed to 6 patients with no further DLTs . All 3 patients in Cohort 2 experienced DLT , consisting of thrombocytopenia , h and –foot skin reaction , and rash/allergic reaction . Sorafenib 200 mg twice daily in combination with everolimus 10 mg daily was established as the MTD . Independently review ed best objective responses revealed that 62 % of patients had some degree of tumor shrinkage . By RECIST , we observed partial response in 1 patient , stable disease in 13 patients , and progressive disease in 3 patients . ConclusionS orafenib 200 mg twice daily with everolimus 10 mg daily represents the MTD of this combination in patients with advanced NET . While the combination is active , toxicity concerns may preclude more widespread use BACKGROUND The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in pre clinical models and phase 1 and 2 trials . METHODS We conducted a multinational , r and omized , double-blind , placebo-controlled phase 3 trial of sunitinib in patients with advanced , well-differentiated pancreatic neuroendocrine tumors . All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline . A total of 171 patients were r and omly assigned ( in a 1:1 ratio ) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo . The primary end point was progression-free survival ; secondary end points included the objective response rate , overall survival , and safety . RESULTS The study was discontinued early , after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib . Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group ( hazard ratio for progression or death , 0.42 ; 95 % confidence interval [ CI ] , 0.26 to 0.66 ; P<0.001 ) . A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied . The objective response rate was 9.3 % in the sunitinib group versus 0 % in the placebo group . At the data cutoff point , 9 deaths were reported in the sunitinib group ( 10 % ) versus 21 deaths in the placebo group ( 25 % ) ( hazard ratio for death , 0.41 ; 95 % CI , 0.19 to 0.89 ; P=0.02 ) . The most frequent adverse events in the sunitinib group were diarrhea , nausea , vomiting , asthenia , and fatigue . CONCLUSIONS Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival , overall survival , and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors . ( Funded by Pfizer ; Clinical Trials.gov number , NCT00428597 . ) The only approved systemic therapy for patients with advanced hepatocellular carcinoma ( HCC ) till now is sorafenib . A preliminary study suggested that capecitabine , an oral fluoropyrimidine , may be effective in advanced HCC . We have tested this hypothesis in this phase 2 study . In this single-center , phase 2 , open-label trial , we r and omly assigned 52 patients with advanced HCC who had not received previous systemic treatment to receive either sorafenib ( at a dose of 400 mg twice daily ) or capecitabine ( 1,000 mg/m2 twice daily ) ( day 1–day 14 ) . Primary outcome was progression-free survival . Secondary outcomes included the overall survival and safety . Median overall survival was 7.05 months in the sorafenib group and 5.07 months in the capecitabine group ( hazard ratio in the capecitabine group 2.36 ; 95 % confidence interval 1.174–4.74 ; P < 0.016 ) . The median progression-free survival was 6 months in the sorafenib group and 4 months in the capecitabine group ( P < 0.005 ) . Three patients in the sorafenib group ( 11.5 % ) and one patient in the capecitabine group ( 3 % ) had a partial response ; one patient ( 3 % ) had a complete response in the sorafenib group . H and –foot skin reaction was more frequent in the sorafenib group , hyperbilirubinemia was more common in the capecitabine group , and diarrhea was equivalent between both groups . In patients with advanced HCC , capecitabine is inferior to sorafenib in terms of median progression-free survival and overall survival , and it should not be used alone for the treatment of advanced HCC , but rather , combination therapy with sorafenib should be considered BACKGROUND Sorafenib and bevacizumab as single agents have shown efficacy and acceptable toxicity in NETs phase II trials . Sorafenib and bevacizumab combination has shown manageable toxicity in phase I trials in solid tumours . The purpose of this study was to evaluate the safety and efficacy of the combination of sorafenib and bevacizumab in patients with advanced neuroendocrine tumours . METHODS Open-label , uncontrolled , multicenter , phase II clinical trial . ELIGIBILITY CRITERIA age ≥18 years , histologically confirmed measurable advanced NETs ; 1 prior chemotherapy allowed ; ECOG-PS 0 - 2 . Patients were treated during 6 months and followed up for an additional 6 months . TREATMENT sorafenib 200 mg bid ( days 1 - 5 of each week ) and bevacizumab 5mg/kg once every 2 weeks ( day 1 , week 1 ) . Tumour response was performed according to RECIST ( v1.0 ) every 2 months during the treatment period . Adverse events were grade d according to CTCAE ( v3.0 ) . FINDINGS 44 Patients enrolled , 59.1 % men , median age 60 years ( range 32 - 76 ) . 70.5 % carcinoid tumours , 29.5 % pancreatic tumour . Baseline target lesions mainly in the liver ( 86.4 % ) . Global PFSR was 90.9 % ( 91.7 % carcinoid tumours and 88.9 % pancreatic tumours ) . Median PFS was 12.4 months , median TTP was 14.5 months , ORR was 9.4 % and DCR was 95.1 % . Most common grade 3 - 4 toxicities : asthenia ( 11.4 % ) and h and -foot skin reaction ( 15.9 % ) . INTERPRETATION Sorafenib and bevacizumab combination showed clinical benefit but unfavourable safety results compared with drugs in monotherapy . Further development of this combination is not warranted and a sequential approach is recommended instead PURPOSE Both tyrosine kinase inhibitors targeting the vascular endothelial growth factor ( VEGF ) receptor and bevacizumab , a monoclonal antibody targeting VEGF , have antitumor activity in neuroendocrine tumors ( NETs ) . Temozolomide , an oral analog of dacarbazine , also has activity against NETs when administered alone or in combination with other agents . We performed a phase II study to evaluate the efficacy of temozolomide in combination with bevacizumab in patients with locally advanced or metastatic NETs . PATIENTS AND METHODS Thirty-four patients ( 56 % with carcinoid , 44 % with pancreatic NETs ) were treated with temozolomide 150 mg/m(2 ) orally per day on days 1 through 7 and days 15 through 21 , together with bevacizumab at a dose of 5 mg/kg per day intravenously on days 1 and 15 of each 28-day cycle . All patients received prophylaxis against Pneumocystis carinii and varicella zoster . Patients were followed for toxicity , biochemical and radiologic response , and survival . RESULTS The combination of temozolomide and bevacizumab was associated with anticipated grade 3 to 4 toxicities , including lymphopenia ( 53 % ) and thrombocytopenia ( 18 % ) . Although the overall radiographic response rate was 15 % ( five of 34 ) , response rates differed between patients with pancreatic NETs ( 33 % ; five of 15 ) and those with carcinoid tumors ( zero of 19 ) . The median progression-free survival was 11.0 months ( 14.3 months for pancreatic NETs v 7.3 months for carcinoid tumors ) . The median overall survival was 33.3 months ( 41.7 months for pancreatic NETs v 18.8 months for carcinoid tumors ) . CONCLUSION Temozolomide and bevacizumab can be safely administered together in patients with advanced NETs , and the combination regimen appears promising for patients with pancreatic NETs . Studies evaluating the relative contributions of these two agents to the observed antitumor activity are warranted |
13,671 | 28,954,800 | No statistically significant differences in intervention effects were found for variations in intervention timing , duration or exercise FITT factors .
Conclusions Exercise interventions , especially when supervised , have statistically significant and small clinical benefit on self-reported QoL and PF in patients with cancer .
Unsupervised exercise intervention effects on PF were larger when prescribed at a higher weekly energy expenditure | Objective Certain exercise prescriptions for patients with cancer may improve self-reported quality of life ( QoL ) and self-reported physical function ( PF ) .
We investigated the effects of exercise on QoL and PF in patients with cancer and studied differences in effects between different intervention-related and exercise-related characteristics . | Background Preliminary studies suggest that physical exercise interventions can improve physical fitness , fatigue and quality of life in cancer patients after completion of chemotherapy . Additional research is needed to rigorously test the effects of exercise programmes among cancer patients and to determine optimal training intensity accordingly . The present paper presents the design of a r and omized controlled trial evaluating the effectiveness and cost-effectiveness of a high intensity exercise programme compared to a low-to-moderate intensity exercise programme and a waiting list control group on physical fitness and fatigue as primary outcomes . Methods After baseline measurements , cancer patients who completed chemotherapy are r and omly assigned to either a 12-week high intensity exercise programme or a low-to-moderate intensity exercise programme . Next , patients from both groups are r and omly assigned to immediate training or a waiting list ( i.e. waiting list control group ) . After 12 weeks , patients of the waiting list control group start with the exercise programme they have been allocated to . Both interventions consist of equal bouts of resistance and endurance interval exercises with the same frequency and duration , but differ in training intensity . Additionally , patients of both exercise programmes are counselled to improve compliance and achieve and maintain an active lifestyle , tailored to their individual preferences and capabilities . Measurements will be performed at baseline ( t = 0 ) , 12 weeks after r and omization ( t = 1 ) , and 64 weeks after r and omization ( t = 2 ) . The primary outcome measures are cardiorespiratory fitness and muscle strength assessed by means of objective performance indicators , and self-reported fatigue . Secondary outcome measures include health-related quality of life , self-reported physical activity , daily functioning , body composition , mood and sleep disturbances , and return to work . In addition , compliance and satisfaction with the interventions will be evaluated . Potential moderation by pre- and post-illness lifestyle , health and exercise-related attitudes , beliefs and motivation will also be assessed . Finally , the cost-effectiveness of both exercise interventions will be evaluated . Discussion This r and omized controlled trial will be a rigorous test of effects of exercise programmes for cancer patients after chemotherapy , aim ing to contribute to evidence -based practice in cancer rehabilitation programmes . Trial registration This study is registered at the Netherl and s Trial Register ( NTR2153 Observational studies demonstrate an association between physical activity and improved outcomes in breast and colon cancer survivors . To test these observations with a large , r and omized clinical trial , an intervention that significantly impacts physical activity in these patients is needed . The Active After Cancer Trial ( AACT ) was a multicenter pilot study evaluating the feasibility of a telephone-based exercise intervention in a cooperative group setting . Sedentary ( engaging in < 60 min of recreational activity/week ) breast and colorectal cancer survivors were r and omized to a telephone-based exercise intervention or usual care control group . The intervention was delivered through the University of California at San Diego ; participants received ten phone calls over the course of the 16-week intervention . All participants underwent assessment of physical activity , fitness , physical functioning , fatigue and exercise self-efficacy at baseline and after the 16-week intervention . One hundred and twenty-one patients were enrolled through ten Cancer and Leukemia Group B ( CALGB ) institutions ; 100 patients had breast cancer and 21 had colorectal cancer . Participants r and omized to the exercise group increased physical activity by more than 100 versus 22 % in controls ( 54.5 vs. 14.6 min , P = 0.13 ) , and experienced significant increases in fitness ( increased 6-min walk test distance by 186.9 vs. 81.9 feet , P = 0.006 ) and physical functioning ( 7.1 vs. 2.6 , P = 0.04 ) as compared to the control group . Breast and colorectal cancer survivors enrolled in a multicenter , telephone-based physical activity intervention increased physical activity and experienced significant improvements in fitness and physical functioning . Lifestyle intervention research is feasible in a cooperative group setting PURPOSE The primary purpose of this study was to examine the effect of aerobic exercise on physiological and psychological function in patients rehabilitating from cancer treatment . A second purpose was to evaluate the differential effects of low- and moderate-intensity exercise on these variables . METHODS Eighteen survivors of breast or colon cancer ( 15 female and 3 male , 40 - 65 yr of age ) served as subjects . The subjects were matched by aerobic capacity and scores on a Quality of Life question naire , and then r and omly assigned to a control , low- ( 25 - 35 % heart rate reserve ( HRR ) ) , or a moderate- ( 40 - 50 % HRR ) intensity exercise group . The exercise groups performed lower-body aerobic exercise three times a week for 10 wk . After the exercise training , there were no statistically significant differences between the two exercise groups on any of the physiological variables . Therefore , the exercise groups were combined into one group for the final analysis . RESULTS The results revealed statistically significant increases in aerobic capacity ( P < 0.001 ) and lower-body flexibility ( P = 0.027 ) , a significant decrease in body fat ( P < 0.001 ) , and a significant increase in quality of life ( P < 0.001 ) and a measure of energy ( P = 0.038 ) in the exercise group when compared with the control group . CONCLUSION Low- and moderate-intensity aerobic-exercise programs were equally effective in improving physiological and psychological function in this population of cancer survivors . Aerobic exercise appears to be a valuable and well-tolerated component of the cancer-rehabilitation process PURPOSE The purpose of our study was to evaluate the effect of cognitive behavioral therapy ( CBT ) , physical exercise ( PE ) , and of these two interventions combined ( CBT/PE ) on menopausal symptoms ( primary outcome ) , body image , sexual functioning , psychological well-being , and health-related quality of life ( secondary outcomes ) in patients with breast cancer experiencing treatment-induced menopause . PATIENTS AND METHODS Patients with breast cancer reporting treatment-induced menopausal symptoms ( N=422 ) were r and omly assigned to CBT ( n=109 ) , PE ( n=104 ) , CBT/PE ( n=106 ) , or to a waiting list control group ( n=103 ) . Self-report question naires were completed at baseline , 12 weeks , and 6 months . Multilevel procedures were used to compare the intervention groups with the control group over time . RESULTS Compared with the control group , the intervention groups had a significant decrease in levels of endocrine symptoms ( Functional Assessment of Cancer Therapy-Endocrine Symptoms ; P<.001 ; effect size , 0.31 - 0.52 ) and urinary symptoms ( Bristol Female Lower Urinary Tract Symptoms Question naire ; P=.002 ; effect size , 0.29 - 0.33 ) , and they showed an improvement in physical functioning ( 36-Item Short Form Health Survey physical functioning subscale ; P=.002 ; effect size , 0.37 - 0.46 ) . The groups that included CBT also showed a significant decrease in the perceived burden of hot flashes and night sweats ( problem rating scale of the Hot Flush Rating Scale ; P<.001 ; effect size , 0.39 - 0.56 ) and an increase in sexual activity ( Sexual Activity Question naire habit subscale ; P=.027 ; effect size , 0.65 ) . Most of these effects were observed at both the 12-week and 6-month follow-ups . CONCLUSION CBT and PE can have salutary effects on endocrine symptoms and , to a lesser degree , on sexuality and physical functioning of patients with breast cancer experiencing treatment-induced menopause . Future work is needed to improve the design and the planning of these interventions to improve program adherence Few r and omized controlled trials have examined the effects of combined aerobic and resistance training in breast cancer survivors soon after completing adjuvant therapy . Breast cancer survivors ( N = 58 ) within 2 years of completing adjuvant therapy were r and omly assigned to an immediate exercise group ( IEG ; n = 29 ) or a delayed exercise group ( DEG ; n = 29 ) . The IEG completed 12 weeks of supervised aerobic and resistance exercise , three times per week . The DEG completed the program during the next 12 weeks . Participants completed patient-rated outcomes at baseline , 6 , 12 , 18 and 24 weeks . The primary endpoint was overall quality of life ( QoL ) measured by the Functional Assessment of Cancer Therapy-Breast scale . Secondary endpoints were fatigue , social physique anxiety , and physical fitness . Follow-up data was obtained on 97 % of participants and exercise adherence was 61.3 % . Repeated measures analyses of variance revealed a significant group by time interaction for overall QoL ( P < 0.001 ) . Specifically , QoL increased in the IEG from baseline to 12 weeks by 20.8 points compared to a decrease in the DEG of 5.3 points ( mean group difference = 26.1 ; 95 % CI = 18.3–32.7 ; P < 0.001 ) . From 12 to 24 weeks , QoL increased in the DEG by 29.5 points compared to an increase of 6.5 points in the IEG ( mean group difference = 23.0 ; 95 % CI = 16.3–29.1 ; P < 0.001 ) . Similar results were obtained for the secondary endpoints . Combined aerobic and resistance exercise soon after the completion of breast cancer therapy produces large and rapid improvements in health-related outcomes PURPOSE Self-directed and supervised exercise were compared with usual care in a clinical trial design ed to evaluate the effect of structured exercise on physical functioning and other dimensions of health-related quality of life in women with stages I and II breast cancer . PATIENTS AND METHODS One hundred twenty-three women with stages I and II breast cancer completed baseline evaluations of generic and disease- and site-specific health-related quality of life , aerobic capacity , and body weight . Participants were r and omly allocated to one of three intervention groups : usual care ( control group ) , self-directed exercise , or supervised exercise . Quality of life , aerobic capacity , and body weight measures were repeated at 26 weeks . The primary outcome was the change in the Short Form-36 physical functioning scale between baseline and 26 weeks . RESULTS Physical functioning in the control group decreased by 4.1 points , whereas it increased by 5.7 points and 2.2 points in the self-directed and supervised exercise groups , respectively ( P = .04 ) . Post hoc analysis showed a moderately large ( and clinical ly important ) difference between the self-directed and control groups ( 9.8 points ; P = .01 ) and a more modest difference between the supervised and control groups ( 6.3 points ; P = .09 ) . No significant differences between groups were observed for changes in quality of life scores . In a secondary analysis of participants stratified by type of adjuvant therapy , supervised exercise improved aerobic capacity ( + 3.5 mL/kg/min ; P = .01 ) and reduced body weight ( -4.8 kg ; P < .05 ) compared with usual care only in participants not receiving chemotherapy . CONCLUSION Physical exercise can blunt some of the negative side effects of breast cancer treatment , including reduced physical functioning . Self-directed exercise is an effective way to improve physical functioning compared with usual care . In participants not receiving chemotherapy , supervised exercise may increase aerobic capacity and reduce body weight compared with usual care Background Over the past years knowledge about benefits of physical activity after cancer is evolving from r and omized exercise intervention trials . However , it has been argued that results may be biased by selective participation . Therefore , we investigated factors influencing participation in a r and omized exercise intervention trial for breast cancer patients . Methods Non-metastatic breast cancer patients were systematic ally screened for a r and omized exercise intervention trial on cancer-related fatigue . Participants and non participants were compared concerning sociodemographic characteristics ( age , marital status , living status , travel time to the training facility ) , clinical data ( body-mass-index , tumor stage , tumor size and lymph node status , comorbidities , chemotherapy ) , fatigue , and physical activity . Reasons for participation or declination were recorded . Results 117 patients ( 52 participants , 65 non participants ) were evaluable for analysis . Multiple regression analyses revealed significantly higher odds to decline participation among patients with longer travel time ( p = 0.0012 ) , living alone ( p = 0.039 ) , with more comorbidities ( 0.031 ) , previous chemotherapy ( p = 0.0066 ) , of age ≥ 70 years ( p = 0.025 ) , or being free of fatigue ( p = 0.0007 ) . No associations were found with BMI or physical activity . By far the most frequently reported reason for declination of participation was too long commuting time to the training facility . Conclusions Willingness of breast cancer patients to participate in a r and omized exercise intervention study differed by sociodemographic factors and health status . Neither current physical activity level nor BMI appeared to be selective for participation . Reduction of personal inconveniences and time effort , e.g. by de central ized training facilities or flexible training schedules , seem most promising for enhancing participation in exercise intervention trials . Trial registration Registered at Clinical Trials.gov : NCT01468766 ( October 2011 ) BACKGROUND Lymphoma patients undergoing therapy must cope with the side-effects of the disease itself , therapy and associated immobility . Peripheral neuropathy ( PNP ) , loss of balance control and weakness not only diminishes patients ' quality of life ( QOL ) , it can also affect planning and the dosage of therapy . Exercise may enable patients to reverse these declines , improving their performance level and QOL . PATIENTS AND METHODS We carried out a r and omized , controlled trial , assigning 61 lymphoma patients either to a control group ( CG ; N=31 ) or to a 36-week intervention ( IG ; N=30 ) , consisting of sensorimotor- , endurance- and strength training twice a week . Primary end point was QOL ; secondary end points included movement coordination , endurance , strength and therapy-induced side-effects . RESULTS Intergroup comparison revealed improved QOL- ( ΔT1-T0 ; P=0.03 ) and PNP-related deep sensitivity in the IG : 87.5 % were able to reduce the symptom , compared with 0 % in the CG ( P<0.001 ) . Significant differences in the change of balance control could be found between the groups , with the IG improving while the CG steadily declined ( monopedal static ΔT3-T0 ; P=0.03 ; dynamic ΔT3-T0 ; P=0.007 ; perturbed mono-ΔT3-T0 ; P=0.009 and bipedal ΔT3-T0 ; P=0.006 ) , failed attempts ( monopedal static ΔT3-T0 ; P=0.02 , dynamic ΔT3-T0 ; P<0.001 and perturbed ΔT3-T0 ; P=0.006 ) and improved time to regain balance ( ΔT3-T0 ; P=0.04 ) . Moreover , the change in the aerobic performance level ( ΔT3-T0 ; P=0.05 ) and additional amount of exercise carried out per week [ metabolic equivalent ( MET ) ; P=0.02 ] differed significantly across groups . CONCLUSIONS Exercise , especially sensorimotor training , is a feasible and promising method to support cancer patients during therapy . It improves patients QOL , reduces restrictions from side-effects such as PNP and improves patients ' balance control , physical performance level and mobility . GERMAN CLINICAL TRIALS REGISTER NUMBER DRKS00003894 Multiple exercise interventions have shown beneficial effects on fatigue and quality of life ( QoL ) in cancer patients , but various psychosocial interventions as well . It is unclear to what extent the observed effects of exercise interventions are based on physical adaptations or rather on psychosocial factors associated with supervised , group-based programs . It needs to be determined which aspects of exercise programs are truly effective . Therefore , we aim ed to investigate whether resistance exercise during chemotherapy provides benefits on fatigue and QoL beyond potential psychosocial effects of group-based interventions . One-hundred-one breast cancer patients starting chemotherapy were r and omly assigned to resistance exercise ( EX ) or a relaxation control ( RC ) group . Both interventions were supervised , group-based , 2/week over 12 weeks . The primary endpoint fatigue was assessed with a 20-item multidimensional question naire , QoL with the EORTC QLQ-C30/BR23 . Analyses of covariance for individual changes from baseline to Week 13 were calculated . In RC , total and physical fatigue worsened during chemotherapy , whereas EX showed no such impairments ( between-group p = 0.098 and 0.052 overall , and p = 0.038 and 0.034 among patients without severe baseline depression ) . Differences regarding affective or cognitive fatigue were not significant . Benefits of EX were also seen to affect role and social function . Effect sizes were between 0.43 and 0.48 . Explorative analyses indicated significant effect modification by thyroxin use ( p-interaction = 0.044 ) . In conclusion , resistance exercise appeared to mitigate physical fatigue and maintain QoL during chemotherapy beyond psychosocial effects inherent to supervised group-based setting s. Thus , resistance exercise could be an integral part of supportive care for breast cancer patients undergoing chemotherapy Patients who undergo hematopoietic SCT ( HSCT ) often experience physical and psychological problems , even long after treatment has been completed . This study was performed to evaluate the effects of a 12-week outpatient physical exercise ( PE ) program , incorporating aerobic and strength exercises , as compared with a usual care control condition on patients ’ physical performance and psychosocial well-being . Patients who had completed HSCT up to 6 months earlier were r and omly assigned to a supervised PE program ( n=64 ) or a usual care control group ( n=67 ) . Primary outcomes were quantified physical performance and self-reported physical functioning . Secondary outcomes were body composition measurement , quantified walking activity and patient-reported outcomes ( physical activity , fatigue and health-related quality of life ) . Assessment s were at baseline , immediately after program completion and at 3-month follow-up . Significant intervention effects were observed at both posttreatment and follow-up on physical performance measures . No other outcomes yielded statistically significant group differences . PE should be considered in the management of HSCT recipients to improve physical performance after discharge from the hospital . Further research is needed to determine how the program can be enhanced so that improved physical performance also translates into improved physical and psychosocial functioning in daily life BACKGROUND Concurrent chemoradiotherapy ( concurrent CRT ) to treat head and neck cancer is associated with significant reductions of weight , mobility , and quality of life ( QOL ) . An intervention focusing on functional exercise may attenuate these losses . METHODS We allocated patients to a 14-week functional resistance and walking program design ed to maintain physical activity during cancer treatment ( MPACT group ; n = 11 ) , or to usual care ( control group ; n = 9 ) . Outcomes were assessed at baseline , and 7 and 14 weeks . RESULTS Compared to controls , the MPACT participants had attenuated decline or improvement in several strength , mobility , physical activity , diet , and QOL endpoints . These trends were statistically significant ( p < .05 ) in knee strength , mental health , head and neck QOL , and barriers to exercise . CONCLUSION In this pilot study of patients with head and neck cancer undergoing concurrent CRT , MPACT training was feasible and maintained or improved function and QOL , thereby providing the basis for larger future interventions with longer follow-up . © 2015 Wiley Periodicals , Inc. Head Neck 38 : E1086-E1096 , 2016 BACKGROUND Exercise has been reported to decrease cancer-related fatigue and to increase quality of life ( QoL ) in various breast cancer ( BC ) population s. However , studies investigating exercise during radiotherapy or resistance training are scarce . We conducted a r and omized , controlled trial ( BEST study ) to assess the efficacy of 12-week resistance training on fatigue beyond possible psychosocial effects of a group-based intervention . PATIENTS AND METHODS One hundred sixty patients with BC stage 0-III were r and omly assigned to a 12-week progressive resistance training ( 2 times/week ) or a 12-week relaxation control ( RC , 2 times/week ) . Both interventions were group-based . The primary end point fatigue was assessed with a 20-item multidimensional question naire , QoL with EORTC question naires . Statistical analyses were based on analysis of covariance models for the individual changes from baseline to week 13 . RESULTS Adherence to the intervention program as well as the completion rate ( 97 % ) for the primary outcome variable fatigue was high . In intention-to-treat analyses for the N = 155 patients , significant between-group mean differences ( MD ) favoring the exercise group ( EX ) were observed for general fatigue ( P = 0.044 ) , especially for the subscale physical fatigue [ MD = -0.8 ; 95 % confidence interval -1.5 to -0.2 , P = 0.013 ] , but not for affective ( P = 0.91 ) or cognitive fatigue ( P = 0.65 ) . For QoL , significantly larger improvements regarding the role function ( P = 0.035 ) and pain ( P = 0.040 ) were noted among exercisers compared with RCs . Future perspective improved significantly stronger in the RC group compared with the EX group ( P = 0.047 ) . CONCLUSIONS The 12-week resistance training program was a safe , feasible and efficacious strategy to improve cancer-related fatigue and components of QoL in BC patients during adjuvant radiotherapy . As exercise was compared with another group-based intervention , results indicate that resistance training effects on fatigue and QoL go beyond psychosocial benefits , and that the clinical ly relevant overall benefit of resistance exercise compared with usual care can be assumed to be higher . TRIAL REGISTRATION Clinical Trials.gov NCT01468766 Introduction Older breast cancer survivors ( BCS ) report more falls and functional limitations than women with no cancer history . Exercise training could reduce risk factors for future falls and disability . Methods We conducted a r and omized , controlled trial in 106 early-stage , postmenopausal BCS who were ≥50 years old at diagnosis and post-treatment . Women were r and omly assigned to a 1-year resistance + impact exercise program or a stretching placebo program . Endpoints were one repetition maximum bench press and leg press strength , timed five chair st and s , 4 m usual walk speed , timed stance tests , h and grip strength , self-report physical function , and fatigue . We also examined the influence of age , adjuvant hormone therapy use , and exercise adherence on study outcomes . Results Women in the resistance + impact training program significantly improved maximal leg ( p < 0 .02 ) and bench ( p < 0 .02 ) press strength compared to the stretching group . Women who attended 50 % or more of prescribed resistance training sessions had significantly better changes in maximal strength measures compared to less adherent women . Conclusions Resistance + impact exercise is superior to stretching at improving maximal muscle strength and exercise adherence contributes to the degree of improvement . Implication s for cancer survivorsOlder BCS can safely engage in resistance exercise that improves lower and upper body strength , thereby reducing a risk factor for falls and future disability . However , the ability of resistance training to shift other indices of fall and disability risk , i.e. , balance and function , is unclear . Strategies to promote adherence to resistance training could lead to greater improvements in strength Summary Our r and omized controlled trial in prematurely menopausal breast cancer survivors showed that impact + resistance training prevented increases in percentage of body fat compared with controls and also improved BMD at the hip and prevented BMD loss at the spine among exercise-trained women who were menopausal for > 1 year . Introduction Cancer treatment-related menopause worsens bone health and body composition in breast cancer survivors ( BCS ) . We investigated whether impact + resistance training could improve bone mineral density ( BMD ) , reduce bone turnover , build muscle , and decrease fat mass in BCS with premature menopause . Methods We conducted a r and omized controlled trial in 71 BCS ( mean age , 46.5 years ) within 5 years of treatment-related menopause . Women were r and omly assigned to one of two groups : ( 1 ) impact + resistance training ( prevent osteoporosis with impact + resistance ( POWIR ) ) or ( 2 ) exercise placebo ( FLEX ) 3 × /week for 1 year . Outcomes were hip and spine BMD ( in grams per square centimeter ) and body composition ( percent body fat ( % BF ) and lean and fat mass ( in kilograms ) ) by DXA and bone turnover markers ( serum osteocalcin ( in nanograms per milliliter ) and urinary deoxypryrodinoline ( in nanomoles per milliliter ) . Results There were no significant group × time interactions for bone outcomes when using an intent-to-treat approach on the full sample . In analyses restricted to BCS who were menopausal for ≥1 year , POWIR increased BMD at the hip and slowed BMD loss at the spine compared with FLEX ( femoral neck — POWIR , 0.004 ± 0.093 g/cm2 vs. FLEX , −0.010 ± 0.089 g/cm2 ; p < 0.01 ; spine — POWIR , −0.003 ± 0.114 g/cm2 vs. FLEX , −0.020 ± 0.110 g/cm2 ; p = 0.03 ) . POWIR prevented increases in % BF ( POWIR , 0.01 % vs. FLEX , 1.3 % ; p < 0.04 ) . Women with attendance to POWIR at ≥64 % had better improvements in % BF than women attending less often ( p < 0.03 ) . Conclusion Impact + resistance training may effectively combat bone loss and worsening body composition from premature menopause in BCS Purpose 1 ) To determine the effect of a home-based walking exercise program on the sleep quality and quality of life of cancer patients , as well as 2 ) to determine if enhanced sleep quality was associated with improvement in quality of life over time . Methods This is a prospect i ve , longitudinal , two-armed , r and omized clinical trial . Participants were recruited from oncology outpatient clinics in two university-based medical centers and were allocated to either usual care ( n = 35 ) or a home-based walking exercise intervention for 8 weeks ( n = 36 ) . Measurements included the Taiwanese version of the Pittsburgh Sleep Quality Index , the Medical Outcomes Study Short Form-36 , the Taiwanese Version Ratings of the Perceived Exertion Scale , and a walking exercise log . This study was analyzed on an intention-to-treat basis . Effects of the walking exercise program on sleep quality and quality of life were analyzed by the generalized estimating equation method . Results Patients in the exercise group reported significant improvements in sleep quality ( β = −3.54 , p < 0.01 ) and the mental health dimension of quality of life ( β = 10.48 , p < 0.01 ) . Among patients who exercised , enhanced sleep quality also corresponded with reduced bodily pain ( β = 0.98 , p = 0.04 ) and improvements over time in the mental health dimension of quality of life ( β = −3.87 , p < 0.01 ) . Conclusions A home-based walking exercise program can be easily incorporated into care for cancer patients who are suffering from sleep disturbances Purpose This study aims to evaluate the feasibility and efficacy of an 8-week supervised exercise program in de-conditioned cancer survivors within 2–6 months of chemotherapy completion . Methods Participants were r and omly assigned to an 8-week , twice-weekly , supervised aerobic exercise training regime ( n = 23 ) or a usual care group ( n = 20 ) . Feasibility was assessed by recruitment rate , program adherence and participant feedback . The primary outcome was aerobic fitness assessed by the Modified Bruce fitness test at baseline ( 0 weeks ) , post-intervention ( 8 weeks ) and at 3-month follow-up . Secondary outcomes included physical activity , waist circumference , fatigue and quality of life . Results The recruitment rate was 81 % and adherence to the supervised exercise was 78.3 % . Meaningful differences in aerobic fitness between the exercise and usual care groups at both the 8-week [ mean 3.0 mL kg−1 min−1 ( 95 % CI −1.1–7.0 ) ] and 3-month follow-up [ 2.1 mL kg−1 min−1 ( −2.3–6.6 ) ] were found , although these differences did not achieve statistical significance ( p values > 0.14 ) . Self-reported physical activity increased in the exercise group ( EG ) compared to the usual care group at both 8-week ( p = 0.01 ) and 3-month follow-up ( p = 0.03 ) and significant differences in favour of the EG were found for physical well-being at both the 8-week ( p = 0.03 ) and 3-month follow-up ( p = 0.04 ) . Improvements in fatigue ( p = 0.01 ) , total quality of life plus fatigue ( p = 0.04 ) , and a composite physical functioning score ( p = 0.01 ) at the 3-month follow-up were also found . Conclusion The PEACH trial suggests that 8 weeks of supervised aerobic exercise training was feasible and may improve aerobic fitness , fatigue and quality of life in de-conditioned cancer survivors during the early survivorship phase . Implication s for Cancer SurvivorsExercise interventions commenced in the early survivorship phase appear safe , feasible and may lead to improvements in QOL and fatigue Purpose This r and omized controlled trial tested the effects of a specially design ed strength and endurance training on the independence and quality of life in lung cancer patients in stages IIIA/IIIB/IV during palliative chemotherapy . Methods Between August 2010 and December 2011 , 46 patients were r and omized into two groups receiving either conventional physiotherapy or special physiotherapeutic training . The Barthel Index served as primary endpoint . The secondary endpoints were the European Organization for Research and Treatment of Cancer Quality of Life Question naire Core-30 ( EORTC QLQ C-30/LC-13 ) question naire , the 6-Minute Walk Test ( 6MWT ) , stair walking , the Modified Borg Scale , and muscle strength . Nonparametrical data were analyzed with the Wilcoxon and Mann – Whitney U test . For parametric , data student t tests were used . A p value of ≤.05 was accepted . Results Twenty-nine patients completed the trial ( Intervention group ( IG ) , n = 18 ; control group ( CG ) , n = 11 ) . Significant differences were detectable in the Barthel Index ( IGmean = 92.08 ; CGmean = 81.67 ; p = .041 ) , in single scores of the EORTC QLQ C-30/LC-13 question naire ( physical functioning , p = .025 ; hemoptysis , p = .019 ; pain in arms or shoulder , p = .048 ; peripheral neuropathy , p = .050 ; cognitive functioning , p = .050 ) , in the 6MWT , stair walking , strength capacity , and in the patient ’s dyspnoea perception during submaximal walking activities ( IG > CG ) . Conclusion According to these findings , lung cancer patients should receive enhanced physical activity intervention during palliative chemotherapy Abstract Background . Physical activity during chemotherapy has been shown in several studies to reduce fatigue , improve symptoms and impact positively on health-related quality of life ( HRQoL ) . Challenges associated with intervention studies on physical activity during cancer treatment relate to consistent adherence . The primary objective was to study feasibility and adherence of physical activity intervention among patients with cancer during adjuvant chemotherapy treatment . The secondary objective was to investigate the effects of physical activity on health aspects , including HRQoL , symptoms and surrogate markers for cardiovascular disease . Material and methods . This r and omized controlled trial included patients with breast cancer ( BRCA ) and colorectal cancer ( CRC ) during adjuvant chemotherapy . The intervention continued for 10 weeks and included daily walks of 10 000 steps and a weekly supervised group walk . Adherence was assessed by a pedometer and the number of participants who reported step counts every week and percentage of participants who achieved the target steps every week . Results . Adherence average reached 91 % during the intervention period ; in total 74 % completed the exercise intervention . The majority of the participants achieved an average of 83 % of the target of 10 000 steps per day for 10 weeks . There was a significant increase in daily physical activity ( p = 0.016 ) in the intervention group . Significant differences were also found for some breast cancer-specific symptoms [ swelling , mobility and pain ( p = 0.045 ) ] . The study showed a relatively small weight gain an average of 0.9 kg in the intervention group and 1.3 kg in the control group . Conclusion . Physical activity in the form of walking is feasible during adjuvant chemotherapy treatment despite increasing symptoms . The physical activity increased in the intervention group during the study time and had a positive impact on breast symptoms and the weight gain was lower in comparison to previous studies Exercise for Health was a r and omized , controlled trial design ed to evaluate two modes of delivering ( face-to-face [ FtF ] and over-the-telephone [ Tel ] ) an 8-month translational exercise intervention , commencing 6-weeks post-breast cancer surgery ( PS ) . Outcomes included quality of life ( QoL ) , function ( fitness and upper body ) and treatment-related side effects ( fatigue , lymphoedema , body mass index , menopausal symptoms , anxiety , depression and pain ) . Generalised estimating equation modelling determined time ( baseline [ 5 weeks PS ] , mid-intervention [ 6 months PS ] , post-intervention [ 12 months PS ] ) , group ( FtF , Tel , Usual Care [ UC ] ) and time-by-group effects . 194 women representative of the breast cancer population were r and omised to the FtF ( n = 67 ) , Tel ( n = 67 ) and UC ( n = 60 ) groups . There were significant ( p < 0.05 ) interaction effects on QoL , fitness and fatigue with differences being observed between the treatment groups and the UC group . Trends observed for the treatment groups were similar . The treatment groups reported improved QoL , fitness and fatigue over time and changes observed between baseline and post-intervention were clinical ly relevant . In contrast , the UC group experienced no change , or worsening QoL , fitness and fatigue , mid-intervention . Although improvements in the UC group occurred by 12-months post-surgery , the change did not meet the clinical ly relevant threshold . There were no differences in other treatment-related side effects between groups . This translational intervention trial , delivered either FtF or Tel , supports exercise as a form of adjuvant breast cancer therapy that can prevent declines in fitness and function during treatment and optimise recovery post-treatment Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more OBJECTIVE To determine the effect of exercise on quality of life in ( a ) a r and omized controlled trial of exercise among recently diagnosed breast cancer survivors undergoing adjuvant therapy and ( b ) a similar trial among post-treatment survivors . METHODS Fifty newly diagnosed breast cancer survivors were recruited through a hospital-based tumor registry and r and omized to a 6-month , home-based exercise program ( n=25 ) or a usual care group ( n=25 ) . In a separate trial , 75 post-treatment survivors were r and omized to a 6-month , supervised exercise intervention ( n=37 ) or to usual care ( n=38 ) . Participants in both studies completed measures of happiness , depressive symptoms , anxiety , stress , self-esteem , and quality of life at baseline and 6 months . RESULTS Forty-five participants completed the trial for newly diagnosed survivors and 67 completed the trial for post-treatment survivors . Good adherence was observed in both studies . Baseline quality of life was similar for both studies on most measures . Exercise was not associated with quality of life benefits in the full sample of either study ; however exercise was associated with improved social functioning among post-treatment survivors who reported low social functioning at baseline ( p<0.05 ) . CONCLUSIONS Exercise did not affect quality of life in either recently diagnosed or post-treatment breast cancer survivors ; however this may be due in part to relatively high baseline functioning among participants in both studies . Strategies for future research include limiting enrollment to survivors who report reduced quality of life on screening question naires and targeting survivor subgroups known to be at particular risk for quality of life impairment Background : High insulin and insulin-like growth factor-I ( IGF-I ) levels may be associated with an increased breast cancer risk and /or death . Given the need to identify modifiable factors that decrease insulin , IGF-I , and breast cancer risk and death , we investigated the effects of a 6-month r and omized controlled aerobic exercise intervention versus usual care on fasting insulin , IGF-I , and its binding protein ( IGFBP-3 ) in postmenopausal breast cancer survivors . Methods : Seventy-five postmenopausal breast cancer survivors were identified from the Yale-New Haven Hospital Tumor Registry and r and omly assigned to an exercise ( n = 37 ) or usual care ( n = 38 ) group . The exercise group participated in 150 minutes per week of moderate-intensity aerobic exercise . The usual care group was instructed to maintain their current physical activity level . A fasting blood sample was collected on each study participant at baseline and 6 months . Blood levels of insulin and IGF were measured with ELISA . Results : On average , exercisers increased aerobic exercise by 129 minutes per week compared with 45 minutes per week among usual care participants ( P < 0.001 ) . Women r and omized to exercise experienced decreases in insulin , IGF-I , and IGFBP-3 , whereas women r and omized to usual care had increases in these hormones . Between-group differences in insulin , IGF-I , and IGFBP-3 were 20.7 % ( P = 0.089 ) , 8.9 % ( P = 0.026 ) , and 7.9 % ( P = 0.006 ) , respectively . Conclusions : Moderate-intensity aerobic exercise , such as brisk walking , decreases IGF-I and IGFBP-3 . The exercise-induced decreases in IGF may mediate the observed association between higher levels of physical activity and improved survival in women diagnosed with breast cancer . ( Cancer Epidemiol Biomarkers Prev 2009;18(1):306–13 BACKGROUND Participation in physical activity can improve the health outcomes of breast cancer survivors . To impact public health , broad-reaching sustainable interventions that promote physical activity are needed . PURPOSE To evaluate the efficacy of two distance-based interventions for promoting physical activity among breast cancer survivors compared with a st and ard recommendation control . METHODS Breast cancer survivors who had finished ' active ' cancer treatment were eligible to participate . Participants ( n = 330 ) were r and omly assigned to receive one of the following mail-delivered interventions : three computer-tailored newsletters , a previously developed breast cancer-specific physical activity booklet or a pamphlet detailing the public health recommendations for physical activity ( control ) . Primary outcomes were self-reported moderate to vigorous aerobic activity and participant 's self-reported resistance training activity at 4 months post-baseline . Secondary outcomes were pedometer step counts , whether or not participants were meeting the physical activity guidelines , time spent in sedentary behaviour , fatigue and health-related quality of life . RESULTS Participants r and omised into the tailored-print intervention group were three times more likely to commence resistance training and meet the resistance-training guidelines immediately after the intervention than participants allocated to the control group . There were no other significant intervention effects . CONCLUSION Computer-tailored newsletters may be an effective strategy for enhancing resistance-based physical activity among breast cancer survivors . The null findings relating to other outcomes may be due to ceiling effects ( in the case of aerobic activity , fatigue and health-related quality of life ) or the sensitivity of the measure used ( in the case of sitting time ) . These issues require further exploration PURPOSE We evaluated the effectiveness of a low-intensity , home-based physical activity program ( Onco-Move ) and a moderate- to high-intensity , combined supervised resistance and aerobic exercise program ( OnTrack ) versus usual care ( UC ) in maintaining or enhancing physical fitness , minimizing fatigue , enhancing health-related quality of life , and optimizing chemotherapy completion rates in patients undergoing adjuvant chemotherapy for breast cancer . PATIENTS AND METHODS We r and omly assigned patients who were scheduled to undergo adjuvant chemotherapy ( N = 230 ) to Onco-Move , OnTrack , or UC . Performance-based and self-reported outcomes were assessed before r and om assignment , at the end of chemotherapy , and at the 6-month follow-up . We used generalized estimating equations to compare the groups over time . RESULTS Onco-Move and OnTrack result ed in less decline in cardiorespiratory fitness ( P < .001 ) , better physical functioning ( P ≤ .001 ) , less nausea and vomiting ( P = .029 and .031 , respectively ) and less pain ( P = .003 and .011 , respectively ) compared with UC . OnTrack also result ed in better outcomes for muscle strength ( P = .002 ) and physical fatigue ( P < .001 ) . At the 6-month follow-up , most outcomes returned to baseline levels for all three groups . A smaller percentage of participants in OnTrack required chemotherapy dose adjustments than those in the UC or Onco-Move groups ( P = .002 ) . Both intervention groups returned earlier ( P = .012 ) , as well as for more hours per week ( P = .014 ) , to work than the control group . CONCLUSION A supervised , moderate- to high-intensity , combined resistance and aerobic exercise program is most effective for patients with breast cancer undergoing adjuvant chemotherapy . A home-based , low-intensity physical activity program represents a viable alternative for women who are unable or unwilling to follow the higher intensity program Objectives To determine functional and psychological benefits of a 12 week supervised group exercise programme during treatment for early stage breast cancer , with six month follow-up . Design Pragmatic r and omised controlled prospect i ve open trial . Setting Three National Health Service oncology clinics in Scotl and and community exercise facilities . Participants 203 women entered the study ; 177 completed the six month follow-up . Interventions Supervised 12 week group exercise programme in addition to usual care , compared with usual care . Main outcome measures Functional assessment of cancer therapy ( FACT ) question naire , Beck depression inventory , positive and negative affect scale , body mass index , seven day recall of physical activity , 12 minute walk test , and assessment of shoulder mobility . Results Mixed effects models with adjustment for baseline values , study site , treatment at baseline , and age gave intervention effect estimates ( intervention minus control ) at 12 weeks of 129 ( 95 % confidence interval 83 to 176 ) for metres walked in 12 minutes , 182 ( 75 to 289 ) for minutes of moderate intensity activity reported in a week , 2.6 ( 1.6 to 3.7 ) for shoulder mobility , 2.5 ( 1.0 to 3.9 ) for breast cancer specific subscale of quality of life , and 4.0 ( 1.8 to 6.3 ) for positive mood . No significant effect was seen for general quality of life ( FACT-G ) , which was the primary outcome . At the six month follow-up , most of these effects were maintained and an intervention effect for breast cancer specific quality of life emerged . No adverse effects were noted . Conclusion Supervised group exercise provided functional and psychological benefit after a 12 week intervention and six months later . Clinicians should encourage activity for their patients . Policy makers should consider the inclusion of exercise opportunities in cancer rehabilitation services . Trial registration Current controlled trials IS RCT N12587864 Patients with head and neck cancer experience loss of weight and muscle mass , decreased functioning , malnutrition , depression , and declines in quality of life during and after treatment . The purpose of this exploratory r and omized study was to determine the optimal timing for the initiation of a lifestyle and progressive resistance exercise training intervention ( during or after radiation therapy ) , as determined by intervention adherence and by comparing between‐group outcomes across 24 weeks BACKGROUND The efficacy of a home-based physical activity ( PA ) intervention for colorectal cancer patients versus contact control was evaluated in a r and omized controlled trial . METHODS Forty-six patients ( mean age = 57.3 years [ SD = 9.7 ] , 57 % female , mean = 2.99 years post-diagnosis [ SD = 1.64 ] ) who had completed treatment for stages 1 - 3 colorectal cancer were r and omized to telephone counseling to support PA ( PA group , n = 20 ) or contact control ( control group , n = 26 ) . PA group participants received 3 months of PA counseling ( based on the transtheoretical model and the social cognitive theory ) delivered via telephone , as well as weekly PA tip sheets . Assessment s of PA ( Seven-day Physical Activity Recall [ 7-day PAR ] and Community Healthy Activities Model Program for Seniors [ CHAMPS ] ) , submaximal aerobic fitness ( Treadwalk test ) , motivational readiness for PA , and psychosocial outcomes were conducted at baseline , 3 , 6 , and 12 months post-baseline . Objective accelerometer data were collected at the same time points . RESULTS The PA group reported significant increases in minutes of PA at 3 months ( 7-day PAR ) and caloric expenditure ( CHAMPS ) compared with the control group , but the group differences were attenuated over time . The PA group showed significant improvements in fitness at 3 , 6 , and 12 months versus the control group . Improvements in motivational readiness for PA were reported in the PA group only at 3 months . No significant group differences were found for fatigue , self-reported physical functioning , and quality of life at 3 , 6 , and 12 months . CONCLUSION A home-based intervention improved survivors ' PA and motivational readiness at 3 months and increased submaximal aerobic fitness at 3 , 6 , and 12 months PURPOSE To examine the effects of aerobic exercise therapy on quality of life ( QoL ) and associated outcomes in women treated for breast cancer . Evidence suggests that exercise may be beneficial , but no trial has included an exercise-placebo and a usual-care group to control for the attention effects that might be associated with aerobic exercise interventions in cancer patients . PATIENTS AND METHODS A total of 108 women who had been treated for breast cancer 12 to 36 months previously were r and omly assigned to supervised aerobic exercise therapy ( n = 34 ) , exercise-placebo ( body conditioning ; n = 36 ) , or usual care ( n = 38 ) . Exercise therapy and exercise-placebo sessions took place three times per week for 8 weeks . Outcomes included QoL , depression , exercise behavior , aerobic fitness ; outcomes were assessed at baseline and at the 8- and 24-week follow-up . RESULTS Analyses of covariance revealed a significant mean difference of 9.8 units in Functional Assessment of Cancer Therapy-General ( primary outcome ) favoring aerobic exercise therapy at 8 weeks , relative to usual care . Significant differences that favored aerobic exercise therapy relative to usual care were recorded for Functional Assessment of Cancer Therapy-Breast , social/family well-being , functional well-being , and breast cancer subscale scores at 8-week follow-up . Psychological health outcomes improved modestly for both intervention groups ; these improvements were sustained for several end points . CONCLUSION Exercise therapy had large , clinical ly meaningful , short-term beneficial effects on QoL in women treated for breast cancer ; this finding can not be attributable to attention , given that the exercise-placebo group did not report similar effects relative to usual care PURPOSE To determine the effects of exercise training on cardiopulmonary function and quality of life ( QOL ) in postmenopausal breast cancer survivors who had completed surgery , radiotherapy , and /or chemotherapy with or without current hormone therapy use . METHODS Fifty-three postmenopausal breast cancer survivors were r and omly assigned to an exercise ( n = 25 ) or control ( n = 28 ) group . The exercise group trained on cycle ergometers three times per week for 15 weeks at a power output that elicited the ventilatory equivalent for carbon dioxide . The control group did not train . The primary outcomes were changes in peak oxygen consumption and overall QOL from baseline to postintervention . Peak oxygen consumption was assessed by a grade d exercise test using gas exchange analysis . Overall QOL was assessed by the Functional Assessment of Cancer Therapy-Breast scale . RESULTS Fifty-two participants completed the trial . The exercise group completed 98.4 % of the exercise sessions . Baseline values for peak oxygen consumption ( P = .254 ) and overall QOL ( P = .286 ) did not differ between groups . Peak oxygen consumption increased by 0.24 L/min in the exercise group , whereas it decreased by 0.05 L/min in the control group ( mean difference , 0.29 L/min ; 95 % confidence interval [ CI ] , 0.18 to 0.40 ; P < .001 ) . Overall QOL increased by 9.1 points in the exercise group compared with 0.3 points in the control group ( mean difference , 8.8 points ; 95 % CI , 3.6 to 14.0 ; P = .001 ) . Pearson correlations indicated that change in peak oxygen consumption correlated with change in overall QOL ( r = 0.45 ; P < .01 ) . CONCLUSION Exercise training had beneficial effects on cardiopulmonary function and QOL in postmenopausal breast cancer survivors The aim of this study was to explore the effects of exercise on angiogenesis and apoptosis-related molecules , quality of life , fatigue and depression in patients who completed breast cancer treatment . Sixty breast cancer patients were r and omised into three groups , as supervised exercise group , home exercise group and education group . Angiogenesis and apoptosis-related cytokine levels and quality of life ( EORTC QOL-C30 : European Organisation for Research and Treatment of Cancer Quality of Life C30 ) , fatigue ( Brief Fatigue Inventory ) and depression ( BDI : Beck Depression Inventory ) scores were compared before and after a 12-week exercise programme . After the exercise programme , statistically significant decreases were found in interleukin-8 and neutrophil activating protein-78 levels in the home exercise group ( P < 0.05 ) . The education group showed a statistically significant increase in monocyte chemoattractant protein-1 level ( P < 0.05 ) . Functional score and global health score of EORTC QOL-C30 in the supervised exercise group and functional score of EORTC QOL-C30 in the home exercise group increased significantly after exercise programme ( P < 0.05 ) . BDI score was significantly lower in the supervised exercise group after the exercise programme ( P < 0.05 ) . Changes in angiogenesis and apoptosis-related molecules in the study groups suggest a possible effect of exercise on these parameters . Exercise programmes are safe and effective on quality of life and depression in breast cancer patients whose treatments are complete PURPOSE Breast cancer chemotherapy may cause unfavorable changes in physical functioning , body composition , psychosocial functioning , and quality of life ( QOL ) . We evaluated the relative merits of aerobic and resistance exercise in blunting these effects . PATIENTS AND METHODS We conducted a multicenter r and omized controlled trial in Canada between 2003 and 2005 that r and omly assigned 242 breast cancer patients initiating adjuvant chemotherapy to usual care ( n = 82 ) , supervised resistance exercise ( n = 82 ) , or supervised aerobic exercise ( n = 78 ) for the duration of their chemotherapy ( median , 17 weeks ; 95 % CI , 9 to 24 weeks ) . Our primary end point was cancer-specific QOL assessed by the Functional Assessment of Cancer Therapy-Anemia scale . Secondary end points were fatigue , psychosocial functioning , physical fitness , body composition , chemotherapy completion rate , and lymphedema . RESULTS The follow-up assessment rate for our primary end point was 92.1 % , and adherence to the supervised exercise was 70.2 % . Unadjusted and adjusted mixed-model analyses indicated that aerobic exercise was superior to usual care for improving self-esteem ( P = .015 ) , aerobic fitness ( P = .006 ) , and percent body fat ( adjusted P = .076 ) . Resistance exercise was superior to usual care for improving self-esteem ( P = .018 ) , muscular strength ( P < .001 ) , lean body mass ( P = .015 ) , and chemotherapy completion rate ( P = .033 ) . Changes in cancer-specific QOL , fatigue , depression , and anxiety favored the exercise groups but did not reach statistical significance . Exercise did not cause lymphedema or adverse events . CONCLUSION Neither aerobic nor resistance exercise significantly improved cancer-specific QOL in breast cancer patients receiving chemotherapy , but they did improve self-esteem , physical fitness , body composition , and chemotherapy completion rate without causing lymphedema or significant adverse events PURPOSE Despite the recognition of fatigue as a common and distressing symptom during cancer treatment , there are few evidence -based interventions available to manage such fatigue . The purpose of this multi-institutional pilot study was to explore the effects of a home-based moderate walking exercise intervention on fatigue , physical functioning , emotional distress , and quality of life ( QOL ) during breast cancer treatment . DESCRIPTION OF STUDY Fifty-two women were recruited from five university hospital outpatient departments for this pilot study with an experimental design . Subjects were r and omly assigned to the walking program or to usual care during adjuvant chemotherapy or radiation therapy for breast cancer . Symptoms , physical functioning , and QOL were measured at baseline , midtreatment , and at the end of treatment . RESULTS Women who exercised at least 90 minutes per week on 3 or more days reported significantly less fatigue and emotional distress as well as higher functional ability and QOL than women who were less active during treatment . CLINICAL IMPLICATION S A home-based walking exercise program is a potentially effective , low-cost , and safe intervention to manage fatigue and to improve QOL during adjuvant chemotherapy or radiation therapy for breast cancer . This health-promoting self-care activity needs further testing in large r and omized clinical trials Objective To assess the effect of a multimodal group exercise intervention , as an adjunct to conventional care , on fatigue , physical capacity , general wellbeing , physical activity , and quality of life in patients with cancer who were undergoing adjuvant chemotherapy or treatment for advanced disease . Design R and omised controlled trial . Setting Two university hospitals in Copenhagen , Denmark . Participants 269 patients with cancer ; 73 men , 196 women , mean age 47 years ( range 20 - 65 ) representing 21 diagnoses . Main exclusion criteria were brain or bone metastases . 235 patients completed follow-up . Intervention Supervised exercise comprising high intensity cardiovascular and resistance training , relaxation and body awareness training , massage , nine hours weekly for six weeks in addition to conventional care , compared with conventional care . Main outcome measures European Organization for Research and Treatment of Cancer Quality of Life Question naire ( EORTC QLQ-C30 ) , Medical Outcomes Study Short Form ( MOS SF-36 ) , Leisure Time Physical Activity Question naire , muscular strength ( one repetition maximum ) , maximum oxygen consumption ( Vo2max ) . Statistical methods The general linear model was used for continuous outcome while analysis of associates between categorical outcomes was performed as analysis of marginal homogeneity in contingency tables . Results Adjusted for baseline score , disease , and demographic covariates , the intervention group showed an estimated improvement at six weeks for the primary outcome , fatigue , of −6.6 points ( 95 % confidence interval −12.3 to −0.9 , P=0.02 ; effect size=0.33 , 0.04 to 0.61 ) . Significant effects were seen on vitality ( effect size 0.55 , 95 % CI 0.27 to 0.82 ) , physical functioning ( 0.37 , 0.09 to 0.65 ) , role physical ( 0.37 , 0.10 to 0.64 ) , role emotional ( 0.32 , 0.05 to 0.59 ) , and mental health ( 0.28 , 0.02 to 0.56 ) scores . Improvement was noted in physical capacity : estimated mean difference between groups for maximum oxygen consumption was 0.16 l/min ( 95 % CI 0.1 to 0.2 , P<0.0001 ) and for muscular strength ( leg press ) was 29.7 kg ( 23.4 to 34.9 , P<0.0001 ) . No significant effect was seen on global health status/ quality of life . Conclusion A supervised multimodal exercise intervention including high and low intensity components was feasible and could safely be used in patients with various cancers who were receiving adjuvant chemotherapy or treatment for advanced disease . The intervention reduced fatigue and improved vitality , aerobic capacity , muscular strength , and physical and functional activity , and emotional wellbeing , but not quality of life . Trial registration Current Controlled trials IS RCT N05322922 Background International evidence -based guidelines recommend physical exercise to form part of st and ard care for all cancer survivors . However , at present , the optimum exercise intensity is unclear . Therefore , we aim ed to evaluate the effectiveness of a high intensity ( HI ) and low-to-moderate intensity ( LMI ) resistance and endurance exercise program compared with a wait list control ( WLC ) group on physical fitness and fatigue in a mixed group of cancer survivors who completed primary cancer treatment , including chemotherapy . Methods Overall , 277 cancer survivors were r and omized to 12 weeks of HI exercise ( n = 91 ) , LMI exercise ( n = 95 ) , or WLC ( n = 91 ) . Both interventions were identical with respect to exercise type , duration and frequency , and only differed in intensity . Measurements were performed at baseline ( 4–6 weeks after primary treatment ) and post-intervention . The primary outcomes were cardiorespiratory fitness ( peakVO2 ) , muscle strength ( grip strength and 30-second chair-st and test ) , and self-reported fatigue ( Multidimensional Fatigue Inventory ; MFI ) . Secondary outcomes included health-related quality of life , physical activity , daily functioning , body composition , mood , and sleep disturbances . Multilevel linear regression analyses were performed to estimate intervention effects using an intention-to-treat principle . Results In the HI and LMI groups , 74 % and 70 % of the participants attended more than 80 % of the prescribed exercise sessions , respectively ( P = 0.53 ) . HI ( β = 2.2 ; 95 % CI , 1.2–3.1 ) and LMI ( β = 1.3 ; 95 % CI , 0.3–2.3 ) exercise showed significantly larger improvements in peakVO2 compared to WLC . Improvements in peakVO2 were larger for HI than LMI exercise ( β = 0.9 ; 95 % CI , −0.1 to 1.9 ) , but the difference was not statistically significant ( P = 0.08 ) . No intervention effects were found for grip strength and the 30-second chair-st and test . HI and LMI exercise significantly reduced general and physical fatigue and reduced activity ( MFI subscales ) compared to WLC , with no significant differences between both interventions . Finally , compared to WLC , we found benefits in global quality of life and anxiety after HI exercise , improved physical functioning after HI and LMI exercise , and less problems at work after LMI exercise . Conclusions Shortly after completion of cancer treatment , both HI and LMI exercise were safe and effective . There may be a dose – response relationship between exercise intensity and peakVO2 , favoring HI exercise . HI and LMI exercise were equally effective in reducing general and physical fatigue . Trial registration This study was registered at the Netherl and s Trial Register [ NTR2153 ] on the 5th of January 2010 Background Exercise started shortly after breast cancer diagnosis might prevent or diminish fatigue complaints . The Physical Activity during Cancer Treatment ( PACT ) study was design ed to primarily examine the effects of an 18-week exercise intervention , offered in the daily clinical practice setting and starting within 6 weeks after diagnosis , on preventing an increase in fatigue . Methods This multi-centre controlled trial r and omly assigned 204 breast cancer patients to usual care ( n = 102 ) or supervised aerobic and resistance exercise ( n = 102 ) . By design , all patients received chemotherapy between baseline and 18 weeks . Fatigue ( i.e. , primary outcome at 18 weeks ) , quality of life , anxiety , depression , and physical fitness were measured at 18 and 36 weeks . Results Intention-to-treat mixed linear model analyses showed that physical fatigue increased significantly less during cancer treatment in the intervention group compared to control ( mean between-group differences at 18 weeks : −1.3 ; 95 % CI −2.5 to −0.1 ; effect size −0.30 ) . Results for general fatigue were comparable but did not reach statistical significance ( -1.0 , 95%CI -2.1 ; 0.1 ; effect size -0.23 ) . At 18 weeks , submaximal cardiorespiratory fitness and several muscle strength tests ( leg extension and flexion ) were significantly higher in the intervention group compared to control , whereas peak oxygen uptake did not differ between groups . At 36 weeks these differences were no longer statistically significant . Quality of life outcomes favoured the exercise group but were not significantly different between groups . Conclusions A supervised 18-week exercise programme offered early in routine care during adjuvant breast cancer treatment showed positive effects on physical fatigue , submaximal cardiorespiratory fitness , and muscle strength . Exercise early during treatment of breast cancer can be recommended . At 36 weeks , these effects were no longer statistically significant . This might have been caused by the control participants ’ high physical activity levels during follow-up . Trial registration Current Controlled Trials IS RCT N43801571 , Dutch Trial Register NTR2138 . Trial registered on December 9th , 2009 PURPOSE To examine the effect of a progressive upper-body exercise program on lymphedema secondary to breast cancer treatment . METHODS Fourteen breast cancer survivors with unilateral upper extremity lymphedema were r and omly assigned to an exercise ( n = 7 ) or control group ( n = 7 ) . The exercise group followed a progressive , 8-week upper-body exercise program consisting of resistance training plus aerobic exercise using a Monark Rehab Trainer arm ergometer . Lymphedema was assessed by arm circumference and measurement of arm volume by water displacement . Patients were evaluated on five occasions over the experimental period . The Medical Outcomes Trust Short-Form 36 Survey was used to measure quality of life before and after the intervention . Significance was set at alpha < or = 0.01 . RESULTS No changes were found in arm circumference or arm volume as a result of the exercise program . Three of the quality -of-life domains showed trends toward increases in the exercise group : physical functioning ( P = .050 ) , general health ( P = .048 ) , and vitality ( P = .023 ) . Mental health increased , although not significantly , for all subjects ( P = .019 ) . Arm volume measured by water displacement was correlated with calculated arm volume ( r = .973 , P < .001 ) , although the exercise and control group means were significantly different ( P < .001 ) . CONCLUSIONS Participation in an upper-body exercise program caused no changes in arm circumference or arm volume in women with lymphedema after breast cancer , and they may have experienced an increase in quality of life . Additional studies should be done in this area to determine the optimum training program Deterioration in exercise tolerance and impairment in quality of life ( QoL ) are common consequences of lobectomy . This study evaluates additional exercise and strength training after lung resection on QoL , exercise tolerance and muscle strength . Fifty-three ( 28 male ) patients attending thoracotomy for lung cancer , mean age , range 64 ( 32 - 82 ) years ; mean pack years ( SD ) 31.9 ( 26.8 ) ; BMI 25.6 ( 4.2 ) ; FEV1 2.0 ( 0.7 ) l were r and omised to control ( usual care ) or intervention ( twice daily training plus usual care ) . After discharge the intervention group received monthly home visits and weekly telephone calls , the control group received monthly telephone calls up to 12 weeks . Assessment pre-operatively , 5 day and 12 weeks post-operatively consisted of quadriceps strength using magnetic stimulation , 6 Minute Walking Distance ( 6MWD ) and QoL-EORTC-QLQ-LC13 . QoL was unchanged over 12 weeks ; 6MWD showed significant deterioration at 5 days post-operatively compared with pre-operatively , mean difference (SD)-131.6 ( 101.8 ) m and -128.0 ( 90.7 ) m in active and control groups respectively ( p=0.89 between groups ) which returned to pre-operative levels by 12 weeks in both groups . Quadriceps strength over the 5 day in-patient period showed a decrease of -8.3 ( 11.3 ) kg in the control group compared to increase of 4.0 ( 21.2 ) kg in the intervention group ( p=0.04 between groups ) . Strength training after thoracotomy successfully prevented the fall in quadriceps strength seen in controls , however , there was no effect on 6MWD or QoL. 6MWD returned to pre-operative levels by 12 weeks regardless of additional support offered Background Fatigue is the most common and disabling symptom affecting quality of life ( QOL ) and daily function in patients who have completed treatment for acute myeloid leukemia ( AML ) . Although trials in patients with various solid tumors have reported improved fatigue and QOL following exercise interventions , there have been no studies in AML patients post treatment . Methods Forty patients aged ≥40 years who had completed treatment for AML were enrolled in a 12-week r and omized phase II exercise intervention to determine feasibility ( recruitment , retention , and adherence ) , efficacy , and safety of the intervention . Patients assigned to the exercise group received an individualized , moderate-intensity , 12-week home-based exercise program with weekly telephone support from a certified exercise physiologist . QOL , fatigue , and fitness outcomes were measured at baseline , 6 weeks , and 12 weeks . Between-group differences in 12-week change scores were calculated using linear regression adjusting for age and baseline function . Results Recruitment and retention rates were 38 % and 91 % , respectively . Adherence was low at 28 % . Analyses did not suggest statistically significant or clinical ly important benefits in QOL , fatigue , or physical fitness with the intervention . The level of adherence did not appear to impact outcomes . There were no adverse events . Conclusion A home-based exercise program for post-treatment AML patients age 40 years or older can be safely delivered with reasonable recruitment and high retention . However , feasibility was hampered by low adherence . Further research and program modification are needed to better underst and and overcome barriers to exercise delivery and adherence in AML survivors Background : Resistance training ( RT ) improves muscular strength , physical functioning and quality of life in prostate cancer survivors , but the optimal frequency of RT is unknown . We conducted a pilot r and omized controlled trial to compare the effects of 3 versus 2 days per week of RT in prostate cancer survivors diagnosed within the past 2 years . Methods : Prostate cancer survivors ( N=30 ) were r and omized to 12 weeks of supervised RT performed either 3 days per week ( n=16 ) or 2 days per week ( n=14 ) . The primary outcome was muscular strength assessed by a multiple repetition maximum test at baseline and postintervention . Secondary outcomes were objective physical functioning , quality of life and psychosocial functioning . Results : A trend ( P<0.10 ) and /or potentially meaningful effects ( st and ardized effect size d⩾0.20 ) were found favoring 3 days per week over 2 days per week for the primary outcome of lower body strength ( mean difference=27.8 kg ; 95 % confidence interval=−0.9 to 56.5 ; P=0.057 ; d=0.72 ) and for the secondary outcomes of 30-s chair st and ( d=0.29 ; P=0.31 ) , sit and reach ( d=0.24 ; P=0.33 ) , 6 -min walk ( d=0.21 ; P=0.42 ) and the physical component summary ( d=0.21 ; P=0.41 ) . Conversely , a trend and /or potentially meaningful effects were found favoring 2 days per week over 3 days per week for the mental component summary ( d=−0.38 ; P=0.10 ) , mental health ( d=−0.44 ; P=0.11 ) , vitality ( d=−0.31 ; P=0.28 ) , role-emotional ( d=−0.23 ; P=0.43 ) , anxiety ( d=0.32 ; P=0.29 ) , happiness ( d=−0.31 ; P=0.36 ) and perceived stress ( d=0.23 ; P=0.39 ) . Conclusions : This pilot r and omized dose – comparison trial provides preliminary data to suggest that RT 3 days per week compared with 2 days per week may improve the strength and physical functioning in prostate cancer survivors , but may also blunt improvements in psychosocial functioning . Larger and more targeted phase II and III trials are needed to confirm the potentially complex effects of RT frequency in prostate cancer survivors OBJECTIVE To show fatigue prevention and quality of life ( QOL ) improvement from cardiovascular exercise during radiotherapy . DESIGN Prospect i ve enrollment ( n=21 ) , r and omized to exercise ( n=11 ) and control groups ( n=10 ) , with pre- and post-radiotherapy between- and within-group comparisons . SETTING Academic medical center . PARTICIPANTS Localized prostate cancer patients undergoing radiotherapy . INTERVENTIONS The interventional group received radiotherapy plus aerobic exercise 3 times a week for 8 weeks whereas the control group received radiotherapy without exercise . MAIN OUTCOME MEASURES Pre- and post-radiotherapy differences in cardiac fitness , fatigue , depression , functional status , physical , social , and functional well-being , leg strength , and flexibility were examined within and between 2 groups . RESULTS No significant differences existed between 2 groups at pre-radiotherapy assessment . At post-radiotherapy assessment , the exercise group showed significant within group improvements in : cardiac fitness ( P<.001 ) , fatigue ( P=.02 ) , Functional Assessment of Cancer Therapy-Prostate ( FACT-P ) ( P=.04 ) , physical well-being ( P=.002 ) , social well-being ( P=.02 ) , flexibility ( P=.006 ) , and leg strength ( P=.000 ) . Within the control group , there was a significant increase in fatigue score ( P=.004 ) and a decline in social well-being ( P<.05 ) at post-radiotherapy assessment . Between-group differences at post-radiotherapy assessment were significant in cardiac fitness ( P=.006 ) , strength ( P=.000 ) , flexibility ( P<.01 ) , fatigue ( P<.001 ) , FACT-P ( P=.006 ) , physical well-being ( P<.001 ) , social well-being ( P=.002 ) , and functional well-being ( P=.04 ) . CONCLUSIONS An 8-week cardiovascular exercise program in patients with localized prostate cancer undergoing radiotherapy improved cardiovascular fitness , flexibility , muscle strength , and overall QOL and prevented fatigue Background Many patients with lung cancer are deconditioned with poor physical fitness . Lung resection reduces physical fitness further , impairing the patient 's ability to function in daily life . Methods We conducted a single-blind r and omised controlled trial of high-intensity endurance and strength training ( 60 min , three times a week , 20 weeks ) , starting 5–7 weeks after surgery . The control group received st and ard postoperative care . The primary outcome was the change in peak oxygen uptake measured directly during walking until exhaustion . Other outcomes included changes in pulmonary function , muscular strength by one-repetition maximum ( 1RM ) , total muscle mass measured by dual energy X-ray absorptiometry , daily physical functioning and quality of life ( QoL ) . Results The intention-to-treat analysis of the 61 r and omised patients showed that the exercise group had a greater increase in peak oxygen uptake ( 3.4 mL/kg/min between-group difference , p=0.002 ) , carbon monoxide transfer factor ( Tlco ) ( 5.2 % predicted , p=0.007 ) , 1RM leg press ( 29.5 kg , p<0.001 ) , chair st and ( 2.1 times p<0.001 ) , stair run ( 4.3 steps , p=0.002 ) and total muscle mass ( 1.36 kg , p=0.012 ) compared with the controls . The mean±SD QoL ( SF-36 ) physical component summary score was 51.8±5.5 and 43.3±11.3 ( p=0.006 ) , and the mental component summary score was 55.5±5.3 and 46.6±14.0 ( p=0.015 ) in the exercise and control groups , respectively . Conclusions In patients recently operated for lung cancer , high-intensity endurance and strength training was well tolerated and induced clinical ly significant improvements in peak oxygen uptake , Tlco , muscular strength , total muscle mass , functional fitness and QoL. This study may provide a basis for exercise therapy after lung cancer surgery . Trial registration number NCT01748981 Objective : To conduct a r and omized controlled trial and compare the effects on cancer survivors ’ quality of life in a 12-week group-based multidisciplinary self-management rehabilitation program , combining physical training ( twice weekly ) and cognitive-behavioral training ( once weekly ) with those of a 12-week group-based physical training ( twice weekly ) . In addition , both interventions were compared with no intervention . Methods : Participants ( all cancer types , medical treatment completed ≥3 months ago ) were r and omly assigned to multidisciplinary rehabilitation ( n = 76 ) or physical training ( n = 71 ) . The nonintervention comparison group consisted of 62 patients on a waiting list . Quality of life was measured using the R AND -36 . The rehabilitation groups were measured at baseline , after rehabilitation , and 3-month follow-up , and the nonintervention group was measured at baseline and 12 weeks later . Results : The effects of multidisciplinary rehabilitation did not outperform those of physical training in role limitations due to emotional problem ( primary outcome ) or any other domains of quality of life ( all p > .05 ) . Compared with no intervention , participants in both rehabilitation groups showed significant and clinical ly relevant improvements in role limitations due to physical problem ( primary outcome ; effect size ( ES ) = 0.66 ) , and in physical functioning ( ES = 0.48 ) , vitality ( ES = 0.54 ) , and health change ( ES = 0.76 ) ( all p < .01 ) . Conclusions : Adding a cognitive-behavioral training to group-based self-management physical training did not have additional beneficial effects on cancer survivors ’ quality of life . Compared with the nonintervention group , the group-based self-management rehabilitation improved cancer survivors ’ quality of life . PT = physical training ; CBT = cognitive-behavioral training ; PT+CBT = physical training plus cognitive-behavioral training ; WLC = waiting-list comparison ; QoL = quality of life ; ANOVA = analysis of variance ; ES = effect size This pilot study examined whether exercise as an adjunctive rehabilitation therapy could benefit women who have early stage breast cancer and are currently receiving chemotherapy/radiotherapy . The study was design ed as a r and omised controlled trial ( RCT ) . Physical functioning , fatigue and Quality of Life ( QoL ) outcomes were evaluated pre and post a 12-week intervention . The results showed that after 12 weeks the women who participated in the exercise programme ( n = 12 ) displayed significantly higher levels of physical functioning and reported higher QoL scores than the controls ( n = 10 ) . Changes in fatigue and satisfaction with life favoured the intervention group but did not reach significance . These results are encouraging and suggest that a structured group exercise programme during adjuvant treatment is a safe , well tolerated and effective way of providing physical and psychological health benefits to women during treatment for early stage breast cancer . Since this was a pilot study the numbers did not allow appropriately powered analyses of some variables of interest and favoured relatively young and socio-economically advantaged women . Future studies need to address these issues and determine if these short-term benefits can be sustained Purpose Cancer and its treatment-related side effects induce loss of physical performance . This study evaluated the effects of multimodal aerobic and strength exercises on physical performance in hospitalized cancer patients while receiving myeloablative chemotherapy . Methods In this prospect i ve pilot study , 48 evaluable patients were r and omly assigned to a training ( TG , n = 24 ) or control ( CG , n = 24 ) group . The TG performed an individually supervised exercise program five times a week with ergometer training and strength exercises for 20 min each during the hospitalization period for chemotherapy . The CG received st and ard physiotherapy . Physical performance was evaluated using spiroergometry , lung function , and muscle strength testing . Treatment-related side effects were assessed by daily interviews , quality of life by EORTC-QLQ-C30 , and fatigue using the Modified Fatigue Impact Scale ( MFIS ) question naire . Results Physical performance significantly increased in the TG ( 8.96 ± 24 W ) and decreased in the CG ( −7.24 ± 20 W , p = 0.02 ) . At 2-mmol/ml blood lactate concentration , the TG achieved significantly increased oxygen consumption ( p = 0.03 ) and expiratory minute ventilation ( p = 0.04 ) compared to the CG . Furthermore , physical functioning increased significantly in the TG ( p = 0.04 ) . Patients in the TG required less antiemetics ( p = 0.01 ) and experienced significantly less fatigue ( p = 0.04 ) , although MFIS analysis was not able to detect this beneficial effect . Patients of the CG displayed higher impairments of cognitive ( p = 0.02 ) and psychosocial function ( p = 0.03 ) after chemotherapy . No adverse events due to the study intervention were observed . Conclusions Multimodal exercise has beneficial effects on physical performance , physical functioning , and treatment-related symptoms even during myeloablative chemotherapy . We suggest an enhanced physical activity intervention program during hospitalization of cancer patients Background : Since physical exercise programs have the potential to help cancer patients regain physical fitness and may exert a range of positive consequences for recovery and psychological well-being , the impact of a physical exercise program was investigated in this prospect i ve study . Patients and Methods : Women with primary nonmetastatic breast cancer after a minimum 4-week period post chemotherapy and /or radiotherapy completion were r and omly assigned to one of 2 groups : intervention group ( IG ) ( n = 30 ) and waiting group ( WG ) ( n = 28 ) . The 10-week twice weekly exercise group program consisted of gymnastics , movement games , relaxation , walking , and jogging . Anxiety , depression , body image , and quality of life were measured using st and ardized question naires . Maximal oxygen uptake ( VO2max/kg ) was assessed as a measure of physical fitness . Results : Patients in the IG improved significantly over time with regard to anxiety ( p = 0.03 , d = 0.45 ) , depression ( p = 0.05 , d = 0.43 ) , individual body image ( p = 0.006 , d = 0.44 ) , and VO2max/kg ( p < 0.001 , d = 0.50 ) , whereas no improvements were observed in the WG . However , this r and omized controlled trial failed to demonstrate significant intervention effects in quality of life and social body image . Conclusions : This prospect i ve study provided evidence for the effectiveness of a 10-week physical exercise intervention to significantly improve psychosocial wellbeing , individual body image , and physical fitness Cheville AL , Girardi J , Clark MM , Rummans TA , Pittelkow T , Brown P , Hanson J , Atherton P , Johnson ME , Sloan JA , Gamble G : Therapeutic exercise during outpatient radiation therapy for advanced cancer : Feasibility and impact on physical well-being . Objective : To characterize the feasibility of delivering a structured physical therapy ( PT ) program as part of a multidisciplinary intervention to patients undergoing outpatient radiation therapy for advanced cancer . Design : A single-blinded , r and omized , controlled trial at a quaternary medical center outpatient clinic . One hundred three adults undergoing radiation therapy for advanced cancer with prognoses ≥6 mos and 5-yr survival estimates ≤50 % were r and omized to usual care or participation in eight 90-min , multidisciplinary interventional sessions with 30 mins of each session devoted to PT . PT consisted of truncal and limb isodynamic strengthening targeting major upper- and lower-limb muscle groups as well as education and provision with instructional material s. Physical well-being and fatigue were assessed with Linear Analog Scale of Assessment . The Profile of Mood States-Short form , including Fatigue-Inertia and Vigor-Activity subscales , was also administered . Results : PT session attendance was 89.3 % . Relative to baseline , mean physical well-being Linear Analog Self Assessment scores at week 4 improved in the intervention group , 0.4 ( SD , 23.6 ) , and declined significantly in the control group , −10.0 ( SD , 21.5 ) ( P = 0.02 ) . Fatigue and vigor were not significantly different between the groups . All intergroup differences had resolved at 8 and 27 wks . Baseline characteristics were not associated with the magnitude or direction of change in outcomes related to physical functioning . Conclusions : Delivery of a st and ardized resistive exercise PT intervention is feasible during outpatient radiation therapy and is associated with preserved physical well-being . However , benefits were not sustained , and fatigue was not affected During radiation therapy , cancer patients may report cancer-related fatigue ( CRF ) , which impairs aerobic capacity , strength , muscle mass , and , ultimately , quality of life ( QOL ) . The purpose of this pilot clinical trial was to examine the feasibility and initial efficacy of a home-based aerobic and progressive resistance exercise intervention for aerobic capacity , strength , muscle mass , CRF , and QOL . Daily steps walked ( DSW ) , daily minutes of resistance exercise ( MRE ) , and number of resistance exercise days ( RED ) were assessed to evaluate intervention adherence . Breast and prostate cancer patients ( n = 38 ) beginning radiation therapy were r and omized to undergo 4 weeks of exercise or no exercise . Participants in the exercise group demonstrated good adherence to the exercise intervention , with significantly more DSW , MRE , and RED at post intervention and 3 month follow-up than controls . Participants in the exercise intervention exhibited significantly higher QOL and significantly lower CRF post intervention and at 3-month follow-up than controls . Results of this pilot study provide positive preliminary evidence that exercise during radiation may be beneficial for cancer patients OBJECTIVE To determine the feasibility and efficacy of a physical activity behavioural change intervention in managing cancer-related fatigue among gynaecological cancer survivors during and post anti-cancer treatments . METHODS A two arm , single blind , r and omised controlled trial was conducted within the Northern Irel and regional Cancer Centre . Thirty three sedentary gynaecological cancer survivors ( stage I-III ; ≤3 years post diagnosis ) , experiencing cancer-related fatigue ( mild-severe ) took part . Participants were r and omly assigned to a behavioural change , moderate intensity physical activity intervention ( n=16 ) or a Contact Control group ( n=17 ) . The primary outcome was fatigue ( Multidimensional Fatigue Symptom Inventory-Short Form and Functional Assessment in Chronic Illness Therapy-Fatigue subscale ) . Secondary outcomes included quality of life , physical functioning , positive and negative affect , depression , body composition , sleep dysfunction and self-reported physical activity . Feasibility was assessed based on the recruitment rate , programme and physical activity adherence and participants ' programme evaluation , including optional focus groups ( n=16 ) . RESULTS Twenty five percent of eligible women took part ( 33/134 ) . Participants were 8.7 ( SD=9.1 ) months post diagnosis , with a mean age of 53 ( SD=10.3 ) years . The majority of the sample had a diagnosis of ovarian ( n=12 ) or endometrial cancer ( n=11 ) . Significant differences favouring the intervention group were observed for fatigue at 12 weeks and 6 months follow-up ( 12 week : mean difference=-11.06 ; 95 % confidence interval (CI)=-21.89 to -0.23 ; effect size (d)=0.13 ; p=0.046 ; 6 month : mean difference=-19.48 ; 95 % CI=-19.67 to -19.15 ; effect size (d)=0.20 ; p=0.01 ) . A mean of 10 calls ( SD=1.2 calls ) were delivered to the Physical Activity Group , and 10 ( SD=1.6 calls ) to the CC group . The intervention was positively perceived based on exit question naire and focus group findings . CONCLUSIONS A physical activity behavioural change intervention for gynaecological cancer survivors is feasible in terms of participants ' programme adherence and evaluation , and the intervention demonstrates improvements in fatigue . However , confirmation in the form of a larger fully powered RCT is warranted INTRODUCTION The evidence on the effectiveness of rehabilitation in lung cancer patients is limited . Whole body vibration ( WBV ) has been proposed as an alternative to conventional resistance training ( CRT ) . METHODS We investigated the effect of radical treatment ( RT ) and of two rehabilitation programmes in lung cancer patients . The primary endpoint was a change in 6-min walking distance ( 6MWD ) after rehabilitation . Patients were r and omised after RT to either CRT , WBVT or st and ard follow-up ( CON ) . Patients were evaluated before , after RT and after 12 weeks of intervention . RESULTS Of 121 included patients , 70 were r and omised to either CON ( 24 ) , CRT ( 24 ) or WBVT ( 22 ) . After RT , 6MWD decreased with a mean of 38 m ( 95 % CI 22 - 54 ) and increased with a mean of 95 m ( 95 % CI 58 - 132 ) in CRT ( p<0.0001 ) , 37 m ( 95 % CI -1 - 76 ) in WBVT ( p=0.06 ) and 1 m ( 95 % CI -34 - 36 ) in CON ( p=0.95 ) , respectively . Surgical treatment , magnitude of decrease in 6MWD by RT and allocation to either CRT or WBVT were prognostic for reaching the minimally clinical ly important difference of 54 m increase in 6MWD after intervention . CONCLUSIONS RT of lung cancer significantly impairs patients ' exercise capacity . CRT significantly improves and restores functional exercise capacity , whereas WBVT does not fully substitute for CRT We conducted a r and omized controlled trial to determine the effects of a home-based exercise intervention on change in quality of life ( QOL ) in recently resected colorectal cancer survivors , most of whom were receiving adjuvant therapy . Participants were r and omly assigned in a 2:1 ratio to either an exercise ( n = 69 ) or control ( n = 33 ) group . The exercise group was asked to perform moderate intensity exercise 3 - 5 times per week for 20 - 30 min each time . The primary outcome was change in QOL as measured by the Functional Assessment of Cancer Therapy-Colorectal ( FACT-C ) scale . Adherence in the exercise group was good ( 75.8 % ) but contamination in the control group was problematic ( 51.6 % ) . Intention-to-treat analysis revealed no significant differences between groups for change in the FACT-C ( mean difference , -1.3 ; 95 % CI , -7.8 to 5.1 ; P = 0.679 ) . In an ' on-treatment ' ancillary analysis , we compared participants who decreased versus increased their cardiovascular fitness over the course of the intervention . This analysis revealed significant differences in favour of the increased fitness group for the FACT-C ( mean difference , 6.5 ; 95 % CI , 0.4 - 12.6 ; P = 0.038 ) . These data suggest that increased cardiovascular fitness is associated with improvements in QOL in colorectal cancer survivors but better controlled trials are needed Objective : Assessment of feasibility and effects of an exercise training programme in patients following cystectomy due to urinary bladder cancer . Design : Single-blind , pilot , r and omized controlled trial . Setting : University hospital , Sweden . Subjects : Eighteen patients ( 64–78 years ) , of 89 suitable , cystectomized due to urinary bladder cancer , were r and omized after hospital discharge to intervention or control . Interventions : The 12-week exercise programme included group exercise training twice a week and daily walks . The control group received only st and ardized information at discharge . Main outcome measures : Trial eligibility and compliance to inclusion were registered . Assessment s of functional capacity , balance , lower body strength and health-related quality of life ( HRQoL ) with SF-36 . Results : Out of 122 patients 89 were eligible , but 64 did not want to participate/were not invited . Twenty-five patients were included , but 7 dropped out before r and omization . Eighteen patients were r and omized to intervention or control . Thirteen patients completed the training period . The intervention group increased walking distance more than the control group , 109 m ( 75–177 ) compared to 62 m ( 36–119 ) ( P = 0.013 ) , and role physical domain in SF-36 more than the control group ( P = 0.031 ) . Ten patients were evaluated one year postoperatively . The intervention group had continued increasing walking distance , 20 m ( 19–36 ) , whereas the control group had shortened the distance −15.5 m ( −43 to −5 ) ( P = 0.010 ) . Conclusions : A 12-week group exercise training programme was not feasible for most cystectomy patients . However , functional capacity and the role-physical domain in HRQoL increased in the short and long term for patients in the intervention group compared with controls Background & objectives : Patients with head and neck cancer ( HNC ) undergoing chemoradiotherapy ( CRT ) suffer from fatigue causing a decrease in functional capacity and quality of life ( QoL ) . Limited research in the field of exercise training among these patients dem and ed the need for this study to assess the effects of exercise training on functional capacity and quality of life . Methods : A r and omized controlled trial was conducted on 48 patients with HNC undergoing CRT . The exercise group received an individually tailored , supervised , exercise programme for six weeks , while the control group did not receive any form of exercise . Functional capacity and QoL were assessed at baseline and at the end of the intervention using the six minute walk distance ( 6MWD ) and medical outcomes survey short form 36 ( SF 36 ) . Results : The mean age of patients was 52 yr with 42 males . After six weeks , the 6MWD improved by 42 metres ( P<0.05 ) in the exercise group while the control group showed a decrease by 96 metres ( P<0.001 ) . There was an improvement on the mental component score ( MCS ) of SF36 for the exercise group ( 4.8 ; P<0.05 ) and the physical component score ( PCS ) remained almost the same , while a decrease in PCS and MCS was seen in the control group ( -5.9 ; P=0.064 and -17.3 ; P<0.05 ) . When 6MWD and SF36 were compared between the groups , there was a statistically significant difference ( P<0.001 ) seen after six weeks . Interpretation & conclusions : Our results showed that the functional capacity and QoL decreased among those not receiving a supervised exercise program , while exercise training improved functional capacity and QoL in HNC patients undergoing CRT CONTEXT Exercise benefits patients with cancer , but studies of home-based approaches , particularly among those with Stage IV disease , remain small and exploratory . OBJECTIVES To conduct an adequately powered trial of a home-based exercise intervention that can be facilely integrated into established delivery and reimbursement structures . METHODS Sixty-six adults with Stage IV lung or colorectal cancer were r and omized , in an eight-week trial , to usual care or incremental walking and home-based strength training . The exercising participants were instructed during a single physiotherapy visit and subsequently exercised four days or more per week ; training and step-count goals were advanced during bimonthly telephone calls . The primary outcome measure was mobility assessed with the Ambulatory Post Acute Care Basic Mobility Short Form . Secondary outcomes included ratings of pain and sleep quality as well as the ability to perform daily activities ( Ambulatory Post Acute Care Daily Activities Short Form ) , quality of life ( Functional Assessment of Cancer Therapy-General ) , and fatigue ( Functional Assessment of Cancer Therapy-Fatigue ) . RESULTS Three participants dropped out and seven died ( five in the intervention and two in the control group , P=0.28 ) . At Week 8 , the intervention group reported improved mobility ( P=0.01 ) , fatigue ( P=0.02 ) , and sleep quality ( P=0.05 ) compared with the usual care group , but did not differ on the other measures . CONCLUSION A home-based exercise program seems capable of improving the mobility , fatigue , and sleep quality of patients with Stage IV lung and colorectal cancer PURPOSE To evaluate the effectiveness of a supervised home-based flexible training program on cardiorespiratory fitness ( CRF ) , mental distress , and health-related quality of life ( HRQOL ) parameters in young and middle-aged cancer patients shortly after curative chemotherapy . PATIENTS AND METHODS One hundred eleven patients age 18 to 50 years who had received chemotherapy for lymphomas or breast , gynecologic , or testicular cancer completed the trial . These patients were r and omly allocated to either an intervention group ( n = 59 ) , which underwent a 14-week training program , or a control group ( n = 52 ) that received st and ard care . Primary outcome was change in CRF , as determined by Astr and -Rhyming indirect bicycle ergometer test ( maximum oxygen uptake [ VO(2max ) ] ) , between baseline ( T0 ) and follow-up ( T1 ) . Secondary outcomes were mental distress , as assessed by the Hospital Anxiety and Depression Scale , and HRQOL , as assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life Question naire . Two-way analysis of covariance was used to analyze changes from T0 to T1 . RESULTS VO(2max ) increased by 6.4 mL/kg(-1)/min(-1 ) in patients in the intervention group and by 3.1 mL/kg(-1)/min(-1 ) in patients in the control group ( P < .01 ) . The fatigue score decreased by 17.0 points in the control group compared with only 5.8 points in the intervention group ( P < .01 ) . There were no intergroup differences in mental distress or HRQOL . CONCLUSION A supervised , home-based , flexible training program has significant effect on CRF in young and middle-aged cancer patients shortly after curative chemotherapy , but it has no favorable effect on patients ' experience of fatigue , mental distress , or HRQOL The aim of this study was to evaluate the impact of a twice-weekly strength training intervention on perceptions of body image in 234 breast cancer survivors ( 112 with lymphedema ) who participated in the Physical Activity and Lymphedema ( PAL ) trial . The study population included two hundred and thirty-four women r and omly assigned to twice-weekly strength training or control group that completed the 32-item Body Image and Relationships Scale ( BIRS ) at baseline and 12 months . Percent change in baseline to 12-month BIRS total and subscale scores , upper and lower body strength , and general quality of life ( QOL ) were compared by intervention status . A series of multiple linear regression models including indicator variables for subgroups based on age , marital status , race , education , BMI , and strength change were used to examine differential intervention impact by subgroup . Strength and QOL variables were assessed as mediators of the intervention effect on BIRS . Results : Baseline BIRS scores were similar across intervention and lymphedema status . Significantly greater improvement in BIRS total score was observed from baseline to 12 months in treatment vs. control participants ( 12.0 vs. 2.0 % ; P < 0.0001 ) . A differential impact of the intervention on the Strength and Health subscale was observed for older women ( > 50 years old ) in the treatment group ( P = 0.03 ) . Significantly greater improvement was observed in bench and leg press among treatment group when compared to control group participants , regardless of lymphedema . Observed intervention effects were independent of observed strength and QOL changes . Twice-weekly strength training positively impacted self-perceptions of appearance , health , physical strength , sexuality , relationships , and social functioning . Evidence suggests the intervention was beneficial regardless of prior diagnosis of lymphedema . Strength and QOL improvements did not mediate the observed intervention effects Cancer treatment is associated with decreased hemoglobin ( Hb ) concentration and aerobic fitness ( VO2 max ) , which may contribute to cancer-related fatigue ( CRF ) and decreased quality of life ( QoL ) . Endurance exercise may attenuate CRF and improve QoL , but the mechanisms have not been thoroughly investigated . Objectives . To ( a ) determine the feasibility of conducting an exercise intervention among women receiving treatment for breast cancer ; ( b ) examine the effects of exercise on Hb and VO2 max and determine their association with changes in CRF and QoL ; and ( c ) investigate changes in selected inflammatory markers . Methods . Fourteen women receiving chemotherapy for Stages I – II breast cancer were r and omly assigned to exercise ( n = 7 ) or usual care ( n = 7 ) . Women in the exercise group performed supervised , individualized treadmill exercise 2–3 times/week for the duration of chemotherapy ( 9–12 weeks ) . Data were collected 4 times over 15–16 weeks . Results . Recruitment rate was 45.7 % . Sixteen women consented and 14 completed the trial , for a retention rate of 87.5 % . Adherence to exercise protocol was 95–97 % , and completion of data collection was 87.5–100 % . Exercise was well tolerated . VO2 max was maintained at prechemotherapy levels in exercisers but declined in the usual-care group ( p < .05 ) . Hb decreased ( p < .001 ) in all participants as they progressed through chemotherapy . Exercise did not have significant effects on CRF or QoL. Changes in inflammatory markers favored the exercise group . Conclusions . Exercise during chemotherapy may protect against chemotherapy-induced decline in VO2 max but not Hb concentration BACKGROUND Exercise improves physical functioning and symptom management during breast cancer chemotherapy , but the effects of different doses and types of exercise are unknown . METHODS A multicenter trial in Canada r and omized 301 breast cancer patients to thrice-weekly supervised exercise during chemotherapy consisting of either a st and ard dose of 25 to 30 minutes of aerobic exercise ( STAN ; n = 96 ) , a higher dose of 50 to 60 minutes of aerobic exercise ( HIGH ; n = 101 ) , or a combined dose of 50 to 60 minutes of aerobic and resistance exercise ( COMB ; n = 104 ) . The primary endpoint was physical functioning assessed by the Medical Outcomes Survey-Short Form (SF)-36 . Secondary endpoints were other physical functioning scales , symptoms , fitness , and chemotherapy completion . All statistical tests were linear mixed model analyses , and the P values were two-sided . RESULTS Follow-up assessment of patient-reported outcomes was 99.0 % . Adjusted linear mixed-model analyses showed that neither HIGH ( + 0.8 ; 95 % confidence interval [ CI ] = -0.8 to 2.4 ; P = .30 ) nor COMB ( + 0.5 ; 95 % CI = -1.1 to 2.1 ; P = .52 ] were superior to STAN for the primary outcome . In secondary analyses not adjusted for multiple comparisons , HIGH was superior to STAN for the SF-36 physical component summary ( P = .04 ) , SF-36 bodily pain ( P = .02 ) , and endocrine symptoms ( P = .02 ) . COMB was superior to STAN for endocrine symptoms ( P = .009 ) and superior to STAN ( P < .001 ) and HIGH ( P < .001 ) for muscular strength . HIGH was superior to COMB for the SF-36 bodily pain ( P = .04 ) and aerobic fitness ( P = .03 ) . No differences emerged for body composition or chemotherapy completion . CONCLUSIONS A higher volume of aerobic or combined exercise is achievable and safe during breast cancer chemotherapy and may manage declines in physical functioning and worsening symptoms better than st and ard volumes OBJECTIVES To investigate whether functionally based resistance exercise could improve strength , physical function , and disability among prostate cancer survivors ( PCS ) on and rogen deprivation therapy ( ADT ) ; and to explore potential mediators of changes in outcomes from exercise . DESIGN R and omized controlled trial . SETTING Academic medical center . PARTICIPANTS PCS ( N=51 ; mean age , 70.2y ) on ADT . INTERVENTION PCS were r and omized to moderate to vigorous intensity resistance training or stretching ( placebo control ) for 1 year . MAIN OUTCOME MEASURES Maximal leg press and bench press strength , objective and self-reported physical function , and self-reported disability . Hierarchical linear modeling was used to test for significant group × time differences adjusting for covariates . RESULTS Retention in the study was 84 % , and median attendance to supervised classes was 84 % in the resistance group . No study -related injuries occurred . Maximal leg strength ( P=.032 ) and bench press strength ( P=.027 ) were improved after 1 year of resistance training , whereas little change occurred from stretching . Self-reported physical function improved with resistance training , whereas decreases occurred from stretching ( P=.016 ) . Disability lessened more with resistance training than stretching ( P=.018 ) . One-year change in leg press strength mediated the relation between groups ( resistance or stretching ) and 1-year change in self-reported disability ( P<.05 ) . CONCLUSIONS One year of resistance training improved muscle strength in and rogen-deprived PCS . Strengthening muscles using functional movement patterns may be an important feature of exercise programs design ed to improve perceptions of physical function and disability . Findings from this study contribute to the mounting evidence that exercise should become a routine part of clinical care in older men with advanced prostate cancer The purpose of this pilot study was to examine the effects of a combined cardiorespiratory and resistance exercise training program of short duration on the cardiorespiratory fitness , strength endurance , task specific functional muscle capacity , body composition and quality of life ( QOL ) in women breast cancer survivors . Sixteen subjects were r and omly assigned to either a training ( n = 8 ; age : 50 + /- 5 yrs ) or control non-exercising group ( n = 8 ; age : 51 + /- 10 yrs ) . The training group followed an 8-week exercise program consisting of 3 weekly sessions of 90-min duration , supervised by an experienced investigator and divided into resistance exercises and aerobic training . Before and after the intervention period , all of the subjects performed a cardiorespiratory test to measure peak oxygen uptake ( VO2peak ) , a dynamic strength endurance test ( maximum number of repetitions for chest and leg press exercise at 30 - 35 % and 100 - 110 % of body mass , respectively ) and a sit-st and test . Quality of life was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 ( EORTC-C30 ) question naire . In response to training , QOL , VO2peak ( mean 3.9 ml/kg/min ; 95 % CI , 0.93 , 6.90 ) performance in leg press ( 17.9 kg ; 95 % CI , 12.8 , 22.4 ) and sit-st and test ( - 0.67 s ; 95 % CI , - 0.52 , - 1.2 ) improved ( p < or = 0.05 ) . We observed no significant changes in the control group . Combined cardiorespiratory and resistance training , even of very brief duration , improves the QOL and the overall physical fitness of women breast cancer survivors BACKGROUND Shoulder dysfunction remains a frequent complication after neck dissection procedures for head and neck cancer . METHODS We conducted a pilot study to evaluate the effects of progressive resistance exercise training ( PRET ) on shoulder dysfunction caused by spinal accessory neurapraxia/neurectomy in patients with head and neck cancer . Twenty patients ( mean age , 61 + /- 7.7 years ) were r and omly assigned to PRET or st and ard care intervention . Subjects assigned to the PRET group exercised three times per week for 12 weeks . The goal of the exercise program was to enhance scapular stability and strength of the upper extremity . The resistance-training program was progressive in terms of number of sets and repetitions performed , as well as the amount of weight lifted , depending on performance status . RESULTS The completion rate for the trial was 85 % ( 17 of 20 ) . The exercise group completed 93 % of scheduled exercise sessions . Significant improvements were found in favor of the PRET group in active shoulder external rotation ( p = .001 ) , shoulder pain ( p = .038 ) , and overall score for shoulder pain and disability ( p = .045 ) . CONCLUSIONS The study results demonstrate a high rate of completion and adherence with our PRET program among patients with head and neck cancer . The preliminary findings , although limited , also suggest a potential therapeutic role for resistance exercise as an adjunct to st and ard physical therapy treatment OBJECTIVE To evaluate the effect of a combined hospital plus home exercise programme following curative surgery for non-small cell lung cancer ( NSCLC ) . DESIGN R and omised controlled trial . SETTING Teaching hospital . PARTICIPANTS One hundred and thirty-one subjects with NSCLC admitted for curative surgery . INTERVENTIONS Participants were r and omised to usual care or a hospital plus home exercise programme . OUTCOMES The primary outcome was the between-group difference in physical activity 4 weeks after surgery . Secondary outcomes were the difference in quadriceps strength , exercise tolerance and quality of life [ Short Form-36 ( SF-36 ) and European Organisation for Research and Treatment of Cancer ( EORTC ) QLQ-LC13 ] from pre-operatively ( baseline ) to 4 weeks after surgery . RESULTS The participants ( n=131 ) had a mean age of 68 [ st and ard deviation ( SD ) 11 ] years and mean forced expiratory volume in 1 second of 2.4 ( SD 1.1)l . There were no significant differences in physical activity between the groups 4 weeks after surgery [ mean difference adjusted for baseline 12minutes/day , 95 % confidence interval ( CI ) -20.2 to 44.1 ] . In addition , there were no significant differences in total SF-36 or EORTC QLQ-LC13 scores from baseline to 4 weeks after surgery . Both groups had recovered their pre-operative walking distance 4 weeks after surgery , and there were no differences between the groups ( mean difference in Incremental Shuttle Walk Test from baseline to 4 weeks after surgery ( -26 m , 95 % CI -94.2 to 42.3 ) . CONCLUSIONS A hospital plus home exercise programme showed little benefit in unselected patients with NSCLC following surgery . Regardless of group allocation , the patients had recovered their pre-operative exercise tolerance levels by 4 weeks after surgery PURPOSE Lymphoma patients commonly experience declines in physical functioning and quality of life ( QoL ) that may be reversed with exercise training . PATIENTS AND METHODS We conducted a r and omized controlled trial in Edmonton , Alberta , Canada , between 2005 and 2008 that stratified 122 lymphoma patients by major disease type and current treatment status and r and omly assigned them to usual care ( UC ; n = 62 ) or 12 weeks of supervised aerobic exercise training ( AET ; n = 60 ) . Our primary end point was patient-rated physical functioning assessed by the Trial Outcome Index-Anemia . Secondary end points were overall QoL , psychosocial functioning , cardiovascular fitness , and body composition . RESULTS Follow-up assessment for our primary end point was 96 % ( 117 of 122 ) at postintervention and 90 % ( 110 of 122 ) at 6-month follow-up . Median adherence to the supervised exercise program was 92 % . At postintervention , AET was superior to UC for patient-rated physical functioning ( mean group difference , + 9.0 ; 95 % CI , 2.0 to 16.0 ; P = .012 ) , overall QoL ( P = .021 ) , fatigue ( P = .013 ) , happiness ( P = .004 ) , depression ( P = .005 ) , general health ( P < .001 ) , cardiovascular fitness ( P < .001 ) , and lean body mass ( P = .008 ) . Change in peak cardiovascular fitness mediated the change in patient-rated physical functioning . AET did not interfere with chemotherapy completion rate or treatment response . At 6-month follow-up , AET was still borderline or significantly superior to UC for overall QoL ( P = .054 ) , happiness ( P = .034 ) , and depression ( P = .009 ) without an increased risk of disease recurrence/progression . CONCLUSION AET significantly improved important patient-rated outcomes and objective physical functioning in lymphoma patients without interfering with medical treatments or response . Exercise training to improve cardiovascular fitness should be considered in the management of lymphoma patients Background : Physical activity can confer many benefits on cancer survivors , including relief of persistent symptoms related to cancer treatment . Objectives : To evaluate the effect of a motivational interviewing ( MI ) intervention on increasing physical activity ( Community Healthy Activities Model Program for Seniors question naire ) and improving aerobic fitness ( 6-minute walk ) , health ( Medical Outcomes Study Short-Form 36 ) , and fatigue ( Schwartz Cancer Fatigue Scale ) in cancer survivors . A secondary purpose was to evaluate whether the effect of MI on physical activities depended on self-efficacy . Methods : Fifty-six physically inactive adult cancer survivors ( mean = 42 months since completion of treatment ) were assigned r and omly to intervention and control groups . The MI intervention consisted of one in-person counseling session followed by two MI telephone calls over 6 months . Control group participants received two telephone calls without MI content . Outcomes were measured at baseline , 3 months , and 6 months , and were analyzed using multilevel modeling . Results : The results of the MI intervention explained significant group differences in regular physical activities ( measured in caloric expenditure per week ) , controlling for time since completion of cancer treatment ( p < .05 ) . Aerobic fitness , physical and mental health , and fatigue were not different between groups . In the intervention group , individuals with high self-efficacy for exercise at baseline increased their physical activity more than those with low self-efficacy ( p < .05 ) . In the control group , increases in physical activity did not depend on self-efficacy . Discussion : Use of MI may increase physical activity in long-term cancer survivors , especially in persons with high self-efficacy for exercise . Multilevel modeling analysis revealed individual changes that would not have been shown by analysis of group means . Future studies with larger sample s or more intense MI interventions may show changes in aerobic fitness , physical and mental health , and fatigue Introduction : Little is known about the effects of rehabilitation for patients with lung cancer after thoracotomy . The primary objective of this study was to evaluate the effect of a multidisciplinary rehabilitation program on quality of life ( QOL ) and secondary objectives were to determine its effects on pain and exercise capacity and the feasibility of combining rehabilitation with adjuvant chemotherapy . Methods : Patients who had undergone a thoracotomy for lung cancer were r and omized between rehabilitation and usual care . Rehabilitation consisted of twice-weekly training for 12 weeks starting 1 month after hospital discharge , scheduled visits to pain specialists , and medical social work . QOL and pain were measured with vali date d question naires at baseline and after 1 , 3 , 6 , and 12 months . Exercise tolerance was assessed at baseline and after 3 months with a 6-minute walking distance test . Results : The study closed prematurely because of the introduction of video-assisted thoracoscopic surgery . Of 57 r and omized patients , 49 patients ( 23 active and 26 control ) were analyzed . QOL was not significantly different between groups , although , the active group reported more pain after 3 and 6 months and more limitations because of physical problems after 3 months . In the active group , 6-minute walking distance improved by 35 m from preoperative baseline , as opposed to the control group that showed a decline by 59 m ( p = 0.024 for difference ) . Patients treated with adjuvant chemotherapy showed decreased attendance at training sessions . Conclusion : Rehabilitation did not result in a better QOL . Exercise tolerance improved at the cost of more pain and more limitations because of physical problems . We suggest that rehabilitation is better postponed for 3 to 4 months after hospital discharge BACKGROUND Research has shown that self-directed stress management training improves mental well-being in patients undergoing chemotherapy . The present study extends this work by evaluating separate and combined effects of stress management training and home-based exercise . METHOD Following assessment of mental and physical well-being , depression , anxiety , exercise , and stress reduction activity before chemotherapy started , patients were r and omized to stress management training ( SM ) , exercise ( EX ) , combined stress management and exercise ( SMEX ) , or usual care only ( UCO ) . Outcomes were reassessed 6 and 12 weeks after chemotherapy started . Significance testing of group-by-time interactions in 286 patients who completed all assessment s was used to evaluate intervention efficacy . RESULTS Interaction effects for mental and physical well-being scores were not significant . Depression scores yielded a linear interaction comparing UCO and SMEX ( p = 0.019 ) , with decreases in SMEX but not UCO . Anxiety scores yielded a quadratic interaction comparing UCO and SMEX ( p = 0.049 ) , with trends for changes in SMEX but not UCO . Additional analyses yielded quadratic interactions for exercise activity comparing UCO and SMEX ( p = 0.022 ) , with positive changes in SMEX but not UCO , and for stress management activity comparing UCO and SM ( p < 0.001 ) and UCO and SMEX ( p = 0.013 ) , with positive changes in SM and SMEX but not UCO . CONCLUSION Only the combined intervention yielded effects on quality of life outcomes , and these were limited to anxiety and depression . These findings are consistent with evidence that only the combined intervention yielded increases in both exercise and stress management activity . Future research should investigate ways to augment this intervention to enhance its benefits AIM The study aim ed at determining whether physical exercise training improves the quality of life ( QoL ) and physical fitness of breast cancer survivors . PATIENTS AND METHODS A total of 573 breast cancer survivors were r and omized into an exercise or a control group , 12-months after adjuvant treatments . EORTC QLQ-C30 and BR-23 question naires were used for evaluation of QoL , FACIT-F for fatigue and the Finnish modified version of Beck 's 13-item depression scale ( RBDI ) for depression . Physical fitness was assessed by a 2-km walking test , and a figure-8 running test and physical activity ( PA ) by metabolic equivalent ( MET ) hours per week ( MET-h/wk ) . RESULTS Figure-8 running time improved significantly among the patients of the intervention group compared with the controls ( p<0.001 ) . No significant between-group differences were observed in 2-km walking time , in PA , EORTC-QLQ-C30 , BR-23 , FACIT-F or BDI . However , there was a linear relationship between increased PA and improved QoL ( p=0.006 ) , irrespective of the intervention . CONCLUSION Increase in physical activity was associated with improved QoL , but no effect of the exercise intervention was observed Background . And rogen deprivation therapy ( ADT ) increases survival rates in prostate cancer ( PCa ) patients with locally advanced disease , but is associated with side effects that may impair daily function . Strength training may counteract several side effects of ADT , such as changes in body composition and physical functioning , which in turn may affect health-related quality of life ( HRQOL ) . However , additional r and omised controlled trials are needed to exp and this knowledge . Material and methods . Fifty-eight PCa patients on ADT were r and omised to either 16 weeks of high-load strength training ( n = 28 ) or usual care ( n = 30 ) . The primary outcome was change in total lean body mass ( LBM ) assessed by dual x-ray absorptiometry ( DXA ) . Secondary outcomes were changes in regional LBM , fat mass , and areal bone mineral density ( aBMD ) measured by DXA ; physical functioning assessed by 1-repetition maximum ( 1RM ) tests , sit-to-st and test , stair climbing test and Shuttle walk test ; and HRQOL as measured by the European Organization for the Research and Treatment of Cancer Quality of Life Question naire Core 30 . Results and Conclusion . No statistically significant effect of high-load strength training was demonstrated on total LBM ( p = 0.16 ) , but significant effects were found on LBM in the lower and upper extremities ( 0.49 kg , p < 0.01 and 0.15 kg , p < 0.05 , respectively ) . Compared to usual care , high-load strength training showed no effect on fat mass , aBMD or HRQOL , but beneficial effects were observed in all 1RM tests , sit-to-st and test and stair climbing tests . Adherence to the training program was 88 % for lower body exercises and 84 % for upper body exercises . In summary , high-load strength training improved LBM in extremities and physical functioning , but had no effect on fat mass , aBMD , or HRQOL in PCa patients on ADT Purpose Following treatment , haematological cancer ( HEM ) patients exhibit significant physical deconditioning and psychological distress . Exercise has been shown as a clinical ly effective and safe intervention for cancer patients , with the potential to reverse the deleterious effects following treatment . Our aim was to investigate the efficacy of a 12-week exercise rehabilitation on cancer-related fatigue ( CRF ) and associated outcomes in HEM patients post-treatment . Methods Patients with a HEM were recruited to participate in a 12-week exercise rehabilitation intervention post-treatment . Pre- , post- and follow-up assessment s were conducted on outcome measures including CRF , quality of life ( QoL ) , psychological distress , cardiovascular fitness , muscle strength ( MS ) and body composition . Patients were given tailored exercise programmes comprising aerobic and resistance exercises , carried out three times per week for 12 weeks in local gyms and clinics . Usual-care participants were offered a delayed , tailored 12-week exercise intervention after the initial study period . Results Thirty-seven patients ( 49 % recruitment rate ) were r and omly assigned to the 12-week exercise rehabilitation ( n = 18 ) or usual care ( n = 19 ) with a 91 % adherence to the exercise intervention . Following the exercise programme , significant improvements were seen in CRF ( p = 0.01 ) , cardiovascular fitness ( p ≤ 0.001 ) , QoL ( p ≤ 0.001 ) , MS ( p ≤ 0.001 ) and body composition ( p = 0.001 ) , with moderate to large effects for all primary outcomes . Patient follow-up at 24 weeks demonstrated outcome maintenance in the exercise rehabilitation group and significant improvements in outcomes in usual-care patients following participation in a delayed exercise programme . There were no adverse reactions or study withdrawals . Conclusions A 12-week exercise rehabilitation programme result ed in significant statistical ( p ≤ 0.05 ) and clinical improvements in CRF and additional outcomes in HEM patients following treatment . Additionally , a 12-week delayed exercise programme showed similar significant improvements in patient outcomes .Trial registration Australian New Zeal and Clinical Trials Registry ACTRN12609000450213 BACKGROUND As patients with pancreas and periampullary cancer ( PPC ) experience improved survival rates and longevity , the focus shifts toward living life while surviving cancer . Fatigue is the most commonly reported symptom in all cancer patients . Exercise has been found to effectively decrease fatigue levels and improve physical functioning in cancer patients . STUDY DESIGN One hundred two patients with resected PPC consented to participate in this study and were r and omized to either an intervention group ( IG ) or a usual care group ( UCG ) . Subjects completed visual analog scales , the FACIT-Fatigue Scale and the Short Form-36v2 after surgery and again 3 to 6 months after hospital discharge . RESULTS Patients in the IG and UCG were comparable with regard to demographics , comorbidities , cancer type and staging , type of resection , preoperative fatigue and pain levels , adjuvant therapy , and baseline walking distance . Patients in the IG had significantly improved scores on the FACIT-Fatigue Scale at study completion , improved fatigue and pain scores , as well as overall physical functioning and mental health composite scores . At study completion , participants in the IG were walking twice as far and were significantly more likely to have continued walking or another form of exercise as compared with the UCG . Using hierarchical cluster analysis , 3 mutually exclusive symptom groupings were identified in the cohort . Kaplan-Meier survival analysis did not indicate an overall survival benefit for the IG . CONCLUSIONS This is the first prospect i ve , r and omized controlled trial to report that participation in a home walking program confers a significant benefit in resected PPC patients with regard to fatigue levels , physical functioning , and health-related quality of life Fatigue is the most prevalent and debilitating symptom experienced by breast cancer patients receiving adjuvant chemotherapy or radiation therapy and few evidence -based treatments are available to manage this distressing side-effect . The purpose of this multi-institutional r and omized controlled trial was to determine the effects of exercise on fatigue levels during treatment for breast cancer . Sedentary women ( N=119 ) with Stage 0-III breast cancer receiving outpatient adjuvant chemotherapy or radiation therapy were r and omized to a home-based moderate-intensity walking exercise program or to usual care for the duration of their cancer treatment . Of participants r and omized to exercise , 72 % adhered to the exercise prescription ; 61 % of the usual care group adhered . The intention-to-treat analysis revealed no group differences in part because of a dilution of treatment effect as 39 % of the usual care group exercised and 28 % of the exercise group did not . When exercise participation was considered using the data analysis method of instrumental variables with principal stratification , a clinical ly important and statistically significant ( p=0.03 ) effect of exercise on pretest-to-posttest change in fatigue levels was demonstrated . Adherence to a home-based moderate-intensity walking exercise program may effectively mitigate the high levels of fatigue prevalent during cancer treatment Curative treatment for acute myeloid leukemia ( AML ) involves induction chemotherapy ( IC ) which is associated with bed rest and toxicities , leading to worsening quality of life ( QOL ) , fatigue , and fitness . Exercise during IC may ameliorate declines but has not been rigorously tested . We examined the efficacy of supervised exercise during IC on QOL , fatigue , and fitness . Eighty-three in patients age 18 - 80 scheduled to receive IC for newly diagnosed or relapsed AML were r and omized 2:1 ( exercise intervention : control group ) . Study measures were completed at baseline , post-IC , and following the first cycle of consolidation . The intervention consisted of a supervised mixed-modality , moderate-intensity exercise program ( 4 - 5 days per week , 30 - 60min per session ) throughout admission . Recruitment was good ( 56 % ) , retention excellent ( 96 % ) , and adherence was 54 % . Global QOL improved similarly in both groups from baseline to post-IC ( between-group difference 3.0 points , p=0.62 ) . Fatigue improved in the exercise group from baseline to post-IC ( potentially clinical ly important between-group difference of 3.6 points , p=0.23 ) . Aerobic fitness , lower body strength , and grip strength improved in the exercise group ( between-group differences p=0.005 , p<0.001 , p=0.03 , respectively ) . Supervised exercise for patients with AML undergoing IC is feasible , safe , and appears effective at improving fitness and possibly fatigue . A larger trial is warranted Before , during , and after allogeneic hematopoietic stem cell transplantation ( allo-HSCT ) , patients experience considerable physical and psychologic distress . Besides graft-versus-host disease and infections , reduced physical performance and high levels of fatigue affect patients ' quality of life . This multicenter r and omized controlled trial examined the effects of a partly self-administered exercise intervention before , during , and after allo-HSCT on these side effects . After r and omization to an exercise and a social contact control group 105 patients trained in a home-based setting before hospital admission , during inpatient treatment and a 6- to 8-week period after discharge . Fatigue , physical performance , quality of life , and physical/psychologic distress were measured by st and ardized instruments at baseline , admission to , and discharge from hospital and 6 to 8 weeks after discharge . The exercise group showed significantly improvement in fatigue scores ( up to 15 % improvement in exercise group vs up to 28 % deterioration in control ; P<.01-.03 ) , physical fitness/functioning ( P=.02-.03 ) and global distress ( P=.03 ) . All effects were at least detectable at one assessment time point after hospitalization or repeatedly . Physical fitness correlated significantly with all reported symptoms/variables . In conclusion , this partly supervised exercise intervention is beneficial for patients undergoing allo-HSCT . Because of low personnel requirements , it might be valuable to integrate such a program into st and ard medical care PURPOSE Radiotherapy for prostate cancer ( PCa ) may cause unfavorable changes in fatigue , quality of life ( QOL ) , and physical fitness . We report results from the Prostate Cancer Radiotherapy and Exercise Versus Normal Treatment study examining the effects of 24 weeks of resistance or aerobic training versus usual care on fatigue , QOL , physical fitness , body composition , prostate-specific antigen , testosterone , hemoglobin , and lipid levels in men with PCa receiving radiotherapy . PATIENTS AND METHODS Between 2003 and 2006 , we conducted a r and omized controlled trial in Ottawa , Canada , where 121 PCa patients initiating radiotherapy with or without and rogen deprivation therapy were r and omly assigned to usual care ( n = 41 ) , resistance ( n = 40 ) , or aerobic exercise ( n = 40 ) for 24 weeks . Our primary end point was fatigue assessed by the Functional Assessment of Cancer Therapy-Fatigue scale . RESULTS The follow-up assessment rate for our primary end point of fatigue was 92.6 % . Median adherence to prescribed exercise was 85.5 % . Mixed-model repeated measures analyses indicated both resistance ( P = .010 ) and aerobic exercise ( P = .004 ) mitigated fatigue over the short term . Resistance exercise also produced longer-term improvements ( P = .002 ) . Compared with usual care , resistance training improved QOL ( P = .015 ) , aerobic fitness ( P = .041 ) , upper- ( P < .001 ) and lower-body ( P < .001 ) strength , and triglycerides ( P = .036 ) , while preventing an increase in body fat ( P = .049 ) . Aerobic training also improved fitness ( P = .052 ) . One serious adverse event occurred in the group that performed aerobic exercise . CONCLUSION In the short term , both resistance and aerobic exercise mitigated fatigue in men with PCa receiving radiotherapy . Resistance exercise generated longer-term improvements and additional benefits for QOL , strength , triglycerides , and body fat PURPOSE To investigate the efficacy and safety of aerobic training ( AT ) in patients with cancer with medically stable heart failure ( HF ) . PATIENTS AND METHODS A retrospective analysis of 90 patients with cancer who have HF and who were r and omly assigned to AT ( n = 47 ) or guideline -based usual care ( UC ; n = 43 ) was performed . AT consisted of three supervised sessions per week at 20 to 45 minutes per session at 60 % to 70 % of heart rate reserve for 12 weeks followed by home-based sessions for 4 to 12 months . The primary end point was all-cause mortality and hospitalization . Secondary end points were other clinical events , safety , and change in exercise capacity ( VO(2peak ) ) and health-related quality of life ( HRQOL ) . RESULTS Median follow-up was 35 months . In intention-to-treat ( ITT ) analyses , all-cause mortality or hospitalization at 2 years was 74 % in the AT group compared with 67 % in the UC group ( adjusted hazard ratio [ HR ] , 1.11 ; 95 % CI , 0.69 to 1.77 ; P = .676 ) . The incidence of cardiovascular mortality or cardiovascular hospitalization was significantly higher in the AT group compared with the UC group ( 41 % v 67 % ; adjusted HR , 1.94 ; 95 % CI , 1.12 to 3.16 ; P = .017 ) . There were no differences in any VO(2peak ) or HRQOL end points . In post hoc analyses based on adherence to AT , all-cause mortality and hospitalization was 66 % in adherent patients ( ≥ 90 minutes per week ) compared with 84 % in nonadherent patients ( < 90 minutes per week ) . CONCLUSION In ITT analyses , AT did not improve clinical outcomes in patients with cancer who had HF . Post hoc analyses suggested that patients not capable of adhering to the planned AT prescription may be at increased risk of clinical events BACKGROUND Two interventions for fatigue were given during curative cancer treatment . The aim of this multicenter r and omized controlled trial ( RCT ) with three conditions was to demonstrate the efficacy and to determine the contribution of physical activity . METHODS Recruited from seven hospitals , 220 patients with various malignancies participated in a RCT . The brief nursing intervention ( BNI ) consisted of two 1-hour sessions , 3 months apart , given by 12 trained nurses , focusing only on physical activity . Cognitive behavior therapy ( CBT ) consisted of up to ten 1-hour sessions , within 6 months , provided by two therapists , focusing on physical activity and psychosocial elements . The control group received only usual care ( UC ) . Assessment s took place before and at least 2 months after cancer treatment , when patients had recovered from acute fatigue . Fatigue was the primary outcome . Efficacy was tested using analyses of covariance . A nonparametric bootstrap approach was used to test whether the effect on fatigue was mediated by physical activity . RESULTS The CBT group was significantly less fatigued than the UC group . Between the BNI and the UC groups , no significant difference was found in fatigue . The mediation hypothesis was rejected . DISCUSSION CBT given during curative cancer treatment proved to be an effective intervention to reduce fatigue at least 2 months after cancer treatment . The BNI was not effective . Contrary to what was expected , physical activity did not mediate the effect of CBT on fatigue . Thus , the reduction in fatigue elicited by CBT was realized without a lasting increase in physical activity Abstract Background . To evaluate the safety and efficacy of moderate-to-high intensity aerobic training in breast cancer patients receiving neoadjuvant chemotherapy . Methods . Twenty patients with stage IIB – IIIC operable breast cancer were r and omly assigned to receive doxorubicin plus cyclophosphamide ( AC ) or AC in combination with aerobic training ( AC + AET ) ( n = 10/group ) for 12 weeks . The AC+ AET group performed three supervised aerobic cycle ergometry sessions per week at 60%–100 % of exercise capacity ( VO2peak ) . Safety outcomes included exercise testing as well as treatment- and exercise training-related adverse events ( AEs ) , whereas efficacy outcomes included cardiopulmonary function and patient-reported outcomes ( PROs ) as measured by a cardiopulmonary exercise test ( CPET ) and Functional Assessment of Cancer Therapy-Breast ( FACT-B ) scale . Results . Twelve non-significant ECG abnormalities and three non-life threatening events occurred during CPET procedures . One AE was reported during aerobic training . There were no significant between group differences for clinician-documented events ( e.g. pain , nausea ) or hematological parameters ( p 's > 0.05 ) . Attendance and adherence rates to aerobic training were 82 % and 66 % , respectively . Intention-to-treat analysis indicated that VO2peak increased by 2.6 ± 3.5 ml/kg/min ( + 13.3 % ) in the AC + AET group and decreased by 1.5 ± 2.2 ml/kg/min ( −8.6 % ) in the AC group ( between group difference , p = 0.001 ) . FACT-B increased 11.1 points in the AC + AET group compared to a 1.5 point decrease in the AC group ( between group difference , p = 0.685 ) . Conclusion . Moderate-to-high intensity aerobic training when conducted with one-on-one supervision is a safe adjunct therapy associated with improvements in cardiopulmonary function and select PROs during neoadjuvant chemotherapy BACKGROUND Long-term prostate cancer ( PCa ) survivors are at increased risk for comorbidities and physical deconditioning . OBJECTIVE To determine the effectiveness of a year-long r and omised controlled trial of exercise training in PCa survivors > 5 yr postdiagnosis on physical functioning . DESIGN , SETTING , AND PARTICIPANTS Between 2010 and 2011 , 100 long-term PCa survivors from Trans-Tasman Radiation Oncology Group 03.04 R and omised And rogen Deprivation and Radiotherapy previously treated with and rogen-deprivation therapy and radiation therapy were r and omly assigned to 6 mo of supervised exercise followed by 6 mo of a home-based maintenance programme ( n=50 ) or printed educational material about physical activity ( n=50 ) for 12 mo across 13 university-affiliated exercise clinics in Australia and New Zeal and . INTERVENTION Supervised resistance and aerobic exercise or printed educational material about physical activity . OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary end point was a 400-m walk as a measure of cardiovascular fitness . Secondary end points were physical function , patient-reported outcomes , muscle strength , body composition , and biomarkers . Analysis of covariance was used to compare outcomes for groups at 6 and 12 mo adjusted for baseline values . RESULTS AND LIMITATIONS Participants undergoing supervised exercise showed improvement in cardiorespiratory fitness performance at 6 mo ( -19 s [ p=0.029 ] ) and 12 mo ( -13 s [ p=0.028 ] ) and better lower-body physical function across the 12-mo period ( p<0.01 ) . Supervised exercise also improved self-reported physical functioning at 6 ( p=.006 ) and 12 mo ( p=0.002 ) , appendicular skeletal muscle at 6 mo ( p=0.019 ) , and objective measures of muscle strength at 6 and 12 mo ( p<0.050 ) . Limitations included the restricted number of participants undertaking body composition assessment , no blinding to group assignment for physical functioning measures , and inclusion of well-functioning individuals . CONCLUSIONS Supervised exercise training in long-term PCa survivors is more effective than physical activity educational material for increasing cardiorespiratory fitness , physical function , muscle strength , and self-reported physical functioning at 6 mo . Importantly , these benefits were maintained in the long term with a home-based programme with follow-up at 12 mo . CLINICAL TRIAL REGISTRY The effect of an exercise intervention on cardiovascular and metabolic risk factors in prostate cancer patients from the RADAR study , ACTRN : ACTRN12609000729224 |
13,672 | 25,056,258 | In the unconscious state , propofol sharply reduces the regional glucose metabolism rate ( rGMR ) and regional cerebral blood flow ( rCBF ) in all brain regions , particularly in the thalamus .
However , GMR , such as in the occipital , temporal , and frontal lobes , was obviously decreased at a sedative dosage of propofol , whereas , changes in the thalamus were not obvious .
Using fMRI , several studies observed a decrease of connectivity of the thalamus versus an increase of connectivity within the pons of the brainstem during propofol-induced mild sedation .
During deep sedation , propofol preserves cortical sensory reactivity , the specific thalamocortical network is moderately affected , whereas the nonspecific thalamocortical network is severely suppressed .
In contrast , several recent fMRI studies are consistent on the systemic decreased effects of propofol in the frontoparietal network .
Accumulating evidence suggest that propofol-induced unconsciousness is associated with a global metabolic and vascular depression in the human brain and especially with a significant reduction in the thalamocortical network and the frontoparietal network | Abstract Functional imaging methods , including positron emission tomography ( PET ) and functional magnetic resonance imaging ( fMRI ) , have become important tools for study ing how anesthetic drugs act in the human brain to induce the state of general anesthesia .
Recent imaging studies using fMRI and PET techniques have demonstrated the regional effects of propofol on the brain .
However , the pharmacological mechanism of the action of propofol in the intact human central nervous system is unclear . | In the present study , we used positron emission tomography to investigate changes in regional cerebral blood flow ( rCBF ) during a general anesthetic infusion set to produce a gradual transition from the awake state to unconsciousness . Five right-h and ed human volunteers participated in the study . They were given propofol with a computer-controlled infusion pump to achieve three stable levels of plasma concentrations corresponding to mild sedation , deep sedation , and unconsciousness , the latter defined as unresponsiveness to verbal comm and s. During awake baseline and each of the three levels of sedation , two scans were acquired after injection of an H215O bolus . Global as well as regional CBF were determined and correlated with propofol concentrations . In addition , blood flow changes in the thalamus were correlated with those of the entire scanned volume to determine areas of coordinated changes . In addition to a generalized decrease in global CBF , large regional decreases in CBF occurred bilaterally in the medial thalamus , the cuneus and precuneus , and the posterior cingulate , orbitofrontal , and right angular gyri . Furthermore , a significant covariation between the thalamic and midbrain blood flow changes was observed , suggesting a close functional relationship between the two structures . We suggest that , at the concentrations attained , propofol preferentially decreases rCBF in brain regions previously implicated in the regulation of arousal , performance of associative functions , and autonomic control . Our data support the hypothesis that anesthetics induce behavioral changes via a preferential , concentration-dependent effect on specific neuronal networks rather than through a nonspecific , generalized effect on the brain We investigated the effects of the general anesthetic agent propofol on cerebral structures involved in the processing of vibrotactile information . Using positron emission tomography ( PET ) and the H(2)(15)O bolus technique , we measured regional distribution of cerebral blood flow ( CBF ) in eight healthy human volunteers . They were scanned under five different levels of propofol anesthesia . Using a computer-controlled infusion , the following plasma levels of propofol were targeted : Level W ( Waking , 0 microg/ml ) , Level 1 ( 0.5 microg/ml ) , Level 2 ( 1.5 microg/ml ) , Level 3 ( 3.5 microg/ml ) , and Level R ( Recovery ) . At each level of anesthesia , two 3-min scans were acquired with vibrotactile stimulation of the right forearm either on or off . The level of consciousness was evaluated before each scan by the response of the subject to a verbal comm and . At Level W , all volunteers were fully awake . They reported being slightly drowsy at Level 1 , they had a slurred speech and slow response at Level 2 , and they were not responding at all at Level 3 . The following variations in regional CBF ( rCBF ) were observed . During the waking state ( Level W ) , vibrotactile stimulation induced a significant rCBF increase in the left thalamus and in several cortical regions , including the left primary somatosensory cortex and the left and right secondary somatosensory cortex . During anesthesia , propofol reduced in a dose-dependent manner rCBF in the thalamus as well as in a number of visual , parietal , and prefrontal cortical regions . At Level 1 through 3 , propofol also suppressed vibration-induced increases in rCBF in the primary and secondary somatosensory cortex , whereas the thalamic rCBF response was abolished only at Level 3 , when volunteers lost consciousness . We conclude that propofol interferes with the processing of vibrotactile information first at the level of the cortex before attenuating its transfer through the thalamus While ubiquitous , pharmacological manipulation of consciousness remains poorly defined and incompletely understood ( Prys-Roberts , 1987 ) . This retards anesthetic drug development , confounds interpretation of animal studies conducted under anesthesia , and limits the sensitivity of clinical monitors of cerebral function to intact perception . Animal and human studies propose a functional “ switch ” at the level of the thalamus , with inhibition of thalamo-cortical transmission characterizing loss of consciousness ( Alkire et al. , 2000 ; Mashour , 2006 ) . We investigated the effects of propofol , widely used for anesthesia and sedation , on spontaneous and evoked cerebral activity using functional magnetic resonance imaging ( fMRI ) . A series of auditory and noxious stimuli was presented to eight healthy volunteers at three behavioral states : awake , “ se date d ” and “ unresponsive . ” Performance in a verbal task and the absence of a response to verbal stimulation , rather than propofol concentrations , were used to define these states clinical ly . Analysis of stimulus-related blood oxygenation level-dependent signal changes identified reductions in cortical and subcortical responses to auditory and noxious stimuli in se date d and unresponsive states . A specific reduction in activity within the putamen was noted and further investigated with functional connectivity analysis . Progressive failure to perceive or respond to auditory or noxious stimuli was associated with a reduction in the functional connectivity between the putamen and other brain regions , while thalamo-cortical connectivity was relatively preserved . This result has not been previously described and suggests that disruption of subcortical thalamo-regulatory systems may occur before , or even precipitate , failure of thalamo-cortical transmission with the induction of unconsciousness Applying graph theoretical analysis of spontaneous BOLD fluctuations in functional magnetic resonance imaging ( fMRI ) , we investigated whole-brain functional connectivity of 11 healthy volunteers during wakefulness and propofol-induced loss of consciousness ( PI-LOC ) . After extraction of regional fMRI time series from 110 cortical and subcortical regions , we applied a maximum overlap discrete wavelet transformation and investigated changes in the brain 's intrinsic spatiotemporal organization . During PI-LOC , we observed a breakdown of subcortico-cortical and corticocortical connectivity . Decrease of connectivity was pronounced in thalamocortical connections , whereas no changes were found for connectivity within primary sensory cortices . Graph theoretical analyses revealed significant changes in the degree distribution and local organization metrics of brain functional networks during PI-LOC : compared with a r and om network , normalized clustering was significantly increased , as was small-worldness . Furthermore we observed a profound decline in long-range connections and a reduction in whole-brain spatiotemporal integration , supporting a topological reconfiguration during PI-LOC . Our findings shed light on the functional significance of intrinsic brain activity as measured by spontaneous BOLD signal fluctuations and help to underst and propofol-induced loss of consciousness Background : Anesthetics may affect the regional cerebral blood flow ( rCBF ) response associated with increased brain activity in humans . rCBF was measured as auditory stimulus rate was increased during propofol and thiopental administration . Methods : After informed consent , 10 right-h and ed male volunteer participants ( aged 33.5 ± 10.4 yr , weighing 74.5 ± 8.4 kg ) received thiopental ( n = 4 ) or propofol ( n = 6 ) intravenously at stepwise target concentrations of propofol 1.2 and 2.5–3 , or thiopental 4 and 7–9 & mgr;g/ml , representing sedative and hypnotic drug concentrations . The latter made volunteers unresponsive to voice or mild stimulation . Quantitative positron emission tomographic brain images were obtained at 0 , 20 , and 40 auditory words per minute at each drug concentration . Using SPM99 analysis , 10-mm spherical regions of interest were identified by peak covariation of word rate with rCBF across all conditions and drug concentrations . Individual mean rCBF responses in these and primary auditory cortex ( Heschl ’s gyri ) were obtained . Results : Significant increases in rCBF with auditory word rate occurred in temporal lobes bilaterally at baseline ( significance , T = 4.95 ) . There was no change in this response during sedation ( T = 5.60 ) . During unresponsiveness seven of 10 participants had a diminished response in the left temporal lobe ( T = 3.18 ) . Global CBF , corrected for changes in Pco2 ( 3 % · mmHg Pco2−1 ) , was reduced 15 % by sedation and 27 % during unresponsiveness . Conclusion : The presence of propofol or thiopental does not affect the rCBF response to increasing stimulus rate during consciousness . Thus , changes in rCBF activation patterns with sedative concentrations of these drugs represent effects on brain activity itself . The neuroanatomical targets of drug effect on memory and attention may be revealed by changes in rCBF patterns associated with these cognitive activities Background : Dynamic action of anesthetic agents was compared at cortical and subcortical levels during induction of anesthesia . Unconsciousness involved the cortical brain but suppression of movement in response to noxious stimuli was mediated through subcortical structures . Methods : Twenty-five patients with Parkinson disease , previously implanted with a deep-brain stimulation electrode , were enrolled during the implantation of the definitive pulse generator . During induction of anesthesia with propofol ( n = 13 ) or sevoflurane ( n = 12 ) alone , cortical ( EEG ) and subcortical ( ESCoG ) electrogenesis were obtained , respectively , from a frontal montage ( F3–C3 ) and through the deep-brain electrode ( p0–p3 ) . In EEG and ESCoG spectral analysis , spectral edge ( 90 % ) frequency , median power frequency , and nonlinear analysis dimensional activation calculations were determined . Results : Sevoflurane and propofol decreased EEG and ESCoG activity in a dose-related fashion . EEG values decreased dramatically at loss of consciousness , whereas there was little change in ESCoG values . Quantitative parameters derived from EEG but not from ESCoG were able to predict consciousness versus unconsciousness . Conversely , quantitative parameters derived from ESCoG but not from EEG were able to predict movement in response to laryngoscopy . Conclusion : These data suggest that in humans , unconsciousness mainly involves the cortical brain , but that suppression of movement in response to noxious stimuli is mediated through the effect of anesthetic agents on subcortical structures Background Functional magnetic resonance imaging of blood oxygenation level – dependent signal changes offers a very promising approach to investigate activated neural networks during anesthesia . Methods Sixteen healthy male volunteers , assigned into two groups of eight subjects ( isoflurane group , control group ) , were investigated by functional magnetic resonance imaging during different experimental conditions . The isoflurane group successively breathed air ( baseline condition ) , isoflurane in air ( 0.42 vol% inspiratory ; isoflurane condition ) and air again ( recovery condition ) while performing a visual search task , whereas the control group breathed air during all experimental conditions . Functional magnetic resonance images were acquired during the entire experimental session . In addition , reaction times and error rates were recorded . Results A significant isoflurane-related decrease ( z > 3.1 corresponding to P < 0.001 ) in task-induced brain activation was found in three distinct cortical regions : the right anterio-superior insula ( Talairach coordinates : x = 32 , y = 22 , z = 8) and the banks of the left and right intraparietal sulcus ( Talairach coordinates : x = −34 , y = −36 , z = 32 ; x = 22 , y = −60 , z = 41 , respectively ) . Subcortical structures ( lateral geniculate nucleus ) and the primary cortices ( motor cortex , visual cortex ) were not affected . All measured parameters indicated a nearly complete recovery of the affected networks within 5 min . Conclusions Our findings indicate that subanesthetic isoflurane affected task-induced activation in specific neural networks rather than causing a global decrease in functional activation Background This study was design ed to identify neuroanatomical locations of propofol 's effects on episodic memory by producing minimal and maximal memory impairment during conscious sedation . Drug-related changes in regional cerebral blood flow ( rCBF ) were located in comparison with rCBF increases during a simple word memory task . Methods Regional cerebral blood flow changes were assessed in 11 healthy volunteers using H215O positron emission tomography ( PET ) and statistical parametric mapping ( SPM99 ) at 600 and 1,000 ng/ml propofol target concentrations . Study groups were based on final recognition scores of auditory words memorized during PET scanning . rCBF changes during propofol administration were compared with those during the word memory task at baseline . Results Nonoverlapping memory effects were evident : low ( n = 4 ; propofol concentration 523 ± 138 ng/ml ; 44 ± 13 % decrement from baseline memory ) and high ( n = 7 ; 829 ± 246 ng/ml ; 87 ± 6 % decrement from baseline ) groups differed in rCBF reductions primarily in right-sided prefrontal and parietal regions , close to areas activated in the baseline memory task , particularly R dorsolateral prefrontal cortex ( Brodmann area 46 ; x , y , z = 51 , 38 , 22 ) . The medial temporal lobe region exhibited relative rCBF increases . Conclusions As amnesia becomes maximal , rCBF reductions induced by propofol occur in brain regions identified with working memory processes . In contrast , medial temporal lobe structures were resistant to the global CBF decrease associated with propofol sedation . The authors postulate that the episodic memory effect of propofol is produced by interference with distributed cortical processes necessary for normal memory function rather than specific effects on medial temporal lobe structures |
13,673 | 16,109,456 | No analgesic in single prophylactic dose provided analgesia for day of operation . | null | null |
13,674 | 19,759,391 | The collected evidence on risk reduction concerns a variety of interventions to reduce medication errors , fall incidents , diagnostic errors , and adverse events in general .
Most studies reported positive effects ; however , interventions were often multifaceted , and it was difficult to disentangle their impact . | The aim of this systematic review was ( a ) to synthesize the evidence on the effectiveness of detection , mitigation , and actions to reduce risks in hospitals and ( b ) to identify and describe components of interventions responsible for effectiveness . | Background : There is widespread interest in improving medication safety , particularly in the hospital setting . Numerous suggestions have been made as to how this should be done , but there is a paucity of data demonstrating the effectiveness of any of the interventions that have been proposed . Objectives : To assess the impact of a wide ranging , community hospital based patient safety program on patient harm as measured by the rate of adverse drug events . Design : An audit of discharged hospital patients was conducted from January 2001 to December 2003 . Baseline data were collected for the first 6 months and multiple drug protocol s and other interventions were instituted on the nursing units and in the pharmacy department over the subsequent 9 months ( transition period ) . These interventions were largely based on information about medication risks acquired from internal medication event reporting . Each month of the study adverse drug events ( ADE ) were sought from a r and om sample of inpatient charts . A trigger tool was used to detect clues to ADEs , the presence of which was confirmed or excluded by detailed manual chart review . The severity of these events was categorized using the classification system of the National Coordinating Council for Medication Error and Reporting and Prevention . Main outcome measures and results : Median ADEs per 1000 doses of medication dispensed declined significantly from 2.04 to 0.65 ( p<0.001 ) . Median ADEs per 100 patient days declined significantly from 5.07 to 1.30 ( p<0.001 ) . The proportion of in patients with one or more ADE in the baseline period was 31 % and declined threefold ( p<0.001 ) . The severity of reported medication events also declined . The number of ADEs associated conclusively with patient harm was 1.67 per total doses delivered in the baseline period and declined eightfold ( p<0.001 ) . Conclusion : The implementation of a carefully planned series of low cost interventions focused on high risk medications , driven by information largely from internal event reporting , and design ed to improve a hospital ’s medication safety leads to a significant decrease in patient harm Objective . Medication errors are common among pediatric patients and in emergency departments ( EDs ) . Such errors may lead to prolonged hospitalization , unnecessary diagnostic tests and treatments , and death . The objective of this study was to determine whether the use of a structured order sheet reduces the incidence of medication errors in a pediatric ED . Methods . The study was a r and omized , controlled study that was conducted in a tertiary care pediatric hospital . Eighteen days were r and omized into 2 study groups : days during which the regular blank order sheets were used and days during which preprinted , formatted , order sheets were used . All patients ’ charts from these days were review ed by 2 medical students , who extracted demographic , clinical , and therapeutic data into a data base . Two pediatric emergency physicians , blinded to the form used , review ed the data base and independently decided whether an error had occurred and the severity of the error . Results . Within the study period , there were 2157 visits to the ED . A total of 2058 ( 95.4 % ) charts were available for review . A total of 411 ( 52.2 % ) orders for drugs in the ED were ordered on the regular form , and 376 ( 47.8 % ) were given on the new form . Drug errors were identified in 68 ( 16.6 % ) orders when the regular form was used and in 37 ( 9.8 % ) of the orders on the new form . Using the new form was associated with a significant reduction in the risk for an error ( odds ratio : 0.55 ; 95 % confidence interval : 0.34–0.90 ) . Conclusions . The use of a preprinted structured order form significantly reduces medication errors among pediatric patients in the ED Objective : Comparison of two flooring types – carpet and vinyl – in the bed areas , and two modes of physiotherapy – conventional therapy and additional leg strengthening exercises – in avoiding falls . Design : R and omized 2 × 2 controlled trial . Setting : Elderly care rehabilitation ward in a community hospital . Subjects : Fifty-four consecutive patients referred for rehabilitation . Outcome measures : The incidence of falls , and the change in strength . Results : There were 10 falls on carpet , and only a single fall on vinyl floor covering ( relative risk 8.3 , 95 % confidence interval 0.95–73 , p = 0.05 ) . There were four falls in those receiving additional exercise , and seven falls in those receiving only conventional physiotherapy ( relative risk 0.21 , 95 % confidence interval 0.04–1.2 , p = 0.12 ) . Fifty-nine per cent of patients were able to complete strength measurements on admission and discharge . In these , h and grip strength improved more in those given additional exercise than conventional physiotherapy ( 2.1 kg versus – 0.3 kg , p < 0.05 ) . Conclusion : There is no evidence to support either intervention in preventing falls on a rehabilitation ward , but within this low-powered study , there was a strong trend towards vinyl being superior Problem : Advance cardiac life support ( ACLS ) training does not address coordination of team re sources to improve the ability of teams to deliver needed treatments reliably and rapidly . Our objective was to use a human simulation training educational environment to develop multidisciplinary team skills and improve medical emergency team ( MET ) performance . We report findings of a crisis team training course that is focused on organization . Setting : Large center for human simulation training at a university affiliated tertiary care hospital . Participants : Ten courses were delivered and 138 clinical ly experienced individuals were trained ( 69 critical care nurses , 48 physicians , and 21 respiratory therapists ) . All participants were ACLS trained and experienced in responding to cardiac arrest situations . Course design : Each course had four components : ( 1 ) a web based presentation and pretest before the course ; ( 2 ) a brief reinforcing didactic session on the day of the course ; ( 3 ) three of five different simulated scenarios ; each followed by ( 4 ) debriefing and analysis with the team . Three of five simulator scenarios were used ; scenario selection and order was r and om . Trainees did not repeat any scenario or role during the training . Participants were video recorded to assist debriefing . Debriefing focused on reinforcing organizational aspects of team performance : assuming design ated roles independently , completing goals ( tasks ) assigned to each role , and directed communication . Measures for improvement : Participants grade d their performance of specific organizational and treatment tasks within specified time intervals by consensus . Simulator “ survival ” depended on supporting oxygenation , ventilation , circulation within 60 seconds , and delivering the definitive treatment within 3 minutes . Effects of change : Simulated survival ( following predetermined criteria for death ) increased from 0 % to 89 % . The initial team task completion rate was 10–45 % and rose to 80–95 % during the third session . Lessons learnt : Training multidisciplinary teams to organize using simulation technology is feasible . This preliminary report warrants more detailed inquiry Background : Until recently , the preparation of paediatric parenteral nutrition formulations in our institution included re-transcription and manual compounding of the mixture . Although no significant clinical problems have occurred , re-engineering of this high risk activity was undertaken to improve its safety . Several changes have been implemented including new prescription software , direct recording on a server , automatic printing of the labels , and creation of a file used to pilot a BAXA MM 12 automatic compounder . The objectives of this study were to compare the risks associated with the old and new processes , to quantify the improved safety with the new process , and to identify the major residual risks . Methods : A failure modes , effects , and criticality analysis ( FMECA ) was performed by a multidisciplinary team . A cause-effect diagram was built , the failure modes were defined , and the criticality index ( CI ) was determined for each of them on the basis of the likelihood of occurrence , the severity of the potential effect , and the detection probability . The CIs for each failure mode were compared for the old and new processes and the risk reduction was quantified . Results : The sum of the CIs of all 18 identified failure modes was 3415 for the old process and 1397 for the new ( reduction of 59 % ) . The new process reduced the CIs of the different failure modes by a mean factor of 7 . The CI was smaller with the new process for 15 failure modes , unchanged for two , and slightly increased for one . The greatest reduction ( by a factor of 36 ) concerned re-transcription errors , followed by readability problems ( by a factor of 30 ) and chemical cross contamination ( by a factor of 10 ) . The most critical steps in the new process were labelling mistakes ( CI 315 , maximum 810 ) , failure to detect a dosage or product mistake ( CI 288 ) , failure to detect a typing error during the prescription ( CI 175 ) , and microbial contamination ( CI 126 ) . Conclusions : Modification of the process result ed in a significant risk reduction as shown by risk analysis . Residual failure opportunities were also quantified , allowing additional actions to be taken to reduce the risk of labelling mistakes . This study illustrates the usefulness of prospect i ve risk analysis methods in healthcare processes . More systematic use of risk analysis is needed to guide continuous safety improvement of high risk activities BACKGROUND We have little systematic information about the extent to which st and ard processes involved in health care -- a key element of quality --are delivered in the United States . METHODS We telephoned a r and om sample of adults living in 12 metropolitan areas in the United States and asked them about selected health care experiences . We also received written consent to copy their medical records for the most recent two-year period and used this information to evaluate performance on 439 indicators of quality of care for 30 acute and chronic conditions as well as preventive care . We then constructed aggregate scores . RESULTS Participants received 54.9 percent ( 95 percent confidence interval , 54.3 to 55.5 ) of recommended care . We found little difference among the proportion of recommended preventive care provided ( 54.9 percent ) , the proportion of recommended acute care provided ( 53.5 percent ) , and the proportion of recommended care provided for chronic conditions ( 56.1 percent ) . Among different medical functions , adherence to the processes involved in care ranged from 52.2 percent for screening to 58.5 percent for follow-up care . Quality varied substantially according to the particular medical condition , ranging from 78.7 percent of recommended care ( 95 percent confidence interval , 73.3 to 84.2 ) for senile cataract to 10.5 percent of recommended care ( 95 percent confidence interval , 6.8 to 14.6 ) for alcohol dependence . CONCLUSIONS The deficits we have identified in adherence to recommended processes for basic care pose serious threats to the health of the American public . Strategies to reduce these deficits in care are warranted Background : Research into adverse events ( AEs ) has highlighted the need to improve patient safety . AEs are unintended injuries or complications result ing in death , disability or prolonged hospital stay that arise from health care management . We estimated the incidence of AEs among patients in Canadian acute care hospitals . Methods : We r and omly selected 1 teaching , 1 large community and 2 small community hospitals in each of 5 provinces ( British Columbia , Alberta , Ontario , Quebec and Nova Scotia ) and review ed a r and om sample of charts for nonpsychiatric , nonobstetric adult patients in each hospital for the fiscal year 2000 . Trained review ers screened all eligible charts , and physicians review ed the positively screened charts to identify AEs and determine their preventability . Results : At least 1 screening criterion was identified in 1527 ( 40.8 % ) of 3745 charts . The physician review ers identified AEs in 255 of the charts . After adjustment for the sampling strategy , the AE rate was 7.5 per 100 hospital admissions ( 95 % confidence interval [ CI ] 5.7– 9.3 ) . Among the patients with AEs , events judged to be preventable occurred in 36.9 % ( 95 % CI 32.0%–41.8 % ) and death in 20.8 % ( 95 % CI 7.8%–33.8 % ) . Physician review ers estimated that 1521 additional hospital days were associated with AEs . Although men and women experienced equal rates of AEs , patients who had AEs were significantly older than those who did not ( mean age [ and st and ard deviation ] 64.9 [ 16.7 ] v. 62.0 [ 18.4 ] years ; p = 0.016 ) . Interpretation : The overall incidence rate of AEs of 7.5 % in our study suggests that , of the almost 2.5 million annual hospital admissions in Canada similar to the type studied , about 185 000 are associated with an AE and close to 70 000 of these are potentially preventable The patient 's problem is recurrent cough . Pulmonary function is normal at the moment , but the patient 's symptoms and family history suggest asthma . Three physicians confer . Physician A suggests inhalant therapy . It 's almost surely asthma , he says . We should begin treatment and move on to the next patient . The best therapy for asthma is an inhaled steroid . Case closed . Wait a moment , says Physician B. You ca n't be so sure that the best therapy is a steroid . -adrenergics may be better . We need to enroll this patient in a r and omized , double-blind trial to increase our certainty about the best medication . Let 's get informed consent and draw lots to assign the patient r and omly to a treatment group . I 've got a better plan than either of you , says Physician C. Our task is to find out what will help this patient , recognizing our uncertainty about both the diagnosis and the best treatment . Let 's run a small-scale test . We 'll begin with the assumption that the patient has asthma and , on the basis of the scientific literature , we 'll start with inhaled steroids . We 'll ask the patient to keep a record of her symptoms and to try steroids for a week , and then we 'll review the situation to see what we 've learned . If the steroid helps , we can keep it ; if not , we can change the dose or test other options . We can imagine circumstances in which each of the three physicians sounds wise . If the diagnosis is certain , the therapy is well established , and the risk for error is low , Physician A 's approach sounds fine . Why belabor the obvious ? Appendicitis ? Appendectomy . Case closed . But if the science is uncertain and the risks are high , the best course may be to invest in more scientific knowledge , and Physician B sounds right . Take , for example , the choice of chemotherapeutic agents for leukemia . Before one protocol is established as the best choice , responsible care may involve the enrollment of patients in carefully design ed r and omized trials . This approach always requires that physicians obtain informed consent and keep the individual patient 's needs and wishes foremost , but it includes the growth of general clinical science as major goal . For some questions , formal research design s other than r and omized , controlled trials ( such as quasi-experimental , casecontrol , and cohort studies ) can provide highly satisfactory answers . But most often , physician and the patient meet on a terrain that is neither of certainty nor of scientific ignorance , and the use of either large-scale , formal research studies or point- and -shoot therapy seems inappropriate . The art of medical care involves a continuing , individualized search in which the physician tries to match incomplete scientific knowledge of disease and treatment with incomplete local knowledge about particular patients at particular times in their lives . In caring for patients , we often do not know the way but find the way , step by step . Thus , Physician C sounds wisest to most persons most of the time . So it is with improvement in general , whether the subject is caring for an individual patient or finding a better system of care . Between once- and -for-all action and formal research design lies a vast terrain in which steady investigation in the form of small-scale tests of change can be useful . Children learning to ride a bicycle call what they do practicing . So do physicians giving patient care . In the jargon of quality improvement , this form of learning in action is called the Plan-Do- Study -Act ( PSA ) cycle . This cycle , also called the Plan-Do-Check-Act cycle , is attributed to Walter Shewhart , founding theorist of the field of statistical process control ( related models can be found in the work of John Dewey and others ) . Specific tests in cycles of action and reflection are at the heart of modern approaches to improvement in organizations , just as they are at the heart of modern approaches to education and learning [ 1 ] . The apparent simplicity of the PSA cycle is deceptive : The cycle is a sophisticated , dem and ing way to achieve learning and change in complex systems . Rationale for Plan-Do- Study -Act Cycles The strong rationale for the use of PSA cycles in the process of improvement comes largely from systems theory , which was explored in the first three papers in this series [ 2 - 4 ] . Briefly , a system is a set of interdependent elements interacting to achieve a common purpose . Bicycle riding is a system ; so is care of a patient with asthma . From the viewpoint of prediction , systems are unruly . If you change a single element of a system , you may be surprised by the result [ 5 ] . A tiny turn of the h and lebars of a new bicycle can leave a young rider sprawling on the asphalt , bewildered by the invisible connections between her h and s and her balance . A physician who dem and s that his special suture material be placed regularly on an otherwise st and ard surgical set-up tray may find that the same suture later appears on other trays , where it is not needed . Complexity mounts and errors occur as complex , nonlinear systems yield irrational effects from separately rational causes . An accumulation of reasonable changes produces an unreasonable mess . In formal science-planned experiments and tests of hypotheses that physicians are trained to value as investigators and to consume as journal readers- research ers try to mitigate the unruliness of systems by gaining experimental control . R and omization is one way to do this . R and om selection spreads messy system noise evenly , allowing the one thing of true interest-the independent variable-to shine its signal clearly through . The larger the sample , the more reliably the noise is evenly assigned and the clearer the signal of effect ( if any ) . When r and omization is not possible , formal science has other ways to h and le system noise . Epidemiologic methods can help stratify potential confounding factors , either statistically or by design . Cohort studies can use time trends to advantage , and casecontrol design s can highlight the effects of exposures . But how do these formal methods for inference from data apply in the world of PSA cycles ? Suppose that we ask a physician why she has just discontinued penicillin treatment in a patient who developed hives while receiving the drug . Because she is allergic to the medicine , the physician replies . But you do n't really know that , we counter . You need to prove it . Here 's how . Give the patient penicillin on 20 different days , r and omly interspersed with 20 days without penicillin . Record the presence or absence of hives each day , draw a two-by-two table , and calculate the Fisher exact test for the null hypothesis . To a good physician , we would sound silly . There is nothing wrong with the Fisher exact test or with examining the null hypothesis , but in this scenario , these tools are out of place . I do n't have to do all of that , the physician would say . I 'm sure enough , and for this patient we have plenty of good alternative therapies as options . In drawing her conclusions about which medicines to use , this physician is no less a scientist than we are with our Fisher exact test . She is an inductive scientist , learning constantly from experience reflected upon and informed by her intimate association with the care of this specific patient . She tries , she observes , and she learns through her own PSA cycles . R and omized , controlled trials would not help much ; on most occasions , they would waste her time . The PSA cycles-short-cycle , small-scale tests linked to reflection-are powerful tools for learning in complex systems when the aim is to improve those systems . They are most helpful when inaction seems inappropriate but action without reflection seems unwise . In health care , inaction is inappropriate when practice variation is so great that not all practitioners can be right , when practice departs from scientific knowledge or trusted experience , when a system is performing poorly relative to its potential , or when inaction by some creates an opportunity for action by others with less knowledge or bad motives . Research tells us , for example , that breast-conserving surgery for breast cancer is underused in the United States [ 6 ] and that most elderly persons with myocardial infa rct ion do not receive -blocker therapy in their post-acute management [ 7 ] . These findings call for action : St and ing still is not an acceptable response , but how can we act with prudence as we ab and on the status quo ? Good physicians use learning cycles frequently as they depart from the status quo in sound clinical work . The use of a medication in an individual patient is best approached as a PSA cycle . We know from formal experiments how a drug will work in general against a given disease , but we always use that drug with the underst and ing that its action may differ in particular patients . Try this , says Physician C , and stay closely in touch . Small-scale trials are usually the best approach because systems are unpredictable and their dynamics are nonlinear . Small changes can have large consequences , remote in space and time ; this makes closed-form solutions and secure predictions difficult or impossible . In health services research , a corollary has been that efficacy ( performance of a treatment or device in the laboratory ) is almost always greater than effectiveness ( performance of the same treatment or device in the field ) [ 8 , 9 ] . Research ers in laboratories take pains to isolate the intervention being studied ; practitioners in the field can not avoid the linkage of that intervention to uncountable additional nonr and om influences . This is not to deny the enormous contribution of formal experimental science to knowledge . When we are uncertain about the benefit of a particular drug or operation relative to that of its alternatives , no investigational design can yield a more confident conclusion than the r and omized , controlled trial . In effect , a r and omized , controlled trial is a superb form of final inspection of a well-crafted , unitary change . But the same is CONTEXT Pharmacist review of medication orders in the intensive care unit ( ICU ) has been shown to prevent errors , and pharmacist consultation has reduced drug costs . However , whether pharmacist participation in the ICU at the time of drug prescribing reduces adverse events has not been studied . OBJECTIVE To measure the effect of pharmacist participation on medical rounds in the ICU on the rate of preventable adverse drug events ( ADEs ) caused by ordering errors . DESIGN Before-after comparison between phase 1 ( baseline ) and phase 2 ( after intervention implemented ) and phase 2 comparison with a control unit that did not receive the intervention . SETTING A medical ICU ( study unit ) and a coronary care unit ( control unit ) in a large urban teaching hospital . PATIENTS Seventy-five patients r and omly selected from each of 3 groups : all admissions to the study unit from February 1 , 1993 , through July 31 , 1993 ( baseline ) and all admissions to the study unit ( postintervention ) and control unit from October 1 , 1994 , through July 7 , 1995 . In addition , 50 patients were selected at r and om from the control unit during the baseline period . INTERVENTION A senior pharmacist made rounds with the ICU team and remained in the ICU for consultation in the morning , and was available on call throughout the day . MAIN OUTCOME MEASURES Preventable ADEs due to ordering ( prescribing ) errors and the number , type , and acceptance of interventions made by the pharmacist . Preventable ADEs were identified by review of medical records of the r and omly selected patients during both preintervention and postintervention phases . Pharmacists recorded all recommendations , which were then analyzed by type and acceptance . RESULTS The rate of preventable ordering ADEs decreased by 66 % from 10.4 per 1000 patient-days ( 95 % confidence interval [ CI ] , 7 - 14 ) before the intervention to 3.5 ( 95 % CI , 1 - 5 ; P<.001 ) after the intervention . In the control unit , the rate was essentially unchanged during the same time periods : 10.9 ( 95 % CI , 6 - 16 ) and 12.4 ( 95 % CI , 8 - 17 ) per 1000 patient-days . The pharmacist made 366 recommendations related to drug ordering , of which 362 ( 99 % ) were accepted by physicians . CONCLUSIONS The presence of a pharmacist on rounds as a full member of the patient care team in a medical ICU was associated with a substantially lower rate of ADEs caused by prescribing errors . Nearly all the changes were readily accepted by physicians Objective : This study determined the incidence , type , nature , preventability and impact of adverse events ( AEs ) among hospitalised patients and potentially preventable deaths in Dutch hospitals . Methods : Using a three-stage retrospective record review process , trained nurses and doctors review ed 7926 admissions : 3983 admissions of deceased hospital patients and 3943 admissions of discharged patients in 2004 , in a r and om sample of 21 hospitals in the Netherl and s ( 4 university , 6 tertiary teaching and 11 general hospitals ) . A large sample of deceased patients was included to determine the occurrence of potentially preventable deaths in hospitals more precisely . Results : One or more AEs were found in 5.7 % ( 95 % CI 5.1 % to 6.4 % ) of all admissions and a preventable AE in 2.3 % ( 95 % CI 1.9 % to 2.7 % ) . Of all AEs , 12.8 % result ed in permanent disability or contributed to death . The proportion of AEs and their impact increased with age . More than 50 % of the AEs were related to surgical procedures . Among deceased hospital patients , 10.7 % ( 95 % CI 9.8 % to 11.7 % ) had experienced an AE . Preventable AEs that contributed to death occurred in 4.1 % ( 95 % CI 3.5 % to 4.8 % ) of all hospital deaths . Extrapolating to a national level , between 1482 and 2032 potentially preventable deaths occurred in Dutch hospitals in 2004 . Conclusions : The incidence of AEs , preventable AEs and potentially preventable deaths in the Netherl and s is substantial and needs to be reduced . Patient safety efforts should focus on surgical procedures and older patients Background : Nosocomial infections occur in approximately 10 % of patients in intensive care units ( ICUs ) . Several studies have shown that a quality improvement initiative can reduce nosocomial infections , mortality , and cost . Context : Our hospital is located in Northern Mississippi and has a 28 bed Medical-Surgical ICU unit with 95 % occupancy . We joined the ICU collaborative with the IMPACT initiative of the Institute of Healthcare Improvement ( IHI ) in October 2002 . A preliminary prospect i ve before ( fiscal year ( FY ) 2001–2 ) and after ( FY 2003 ) hypothesis generating study was conducted of outcomes result ing from small tests of change in the management of ICU patients . Key measures for improvement : Nosocomial infection rates , adverse events per ICU day , average length of stay , and average cost per ICU episode . Strategy for change : Four changes were implemented : ( 1 ) physician led multidisciplinary rounds ; ( 2 ) daily “ flow ” meeting to assess bed availability ; ( 3 ) “ bundles ” ( sets of evidence based best practice s ) ; and ( 4 ) culture changes with a focus on the team decision making process . Effects of change : Between baseline and re-measurement periods , nosocomial infection rates declined for ventilator associated pneumonia ( from 7.5 to 3.2 per 1000 ventilator days , p = 0.04 ) and bloodstream infections ( from 5.9 to 3.1 per 1000 line days , p = 0.03 ) , with a downward trend in the rate of urinary tract infections ( from 3.8 to 2.4 per 1000 catheter days , p = 0.17 ) . There was a strong downward trend in the rates of adverse events in the ICU as well as the average length of stay per episode . From FY 2002 to FY 2003 the cost per ICU episode fell from $ 3406 to $ 2973 . Lessons learned : A systematic approach through collaboration with IHI ’s IMPACT initiative may have contributed to significant improvements in care in the ICU setting . Multidisciplinary teams appeared to improve communication , and bundles provided consistency of evidence based practice s. The flow meetings allowed for rapid prioritization of activity and a new decision making culture empowered team members . The impact of these changes needs to be assessed more widely using rigorous study design OBJECTIVE To evaluate the effectiveness of a personal digital assistant (PDA)-based clinical decision support system ( CDSS ) on nonsteroidal anti-inflammatory drug ( NSAID ) prescribing safety in the outpatient setting . DESIGN The design was a r and omized , controlled trial conducted in a university-based resident clinic . Internal medicine residents received a PDA-based CDSS suite . For intervention residents , the CDSS included a prediction rule for NSAID-related gastrointestinal risk assessment and treatment recommendations . Unannounced st and ardized patients ( SPs ) trained to portray musculoskeletal symptoms presented to study physicians . Safety outcomes were assessed from the prescriptions given to the SPs . Each prescription was review ed by a committee of clinicians blinded to participant , intervention group assignment , and baseline or follow-up status . MEASUREMENTS Prescriptions were judged as safe or unsafe . The main outcome measure was the differential change in unsafe prescribing of NSAIDs for the intervention versus the control group . RESULTS At baseline , the mean proportion of cases per physician with unsafe prescriptions for the two groups was similar ( 0.27 vs. 0.29 , p > 0.05 ) . Controlling for baseline performance , intervention participants prescribed more safely than controls after receiving the CDSS ( 0.23 vs. 0.45 [ F = 4.24 , p < 0.05 ] ) . With the CDSS , intervention participants documented more complete assessment of patient gastrointestinal risk from NSAIDs . CONCLUSION PARTICIPANTS provided with a PDA-based CDSS for NSAID prescribing made fewer unsafe treatment decisions than participants without the CDSS The present study examined the clinical efficacy of a bed alarm system in reducing falls from bed on a geriatric evaluation and treatment unit . A nine-month case-controlled study was design ed , in which 70 patients ( 60 women , 10 men ; mean age 84 years , range 67 - 97 years ) at increased risk for bed falls were r and omly assigned to either an experimental or a control group . Subjects in the experimental group ( n = 35 ) received a bed alarm system and those in the control group ( n = 35 ) did not . Outcome measures included bed falls , performance of the bed alarm system , and staff attitudes toward the use of the system . Although results failed to demonstrate a statistical difference in bed falls between the experimental ( n = 1 ) and control ( n = 4 ) groups ( p = 1.00 ) , there was a clinical trend toward reduced falls in the experimental group . The system functioned properly , activating an alarm in all instances when patients were transferring from bed , and with the exception of one case , nurses could respond in a timely fashion to assist patients and prevent bed falls . The system did not produce any adverse effects in patients , nor did the device interfere with the rendering of medical care . The system was well accepted by patients , families , and nurses . These data suggest that bed alarm systems are beneficial in guarding against bed falls and are an acceptable method of preventing falls PURPOSE To evaluate the effectiveness of a Falls Prevention Program ( FPP ) in reducing patient fall rate and to examine predictors of falls . SAMPLE A nonr and om , stratified convenience sample of 292 subjects was selected from medical-surgical/critical care patients at a large community hospital system . The sample included 101 patients who fell prior to the FPP , 98 patients who fell after FPP , and 93 patients who did not fall after FPP . METHODS A retrospective , preimplementation/long-term , postimplementation , comparative , descriptive design was used to address differences in patients who fell before and after FPP . Prediction factors associated with incidence of falls were assessed using a sample that included patients who fell and patients who did not fall in 1995 . Data were collected about the patients and the fall incidents via a retrospective chart and incident report review . FINDINGS No decrease in patient fall rate was found between patients who fell before and after implementation of the FPP . Patients tended to fall attempting to get out of the bed , suffering no injury . Model testing of the linear results of patients who fell and patients who did not fall after the implementation of the FPP demonstrated that fall prediction factors included age 60 or over , impaired memory , muscle weakness , and need of ambulatory assistance ( Log linear chi-square : 6.048 , df 4 , p = 0.811 ( p > .05 ) . CONCLUSION Identification of patients who exhibit characteristics of the fall prediction model may be useful in reducing falls in medical-surgical/critical care patients . Further testing of the four-factor model with subsequent inclusion of focused interventions may impact the incidence of falls Background : At the time of transition from hospital to home , many patients are challenged by multi-drug regimens . The authors ’ st and ard patient education tool is a personalised Medication Discharge Worksheet ( MDW ) that includes a list of medications and administration times . Nonetheless , patient underst and ing , satisfaction , and safety remain suboptimal . Therefore , the authors design ed a new tool : Durable Display at Discharge ( 3D ) . Unlike MDW , 3D features ( 1 ) space in which a tablet or pill is to be affixed and displayed , ( 2 ) trade name ( if apt ) , ( 3 ) unit strength , ( 4 ) number ( and /or fraction ) of units to be taken , ( 5 ) purpose ( indication ) , ( 6 ) comment/ caution , ( 7 ) larger font , ( 8) card stock durability and ( 9 ) a reconciliation feature . Methods : The authors conducted an exploratory , r and omised trial ( n = 138 ) to determine whether 3D , relative to MDW , improves patient satisfaction , improves patient underst and ing and reduces self-reported medication errors . Trained survey research personnel , blinded to hypotheses , interviewed patients by telephone 7–14 days after discharge . Results : Both tools were similarly associated with high satisfaction and few self-reported errors . However , 3D subjects demonstrated greater underst and ing of their medications . Conclusions : Although both tools are associated with similarly high levels of patient satisfaction and low rates of self-reported medication error , 3D appears to promote patient underst and ing of the medications , and warrants further study Objectives : To assess the effectiveness of an intervention package comprising intense education , a range of reporting options , changes in report management and enhanced feedback , in order to improve incident-reporting rates and change the types of incidents reported . Design , setting and participants : Non-equivalent group controlled clinical trial involving medical and nursing staff working in 10 intervention and 10 control units in four major cities and two regional hospitals in South Australia . Main outcome measures : Comparison of reporting rates by type of unit , profession , location of hospital , type of incident reported and reporting mechanism between baseline and study periods in control and intervention units . Results : The intervention result ed in significant improvement in reporting in inpatient areas ( additional 60.3 reports/10 000 occupied bed days ( OBDs ) ; 95 % CI 23.8 to 96.8 , p<0.001 ) and in emergency departments ( EDs ) ( additional 39.5 reports/10 000 ED attendances ; 95 % CI 17.0 to 62.0 , p<0.001 ) . More reports were generated ( a ) by doctors in EDs ( additional 9.5 reports/10 000 ED attendances ; 95 % CI 2.2 to 16.8 , p = 0.001 ) ; ( b ) by nurses in inpatient areas ( additional 59.0 reports/10 000 OBDs ; 95 % CI 23.9 to 94.1 , p<0.001 ) and ( c ) anonymously ( additional 20.2 reports/10 000 OBDs and ED attendances combined ; 95 % CI 12.6 to 27.8 , p<0.001 ) . Compared with control units , the study result ed in more documentation , clinical management and aggression-related incidents in intervention units . In intervention units , more reports were su bmi tted on one-page forms than via the call centre ( 1005 vs 264 reports , respectively ) . Conclusions : A greater variety and number of incidents were reported by the intervention units during the study , with improved reporting by doctors from a low baseline . However , there was considerable heterogeneity between reporting rates in different types of units Objective : To increase patient safety event reporting in three intensive care units ( ICUs ) using a new voluntary card-based event reporting system and to compare and evaluate observed differences in reporting among healthcare workers across ICUs . Design : Prospect i ve , single-center , interventional study . Setting : A medical ICU ( 19 beds ) , surgical ICU ( 24 beds ) , and cardiothoracic ICU ( 17 beds ) at a 1,371-bed urban teaching hospital . Patients : Adult patients admitted to these three study ICUs . Interventions : Use of a new , internally design ed , card-based reporting program to solicit voluntary anonymous reporting of medical errors and patient safety concerns . Measurements and Main Results : During a 14-month period , 714 patient safety events were reported using a new card-based reporting system , reflecting a significant increase in reporting compared with pre-intervention Web-based reporting ( 20.4 reported events/1,000 patient days pre-intervention to 41.7 reported events/1,000 patient days postintervention ; rate ratio , 2.05 ; 95 % confidence interval , 1.79–2.34 ) . Nurses su bmi tted the majority of reports ( nurses , 67.1 % ; physicians , 23.1 % ; other reporters , 9.5 % ) ; however , physicians experienced the greatest increase in reporting among their group ( physicians , 43-fold ; nurses , 1.7-fold ; other reporters , 4.3-fold ) relative to pre-intervention rates . There were significant differences in the reporting of harm by job description : 31.1 % of reports from nurses , 36.2 % from other staff , and 17.0 % from physicians described events that did not reach/affect the patient ( p = .001 ) ; and 33.9 % of reports from physicians , 27.2 % from nurses , and 13.0 % from other staff described events that caused harm ( p = .005 ) . Overall reported patient safety events per 1,000 patient days differed by ICU ( medical ICU = 55.5 , cardiothoracic ICU = 25.3 , surgical ICU = 40.2 ; p < .001 ) . Conclusions : This card-based reporting system increased reporting significantly compared with pre-intervention Web-based reporting and revealed significant differences in reporting by healthcare worker and ICU . These differences may reveal important preferences and priorities for reporting medical errors and patient safety events Background : Medication errors are common in the neonatal intensive care unit ( NICU ) . Various strategies to reduce errors have been described in adult and paediatric patients but there are few published data on their effect in the NICU . Aim : To describe the medication errors occurring within an NICU , and assess the impact of a combined risk management/ clinical pharmacist led education programme on these errors . Methods : Medication errors were identified prospect ively over one year by critical incident reporting . Four months into the study , a pharmacist led education programme was instituted . This involved a daily , cot side , pharmacist led review of medication orders . Each new member of pharmacy , nursing , or medical staff was also required to successfully complete a series of dose calculations . In addition , a risk management approach was used to make several changes in practice during the study period . Results : A total of 105 errors were identified , four serious , 45 potentially serious , and 56 minor . The four serious errors included two tenfold dose miscalculations . Most ( 71 % ) of the errors were due to poor prescribing . After the introduction of our interventions , monthly medication errors fell from a mean ( SD ) of 24.1 ( 1.7 ) per 1000 neonatal activity days to 5.1 ( 3.6 ) per 1000 days ( p < 0.001 ) in the following three months . The subsequent change over of junior medical staff was associated with a significant increase in medication errors to 12.2 ( 3.6 ) per 1000 neonatal activity days ( p = 0.037 ) . However , the number remained significantly less than before our interventions ( p < 0.001 ) . Three serious errors occurred in the first four months compared with one in the second eight month period , the latter corresponding to the six monthly change over of junior medical staff . Conclusions : Medication errors are common in NICUs . Fortunately , actual harm to an infant is rare . Interventions to reduce errors , particularly within the context of a risk management programme , are effective BACKGROUND Patient falls constitute a major threat to health services ' ability to provide care . Previous studies confirm that nurses can identify patients at risk and that a preventative programme can reduce the rate of falls but few studies have been evaluated over time . AIMS AND OBJECTIVES A study was undertaken to test a Falls Prevention Programme in an acute medical area that was re-evaluated 5 years later to determine if the effects were sustainable . DESIGN The design included two groups of patients admitted before and after the programme . Variables such as staffing , equipment , environment and routines were controlled . However , because of ethical approval constraints , some variables such as age , mental status , mobility and gender were not . METHODS The programme included a risk assessment tool , a choice of interventions , a graphic that alerted others to ' at risk patients ' and simple patient and staff education . Data were collected using incident forms and a formula was used to calculate a rate of falls . A non-paired t-test compared rates and anova examined the relationship of age , gender , mobility and mental status on the incidence of falls . Control graphs determined the stability of the process . RESULTS The falls rate was significantly reduced . Control graphs demonstrate that the process achieved greater control with less variation . In the next 5 years the falls rate increased to preprogramme levels and control graphs demonstrated that the process was no longer controlled . Compliance with the programme had deteriorated . CONCLUSIONS The practice review considered skill mix , patient activity and acuity but provided no definitive answers to explain non-compliance . The implication s to nursing are discussed . RELEVANCE TO CLINICAL PRACTICE Clinicians are called to conduct more rigorous research into falls prevention but it may be more useful to direct research towards examining nursing work and increasing nurse autonomy in falls prevention |
13,675 | 21,099,614 | : Moderate-to-high levels of anticardiolipin antibodies are associated with preeclampsia , but there is insufficient evidence to use anticardiolipin antibodies as predictors of preeclampsia in clinical practice | OBJECTIVE : To systematic ally review the evidence of the association of anticardiolipin antibodies with preeclampsia . | OBJECTIVE To evaluate the prevalence in normal pregnancies of anti-32 glycoprotein I ( anti-beta2GPI ) antibodies , and their association with obstetrical complications . STUDY DESIGN Prospect i ve study of anti-beta2GPI and anticardiolipin ( CL ) antibodies in 510 healthy pregnant women at 15 - 18 weeks . According to the results , women were categorized into three groups : group I , negative for both antibodies ; group II , positive for anti-beta2GPI antibodies ; group III , positive for aCL only . The rates of fetal loss , abruptio placentae , preeclampsia-eclampsia , and fetal growth retardation were compared in the three groups . RESULTS Anti-beta2GPI antibodies were found in 20 women ( 3.9 % ) and aCL in 8 patients ( 1.6 % ) . Obstetrical complications were more frequent , even if not significantly different , in group II , 15 % , than in group I , 4.1 % ( difference 10.9 % ; 95 % confidence interval ( CI ) : 1.6 - 20.2 % ; p=0.0575 ) , while no complications were seen in group III . Preeclampsia-eclampsia were significantly more frequent in group II ( 10 % ) than in group I ( 0.8 % ; difference 9.2 % ; 95 % CI : 4.4 - 14 % ; p=0.021 ) . The prevalence of fetal growth retardation was not significantly different in the two groups ( 5 % vs. 2 % , respectively ) . COMMENT Our findings indicate that anti-beta2GPI antibodies are associated with some obstetrical complications , mainly preeclampsia-eclampsia , even if more conventional antiphospholipid antibodies are not present . This observation suggests that these antibodies should be investigated in such cases , in order to improve the outcome of subsequent pregnancies , as well as in women with a history of early and /or recurrent severe preeclampsia in order to start a prophylactic treatment ( i.e. low-dose aspirin or heparin ) Objective To investigate the association of anticardiolipin antibody with the genesis of spontaneous abortion , fetal growth restriction ( FGR ) , and preeclampsia . Methods Eight hundred sixty pregnant women constituted the study population . Anticardiolipin antibody was screened by enzyme-linked immunosorbent assay during the first trimester of pregnancy . The outcome of pregnancy in these women was analyzed prospect ively , and the rate of occurrence of spontaneous abortion , preeclampsia , and FGR was compared in the anticardiolipin antibody-positive and -negative groups . Results Anticardiolipin antibody was positive in 60 of the 860 women ( 7.0 % ) and negative in 800 ( 93.0 % ) . The rate of spontaneous abortions in the anticardiolipin antibody-positive group , 25.0 % , was significantly higher than that in the anticardiolipin antibody-negative group , at 9.8 % ( P < .001 ; relative risk [ RR ] 2.56 , 95 % confidence interval ( CI ) 1.37–4.81 ) . The rates of preeclampsia ( 11.7 % ) and FGR ( 11.7 % ) in the anticardiolipin antibody-positive group were also significantly higher than those in the -negative group ( 1.9 and 1.9 % , respectively ; for preeclampsia , P < .001 ; RR 6.22 , 95 % CI 2.43–16.0 and for FGR , P < .001 ; RR 6.22 , 95 % CI 2.43–16.0 ) . Conclusion Anticardiolipin antibody is associated with adverse outcomes of pregnancy such as spontaneous abortion , preeclampsia , and FGR OBJECTIVE : To test the feasibility of creating a valid and reliable checklist with the following features : appropriate for assessing both r and omised and non-r and omised studies ; provision of both an overall score for study quality and a profile of scores not only for the quality of reporting , internal validity ( bias and confounding ) and power , but also for external validity . DESIGN : A pilot version was first developed , based on epidemiological principles , review s , and existing checklists for r and omised studies . Face and content validity were assessed by three experienced review ers and reliability was determined using two raters assessing 10 r and omised and 10 non-r and omised studies . Using different raters , the checklist was revised and tested for internal consistency ( Kuder-Richardson 20 ) , test-retest and inter-rater reliability ( Spearman correlation coefficient and sign rank test ; kappa statistics ) , criterion validity , and respondent burden . MAIN RESULTS : The performance of the checklist improved considerably after revision of a pilot version . The Quality Index had high internal consistency ( KR-20 : 0.89 ) as did the subscales apart from external validity ( KR-20 : 0.54 ) . Test-retest ( r 0.88 ) and inter-rater ( r 0.75 ) reliability of the Quality Index were good . Reliability of the subscales varied from good ( bias ) to poor ( external validity ) . The Quality Index correlated highly with an existing , established instrument for assessing r and omised studies ( r 0.90 ) . There was little difference between its performance with non-r and omised and with r and omised studies . Raters took about 20 minutes to assess each paper ( range 10 to 45 minutes ) . CONCLUSIONS : This study has shown that it is feasible to develop a checklist that can be used to assess the method ological quality not only of r and omised controlled trials but also non-r and omised studies . It has also shown that it is possible to produce a checklist that provides a profile of the paper , alerting review ers to its particular method ological strengths and weaknesses . Further work is required to improve the checklist and the training of raters in the assessment of external validity OBJECTIVE To estimate whether antiphospholipid antibodies , specifically anticardiolipin and anti – β2-glycoprotein-Iantibodies , are associated with preeclampsia . METHODS Plasma was prospect ively obtained from four groups of pregnant women : those with 1 ) mild preeclampsia ( n = 109 ) ; 2 ) severe preeclampsia ( n = 134 ) ; 3 ) hemolysis , elevated liver enzymes , low platelets ( HELLP ) syndrome ( n = 57 ) ; and 4 ) normotensive controls ( n = 100 ) . Anticardiolipin and anti – β2-glycoprotein-I levels were determined by enzyme-linked immunoassay . RESULTS Subjects with mild preeclampsia , severe preeclampsia , and HELLP syndrome did not have significantly elevated levels of immunoglobulin G ( IgG ) and IgM anticardiolipin and anti – β2-glycoprotein-I antibodies compared with normotensive controls ( P > .05 , Kruskal – Wallis ) . Similarly , subjects with mild preeclampsia , severe preeclampsia , and HELLP syndrome did not have a significantly higher proportion of women testing positive for each autoantibody compared with normotensive controls ( χ2 ) . The proportion of patients testing positive for anticardiolipin and anti – β2-glycoprotein-I antibodies were similar in patients with preeclampsia developing before and after 34 weeks ' gestation ( χ2 ) . CONCLUSION Circulating levels of both anticardiolipin and anti – β2-glycoprotein-I antibodies were not increased in patients with mild preeclampsia , severe preeclampsia , or HELLP syndrome compared with normotensive controls . Our data do not support routine testing for anticardiolipin and anti – β2-glycoprotein-I antibodies in women with preeclampsia Objective : To determine whether specific subtypes of early-onset hypertensive disorders of pregnancy ( haemolysis , elevated liver enzymes , low platelets [ HELLP ] syndrome ; severe preeclampsia ; eclampsia ; and fetal growth restriction ) differ in increased prevalences of thrombophilic disorders . Design : Cohort study . Setting : Two university hospitals in Amsterdam , the Netherl and s. Population : 216 patients participating in a r and omized clinical trial with severe and early-onset hypertensive disorders of pregnancy . Methods : More than 3 months after delivery , all patients were invited for a thrombophilia screening protocol , including hereditary thrombophilic disorders ( Factor II or V-Leiden mutation , APC-resistance , protein S deficiency ) , antiphospholipid antibodies ( anticardiolipin antibodies and lupus anticoagulant activity ) , and hyperhomocysteinemia ( before and after methionin challenge ) . Disease expression was classified by HELLP syndrome , severe preeclampsia , or neonatal birth weight ratio below the median ( 0.65 ) . Univariate and multinomial regression analyses examined the association of disease expression with thrombophilic disorders , and other associated factors ( chronic hypertension , smoking , body mass index , positive family history of cardiovascular morbidity , and demographic parameters ) . Main outcome measures : incidence of thrombophilic disorders in different subtypes of disease . Results : Overall prevalence of thrombophilic disorders in 206 ( 95 % ) screened women was 36 % . Chronic hypertension was present in 32 % , and 34 % had a positive family history of cardiovascular morbidity . Multinomial regression analysis showed that hereditary thrombophilia was more frequent among women with infants with a birth weight ratio < 0.65 than in women with HELLP syndrome or severe preeclampsia ( p = 0.01 , OR 5.1 ( 1.5 to 7.3 ) and OR 3.4 ( 1.1 to 10.6 ) , respectively ) . High body mass index was less frequent in women with HELLP syndrome than in those with severe preeclampsia or fetal growth restriction ( p = 0.06 , OR 0.5 ( 0.3 to 0.9 ) and OR 0.4 ( 0.2 to 1.0 ) , respectively ) . Conclusion : In this population , the high prevalence of thrombophilic factors and chronic hypertension was confirmed . There were small differences between groups . Hereditary thrombophilic disorders were associated with fetal growth restriction but not with type of maternal disease , suggesting an effect on placental function . Maternal body mass index was lower in women with HELLP syndrome OBJECTIVE The aim of this prospect i ve study was to determine the impact of thrombophilia on the recurrence of preeclampsia . STUDY DESIGN In a multicenter , observational , cohort design , 172 white patients with a previous pregnancy complicated by preeclampsia were observed in the next pregnancy . They were evaluated for heritable thrombophilia ( factor V Leiden and factor II G20210A mutations , protein S , protein C , and antithrombin deficiency ) , hyperhomocystinemia , lupus anticoagulant , and anticardiolipin antibodies . Development of preeclampsia and maternal complications and both gestational age at delivery and birthweight were recorded . RESULTS Sixty women ( 34.9 % ) showed the presence of a thrombophilic defect . They had a higher risk for the recurrence of preeclampsia ( odds ratio [ OR ] , 2.5 ; 95 % confidence interval [ CI ] , 1.2 - 5.1 ) , compared to patients without thrombophilia . Similar findings were observed considering only heritable thrombophilia . Thrombophilic patients were at increased risk for the occurrence of very early preterm delivery ( < 32 weeks ; OR , 11.6 ; 95 % CI , 3.4 - 43.2 ) . CONCLUSION When counseling white women with a history of preeclampsia , screening for thrombophilia can be useful for preconceptional counseling and pregnancy management Antiphospholipid antibody ( aPL ) is associated with thromboembolism . There is scant evidence of a relationship between the aPL profile and serious adverse pregnancy outcome . The aim of this study was to assess whether aPL measurements during early pregnancy were useful in predicting a serious adverse pregnancy outcome . In this prospect i ve study , we measured aPLs , including lupus anticoagulant ( LA ) , IgG , IgM , IgA anticardiolipin antibody ( aCL ) , IgG , IgM phosphatidylserine-dependent antiprothrombin antibody , and IgG kininogen-dependent antiphosphatidylethanolamine antibody ( aPE ) during the first trimester in a consecutive series of 1155 women . The 99 th percentile cut-off values in each aPL were determined using sample s from 105 women who did not exhibit any pregnancy morbidity . We assessed the predictive risk of a serious adverse pregnancy outcome adjusted for confounding factors . We found that IgG aCL was associated with developing pregnancy-induced hypertension ( PIH ) ( odds ratio 11.4 , 95 % CI 2.7 - 48 ) ; IgG aPE with PIH ( 8.3 , 2.4 - 29 ) , severe PIH ( 20.4 , 4.5 - 91 ) , and premature delivery ( PD ) ( 12.7 , 3.1 - 50 ) ; and LA with PD ( 11.0 , 2.8 - 44 ) and low birth weight ( 8.0 , 2.1 - 31 ) . The combinations of IgG aPE plus IgG aCL ( 17.5 , 4.7 - 66.7 ) or IgG aPE plus LA ( 22.2 , 5.4 - 909 ) measurements predicted severe PIH with 30.8 % sensitivity and 99.2 % specificity . We conclude that aPL measurements during early pregnancy may be useful in predicting adverse pregnancy outcome OBJECTIVE To determine whether higher levels of anti-beta2-glycoprotein 1 before 25 weeks ' gestation are independently associated with either pregnancy loss or pregnancy-induced hypertension . METHODS Serum sample s for the immunoglobulin ( Ig ) G and IgM isotypes of anti-beta2-glycoprotein 1 , anticardiolipin antibody , and antiphosphatidylserine were collected from 325 low-risk nulliparas who presented for prenatal care before 25 weeks ' gestation . This cohort was followed prospect ively for the development of pregnancy loss and pregnancy-induced hypertension . RESULTS The adjusted odds ratios ( OR ) and 95 % confidence intervals ( CI ) of elevated antiphospholipid antibody levels for pregnancy loss were : IgG anti-beta2-glycoprotein 1 , OR 1.2 ( CI 0.5 , 2.8 ) ; IgG anticardiolipin antibody , OR 8.4 ( CI 2.3 , 31 ) ; and IgG antiphosphatidylserine , OR 5.2 ( CI 1.4 , 18.7 ) . The relative risks of pregnancy loss for all IgG antiphospholipid antibodies were higher among women who had blood collected after 10 weeks ' gestation compared with those studied before 10 weeks ' gestation . However , there were only marginal differences in the attributable risks , suggesting that the impact of elevated levels of antiphospholipid antibodies might be similar in early and later stages of pregnancy . None of the antiphospholipid antibodies was associated with pregnancy-induced hypertension . CONCLUSION In this study , elevated levels of IgG anticardiolipin and IgG antiphosphatidylserine antibodies were markers of pregnancy loss , but an elevated level of anti-beta2-glycoprotein was not a strong predictor of fetal loss OBJECTIVE The aim of this study was to determine whether positive results of tests for any of 5 antiphospholipid antibodies are associated with recurrent preeclampsia among women with a history of preeclampsia in a previous pregnancy . STUDY DESIGN Second-trimester serum sample s were obtained from 317 women with preeclampsia in a previous pregnancy who were being followed up in a prospect i ve treatment trial . The serum sample s were measured by enzyme-linked immunoassay for immunoglobulin G and immunoglobulin M antibodies against 5 phospholipids . Positive results were analyzed with regard to preeclampsia , severe preeclampsia , intrauterine growth restriction , and preterm delivery . RESULTS Sixty-two of the 317 women ( 20 % ) had recurrent preeclampsia develop , 19 ( 6 % ) had severe preeclampsia , and 18 ( 5.8 % ) were delivered of infants with growth restriction . Positive results of tests for immunoglobulin G or immunoglobulin M antiphospholipid antibodies were not associated with recurrent preeclampsia . Positive results for immunoglobulin G or immunoglobulin M antibodies at the 99th percentile were also not associated with preterm delivery . Positive results at the 99th percentile for immunoglobulin G antiphosphatidylserine antibody were associated with severe preeclampsia , and positive results at the 99th percentile for immunoglobulin G anticardiolipin , antiphosphatidylinositol , and antiphosphatidylglycerol antibodies were associated with intrauterine growth restriction . The positive predictive values for these outcomes all were approximately 30 % . CONCLUSION Positive results of testing for antiphospholipid antibodies in the second trimester were not associated with recurrent preeclampsia among women at risk because of a history of preeclampsia . Positive results for immunoglobulin G antiphosphatidylserine antibody were associated with severe preeclampsia , and positive results for immunoglobulin G anticardiolipin , antiphosphatidylinositol , and antiphosphatidylglycerol antibodies were associated with intrauterine growth restriction . However , the positive predictive values for all these associations were modest . Testing for antiphospholipid antibodies during pregnancy is of little prognostic value in the assessment of the risk for recurrent preeclampsia among women with a history of preeclampsia The object of this study was to evaluate the changes in fibrinolysis and clotting inhibitors in patients with preeclampsia and to describe the connection between preeclampsia and blood pressure values . Two groups of pregnant women were prospect ively studied at delivery : group 1 women without preeclampsia and group 2 patients with preeclampsia . The variables that were registered are : diastolic blood pressure ( DBP ) , systolic blood pressure ( SBP ) , mean blood pressure ( MBP ) , hemoglobin ( Hb ) , platelet count ( Plt ) , lupus like inhibitor , anticardiolipin antibodies ( ACA ) , antinuclear antibodies ( ANA ) , fibronectina , D dimer , protein S ( PS ) , protein C ( PC ) and vo Willebr and factor ( vWF ) . 62 pregnant women were included . The patients of group 2 presented high values of Hb ( p 0.01 ) , fibronectin ( p 0.0001 ) , D-dimer ( p 0.01 ) and lower PC ( p 0.04 ) . We found an association between fibronectin and higher values of SBP , DBP , MBP and Hb ( p 0.0007 ) versus lower values of VFW and PC ( p 0.002 ) . The low values of total PS were associated with high D-dimer and SBP results ( p 0.04 and 0.002 respectively ) . All patients were ACA/ANA negative . In preclampsia there is a increased hemoconcentration and drop in clotting inhibitors ( PC ) , without fibrinolytic compensatory response ( lower D-dimer ) and remarked vasopressive effect ( hig fibronectin ) . This changes depend on the stratification of blood pressure . Th SBP and MBP values depend on the haemodynamic changes ( Hb , fibronectin ) , while the increase in DBP expresses a non compensated thrombophilic state BACKGROUND Antiphospholipid antibodies are associated with thrombocytopenia and fetal loss , and have been reported elevated in patients with preeclampsia-eclampsia . Site : Preeclampsia-Eclampsia Research Unit , Instituto Materno Infantil del Estado de Mexico , Toluca , Mexico and the Specialty Hospital Research Unit , La Raza Medical Center , Mexico City , Mexico . OBJECTIVE To determine the presence of anticardiolipin antibodies ( IgG-IgM ) as markers of acute endothelial damage in patients with preeclampsia . MATERIAL AND METHODS A r and omized case control study composed of two groups : Group A ( cases ) , 18 patients with preeclampsia-eclampsia and group B ( control ) , 18 normal pregnancies . Antiphospholipid ( anticardiolipin ) antibodies were determined in both groups in addition to with coagulation tests and clinical variables in mother and newborn in day of admission and nine weeks after obstetrical resolution . We excluded patients with anticoagulant or dialysis therapy , taking NSAIDs or who recently required transfusion or plasmaferesis . RESULTS There were significant differences in levels of IgM and in weights and mortality among newborns between the two groups . In terms of maternal complications , we found HELLP syndrome as leading cause . We also observed in the case group significant differences in mean arterial pressure ( MAP ) and IgM levels between admission day and nine weeks later . Our results lead us to the conclusion that there must be exist immunologic mechanism that induces synthesis of anticardiolipin antibodies ( IgM isotype ) during acute state of the disease , accounting for vascular changes and prothrombotic state responsible for maternal and neonatal complications Our aim was to eluci date prospect ively whether beta 2-glycoprotein I-dependent anticardiolipin antibodies ( beta 2GPI-dependent aCL ; autoimmune type ) can predict an adverse pregnancy outcome in healthy pregnant women and whether beta 2GPI-dependent aCL should be applied for routine screening of the pregnant population . A prospect i ve cohort study was performed on 1600 healthy pregnant women from whom blood sample s were obtained at about week 10 of gestation . We used a modified enzyme-linked immunosorbent assay with which to divide the subjects into three study groups : beta 2GPI-independent aCL positive , beta 2GPI-dependent aCL positive and aCL negative . Their subsequent pregnancy outcomes were ascertained and the three study groups were compared statistically for the following poor pregnancy outcomes : intrauterine fetal death ( IUFD ) after 12 gestational weeks , intrauterine growth retardation ( IUGR ) and pre-eclampsia . The total number of patients eligible for this study was 1125 . The prevalence of beta 2GPI-dependent aCL positive was eight ( 0.7 % ) , beta 2GPI-independent aCL positive was 17 ( 1.5 % ) and aCL negative was 1100 ( 97.8 % ) . Beta 2-GPI-dependent aCL positivity was significantly associated with poor pregnancy outcome : 25.0 % of beta 2GPI-dependent aCL-positive and 0.5 % of aCL-negative patients experienced IUFD [ relative risk 52.4 ; 95 % confidence interval ( CI ) , 12.7 - 216.3 ; P = 0.0009 ] ; 37.5 % of beta 2GPI-dependent aCL-positive and 2.9 % of aCL-negative patients experienced IUGR ( relative risk 18.4 ; 95 % CI , 4.6 - 74.0 ; P = 0.001 ) ; and 50.0 % of beta 2GPI-dependent aCL-positive and 4.0 % aCL-negative patients experienced pre-eclampsia ( relative risk 22.1 ; 95 % CI , 5.7 - 85.7 ; P = 0.0002 ) . In contrast , beta 2GPI-independent aCL did not show any significant association with such adverse pregnancy outcomes . beta 2GPI-dependent aCL are significantly highly associated with adverse pregnancy outcomes in healthy pregnant women and can be used for prediction purpose s , whereas beta 2GPI-independent aCL can not . Our results suggest that routine screening for beta 2GPI-dependent aCL should be introduced for the general pregnant population OBJECTIVE To confirm the association of antiphospholipid antibodies with early onset of severe pre-eclampsia before 30 weeks ' gestation . STUDY DESIGN Thirty-four patients with diastolic blood pressure levels > or = 110 mmHg and at least 2 + proteinuria before the 30th week of pregnancy were r and omly chosen for inclusion in the study . Blood sample s were taken for assessment of anticardiolipin antibodies ( ACAs ) , lupus anticoagulant , syphilitic serology and antinuclear antibodies . Fifteen normal antenatal patients matched for age , parity and gestational age acted as control subjects . RESULTS Four of the 34 women ( 11.7 % ) in the study group had elevated levels of both ACAs and lupus anticoagulant , compared with none in the control group . This was not found to be statistically different . CONCLUSION Given the low incidence of positive ACAs in early-onset severe pre-eclampsia it is unlikely that they are implicated in its pathogenesis . It is possible that they represent a small subset of patients with alternative or combined pathology |
13,676 | 12,237,193 | The odds-ratio for a 50 % reduction in pain was 9.62 and the number needed to treat was 2.32 , indicating that the psychological treatments examined are effective in reducing the pain of headache . | null | null |
13,677 | 30,743,995 | The majority , particularly “ behavioural and policy ” preventive interventions , were cost-effective , even cost-saving . | Many suggested policy interventions for childhood and adolescent obesity have costs and effects that fall outside the health care sector .
These cross-sectorial costs and consequences have implication s for how economic evaluation is applied and although previous systematic review s have provided a summary of cost-effectiveness , very few have conducted a review of methods applied .
We undertook this comprehensive review of economic evaluations , appraising the methods used , assessing the quality of the economic evaluations , and summarising cost-effectiveness . | OBJECTIVE To assess from a societal perspective the incremental cost-effectiveness of a family-based GP-mediated intervention targeting overweight and moderately obese children . The intervention was modelled on the LEAP ( live , eat and play ) trial , a r and omised controlled trial conducted by the Centre for Community Child Health , Melbourne , Australia in 2002 - 2003 . This study was undertaken as part of the assessing cost-effectiveness ( ACE ) in obesity project which evaluated , using consistent methods , 13 interventions targeting unhealthy weight gain in children and adolescents . METHOD A logic pathway was used to model the effects of the intervention compared to no intervention on body mass index ( BMI ) and health outcomes ( disability-adjusted life years-DALYs ) . Disease costs and health benefits were tracked until the cohort of eligible children reached the age of 100 years or death . Simulation-modelling techniques were used to present a 95 % uncertainty interval around the cost-effectiveness ratio . The intervention was also assessed against a series of filters ( ' equity ' , ' strength of evidence ' , ' acceptability ' , ' feasibility ' , sustainability ' and ' side-effects ' ) to incorporate additional factors that impact on re source allocation decisions . RESULTS The intervention , as modelled , reached 9685 children aged 5 - 9 years with a BMI z-score of > or=3.0 , and cost $ AUD6.3 M ( or $ AUD4.8 M excluding time costs ) . It result ed in an incremental saving of 2300 BMI units which translated to 511 DALYs . The cost-offsets stemming from the intervention totalled $ AUD3.6 M , result ing in a net cost per DALY saved of $ AUD4670 ( dominated ; $ 0.1 M ) ( dominated means intervention costs more for less effect ) . CONCLUSION Compared to a ' no intervention ' control group , the intervention was cost-effective under current assumptions , although the uncertainty intervals were wide . A key question related to the long-term sustainability of the small incremental weight loss reported , based on the 9-month follow-up results for LEAP BACKGROUND Effective programmes to help children manage their weight are required . ' Families for Health ' focuses on a parenting approach , design ed to help parents develop their parenting skills to support lifestyle change within the family . Families for Health version 1 showed sustained reductions in mean body mass index ( BMI ) z-score after 2 years in a pilot project . OBJECTIVE The aim was to evaluate its effectiveness and cost-effectiveness in a r and omised controlled trial ( RCT ) . DESIGN The trial was a multicentre , investigator-blind RCT , with a parallel economic and process evaluation , with follow-up at 3 and 12 months . R and omisation was by family unit , using a 1 : 1 allocation by telephone registration , stratified by three sites , with a target of 120 families . SETTING Three sites in the West Midl and s , Engl and , UK . PARTICIPANTS Children aged 6 - 11 years who were overweight ( ≥ 91st centile BMI ) or obese ( ≥ 98th centile BMI ) , and their parents/carers . Recruitment was via referral or self-referral . INTERVENTIONS Families for Health version 2 is a 10-week , family-based community programme with parallel groups for parents and children , addressing parenting , lifestyle , social and emotional development . Usual care was the treatment for childhood obesity provided within each locality . MAIN OUTCOME MEASURES Joint primary outcome measures were change in children 's BMI z-score and incremental cost per quality -adjusted life-year ( QALY ) gained at 12 months ' follow-up ( QALYs were calculated using the European Quality of Life-5 Dimensions Youth version ) . Secondary outcome measures included changes in children 's waist circumference , percentage body fat , physical activity , fruit/vegetable consumption and quality of life . Parents ' BMI and mental well-being , family eating/activity , parent-child relationships and parenting style were also assessed . The process evaluation documented recruitment , reach , dose delivered , dose received and fidelity , using mixed methods . RESULTS The study recruited 115 families ( 128 children ; 63 boys and 65 girls ) , with 56 families r and omised to the Families for Health arm and 59 to the ' usual-care ' control arm . There was 80 % retention of families at 3 months ( Families for Health , 46 families ; usual care , 46 families ) and 72 % retention at 12 months ( Families for Health , 44 families ; usual care , 39 families ) . The change in BMI z-score at 12 months was not significantly different in the Families for Health arm and the usual-care arm [ 0.114 , 95 % confidence interval ( CI ) -0.001 to 0.229 ; p = 0.053 ] . However , within-group analysis showed that the BMI z-score was significantly reduced in the usual-care arm ( -0.118 , 95 % CI -0.203 to -0.034 ; p = 0.007 ) , but not in the Families for Health arm ( -0.005 , 95 % CI -0.085 to 0.078 ; p = 0.907 ) . There was only one significant difference between groups for secondary outcomes . The economic evaluation , taking a NHS and Personal Social Services perspective , showed that mean costs 12 months post r and omisation were significantly higher for Families for Health than for usual care ( £ 998 vs. £ 548 ; p < 0.001 ) . The mean incremental cost-effectiveness of Families for Health was estimated at £ 552,175 per QALY gained . The probability that the Families for Health programme is cost-effective did not exceed 40 % across a range of thresholds . The process evaluation demonstrated that the programme was implemented , as planned , to the intended population and any adjustments did not deviate widely from the h and book . Many families waited more than 3 months to receive the intervention . Facilitators ' , parents ' and children 's experiences of Families for Health were largely positive and there were no adverse events . Further analysis could explore why some children show a clinical ly significant benefit while others have a worse outcome . CONCLUSIONS Families for Health was neither effective nor cost-effective for the management of obesity in children aged 6 - 11 years , in comparison with usual care . Further exploration of the wide range of responses in BMI z-score in children following the Families for Health and usual-care interventions is warranted , focusing on children who had a clinical ly significant benefit and those who showed a worse outcome with treatment . Further research could focus on the role of parents in the prevention of obesity , rather than treatment . TRIAL REGISTRATION Current Controlled Trials IS RCT N45032201 . FUNDING This project was funded by the National Institute for Health Research ( NIHR ) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol . 21 , No. 1 . See the NIHR Journals Library website for further project information Background The dramatic rise of overweight and obesity among Chinese children has greatly affected the social economic development . However , no information on the cost-effectiveness of interventions in China is available . The objective of this study is to evaluate the cost and the cost-effectiveness of a comprehensive intervention program for childhood obesity . We hypothesized the integrated intervention which combined nutrition education and physical activity ( PA ) is more cost-effective than the same intensity of single intervention . Methods And Findings : A multi-center r and omized controlled trial conducted in six large cities during 2009 - 2010 . A total of 8301 primary school students were categorized into five groups and followed one academic year . Nutrition intervention , PA intervention and their shared common control group were located in Beijing . The combined intervention and its ’ control group were located in other 5 cities . In nutrition education group , ‘ nutrition and health classes ’ were given 6 times for the students , 2 times for the parents and 4 times for the teachers and health workers . " Happy 10 " was carried out twice per day in PA group . The comprehensive intervention was a combination of nutrition and PA interventions . BMI and BAZ increment was 0.65 kg/m2 ( SE 0.09 ) and 0.01 ( SE 0.11 ) in the combined intervention , respectively , significantly lower than that in its ’ control group ( 0.82±0.09 for BMI , 0.10±0.11 for BAZ ) . No significant difference were found neither in BMI nor in BAZ change between the PA intervention and its ’ control , which is the same case in the nutrition intervention . The single intervention has a relative lower intervention costs compared with the combined intervention . Labor costs in Guangzhou , Shanghai and Jinan was higher compared to other cities . The cost-effectiveness ratio was $ 120.3 for BMI and $ 249.3 for BAZ in combined intervention , respectively . Conclusions The school-based integrated obesity intervention program was cost-effectiveness for children in urban China . Trial Registration Chinese Clinical Trial Registry ChiCTR-PRC-09000402 URL : BACKGROUND A school-based obesity prevention study ( Medical College of Georgia FitKid Project ) started in the fall of 2003 in 18 elementary schools . Half of the schools were r and omized to an after-school program that included moderate-to-vigorous physical activity , healthy snacks , homework assistance , and academic enrichment . All third grade rs were invited to enroll . The objective of this study was to assess the cost-effectiveness ( CE ) of the first-year intervention . METHODS St and ard CE analysis methods and a societal perspective were used . Program delivery costs incurred during the first-year intervention and the usual after-school care costs that would occur in the absence of the intervention were estimated ( in 2003 dollars ) . Net intervention costs were calculated by subtracting the usual after-school care costs from the intervention costs . The effectiveness of the intervention was measured as percent body fat ( % BF ) reduction compared with a control condition . The CE was assessed as the net intervention cost divided by the effectiveness of the intervention . RESULTS The intervention costs totaled $ 174,070 , $ 558/student , or $ 956/student who attended > or = 40 % of the intervention sessions . The usual after-school care costs were estimated at $ 639/student . Students who attended > or = 40 % of the intervention reduced % BF by 0.76 % ( 95 % confidence interval : -1.42 to -0.09 ) at an additional cost of $ 317/student . CONCLUSIONS Subjects who attended > or = 40 % of the intervention achieved a significant reduction in % BF at a relatively low cost . School-based obesity prevention programs of this type are likely to be a cost-effective use of public funds and warrant careful consideration by policy makers and program planners Abstract Background Few school-based interventions have been successful in reducing physical activity decline and preventing overweight and obesity in adolescent population s. As a result , few cost effectiveness analyses have been reported . The aim of this paper is to report the cost and cost effectiveness of the Physical Activity 4 Everyone ( PA4E1 ) intervention which was a multi-component intervention implemented in secondary schools located in low-income communities . Cost effectiveness was assessed using both the physical activity and weight status trial outcomes . Methods Intervention and Study Design : The PA4E1 cluster r and omised controlled trial was implemented in 10 Australian secondary schools ( 5 intervention : 5 control ) and consisted of intervention schools receiving seven physical activity promotion strategies and six additional strategies that supported school implementation of the intervention components . Costs associated with physical activity strategies , and intervention implementation strategies within the five intervention schools were estimated and compared to the costs of usual physical activity practice s of schools in the control group . The total cost of implementing the intervention was estimated from a societal perspective , based on the number of enrolled students in the target grade at the start of the intervention ( Grade 7 , n = 837 ) . Economic Outcomes : The economic analysis outcomes were cost and incremental cost effectiveness ratios for the following : minutes of moderate-to-vigorous physical activity ( MVPA ) per day gained , MET hours gained per person/day ; Body Mass Index ( BMI ) unit avoided ; and 10 % reduction in BMI z-score . Results The intervention cost AUD $ 329,952 over 24 months , or AUD$394 per student in the intervention group . This result ed in a cost effectiveness ratio of AUD$56 ( $ 35–$147 ) per additional minute of MVPA , AUD$1 ( $ 0.6–$2.7 ) per MET hour gained per person per day , AUD$1408 ( $ 788–$6,570 ) per BMI unit avoided , and AUD$563 ( $ 282–$3,942 ) per 10 % reduction in BMI z-score . Conclusion PA4E1 is a cost effective intervention for increasing the physical activity levels and reducing unhealthy weight gain in adolescence , a period in which physical activity typically declines . Additional modelling could explore the potential economic impact of the intervention on morbidity and mortality . Trial registration Australian New Zeal and Clinical Trials Registry ACTRN12612000382875 OBJECTIVE : Family-based , behavioral treatment has been shown to be an effective intervention for the management of pediatric obesity . The goal of this study was to compare the cost-effectiveness of two protocol s for the delivery of family-based behavioral treatment . REA SEARCH METHODS AND PROCEDURES : Thirty-one families with obese children were r and omized to groups in which families were provided mixed treatment incorporating both group and individualized treatment vs group treatment only . Cost-effectiveness of treatment was defined as the magnitude of reduction in st and ardized BMI and percentage overweight per dollar spent for recruitment and treatment . Anthropometric data were assessed at baseline , 6 months and 12 months post-r and omization . RESULTS : Results for the 24 families with complete data showed the group intervention was significantly more cost-effective than the mixed treatment . This was due to the similarity between the two groups in Z- BMI or percentage overweight change for children and their parents , while the mixed treatment was significantly more expensive to deliver than the group treatment . DISCUSSION : These findings suggest that a family-based , behavioral intervention employing group treatment alone is a more cost-effective approach to treating pediatric obesity than a mixed group plus individual format Objective To estimate the long‐term cost‐effectiveness of an obesity prevention nutrition education curriculum ( Food , Health , & Choices ) as delivered to all New York City fifth‐ grade public school students over 1 year . Methods This study is a st and ard cost‐effectiveness analysis from a societal perspective , with a 3 % discount rate and a no‐intervention comparator , as recommended by the US Panel on Cost‐effectiveness in Health and Medicine . Costs of implementation , administration , and future obesity‐related medical costs were included . Effectiveness was based on a cluster‐r and omized , controlled trial in 20 public schools during the 2012–2013 school year and linked to published estimates of childhood‐to‐adulthood body mass index trajectories using a decision analytic model . Results The Food , Health , & Choices intervention was estimated to cost $ 8,537,900 and result in 289 fewer males and 350 fewer females becoming obese ( 0.8 % of New York City fifth‐ grade public school students ) , saving 1,599 quality ‐adjusted life‐years ( QALYs ) and $ 8,098,600 in direct medical costs . Food , Health , & Choices is predicted to be cost‐effective at $ 275/QALY ( 95 % confidence interval , –$2,576/QALY to $ 2,084/QALY ) with estimates up to $ 6,029/QALY in sensitivity analyses . Conclusions and Implication s This cost‐effectiveness model suggests that a nutrition education curriculum in public schools is effective and cost‐effective in reducing childhood obesity , consistent with the authors ’ hypothesis and previous literature . Future research should assess the feasibility and sustainability of scale‐up Objective To assess relationships between current physical activity ( PA ) , dietary intake and body mass index ( BMI ) in English children . Design and setting Longitudinal birth cohort study in northeast Engl and , cross-sectional analysis . Participants 425 children ( 41 % of the original cohort ) aged 6–8 years ( 49 % boys ) . Main outcome measures PA over 7 days was measured objective ly by an accelerometer ; three categories of PA were created : ‘ active ’ ≥60 min/day moderate-to-vigorous-intensity PA ( MVPA ) ; ‘ moderately active ’ 30–59 min/day MVPA ; ‘ inactive ’ < 30 min/day MVPA . Dietary intake over 4 days was measured using a prospect i ve dietary assessment tool which incorporated elements of the food diary and food frequency methods . Three diet categories were created : ‘ healthy ’ , ‘ unhealthy ’ and ‘ mixed ’ , according to the number of portions of different foods consumed . Adherence to the ‘ 5-a-day ’ recommendations for portions of fruit and vegetables was also assessed . Children were classified as ‘ healthy weight ’ or ‘ overweight or obese ’ ( OW/OB ) according to International Obesity Taskforce cutpoints for BMI . Associations between weight status and PA/diet categories were analysed using logistic regression . Results Few children met the UK-recommended guidelines for either MVPA or fruit and vegetable intake , with just 7 % meeting the recommended amount of MVPA of 60 min/day , and 3 % meeting the 5-a-day fruit and vegetable recommendation . Higher PA was associated with a lower OR for OW/OB in boys only ( 0.20 , 95 % CI 0.04 to 0.88 ) . There was no association detected between dietary intake and OW/OB in either sex . Conclusions Increasing MVPA may help to reduce OW/OB in boys ; however , more research is required to examine this relationship in girls . Children are not meeting the UK guidelines for diet and PA , and more needs to be done to improve this situation BACKGROUND Obesity runs in families , and family-based behavioral treatment ( FBT ) is associated with weight loss in overweight/obese children and their overweight/obese parents . This study was design ed to estimate the costs and cost-effectiveness of FBT compared to separate group treatments of the overweight/obese parent and child ( PC ) . METHODS Fifty overweight/obese 8- to 12-year-old children with overweight/obese parents were r and omly assigned to 12 months of either FBT or PC treatment program . Assessment of societal costs ( payer plus opportunity costs ) were completed based on two assumptions : ( 1 ) programs for parent and child were available on separate days ( PC-1 ) or ( 2 ) interventions for parent and child were available in the same location at sequential times on the same day ( PC-2 ) . Cost-effectiveness was calculated based on societal cost per unit of change using percent over BMI for children and weight for parents . RESULTS The average societal cost per family was $ 1,448 for FBT and $ 2,260 for PC-1 ( p < 0.001 ) and $ 2,124 for PC-2 ( p < 0.001 ) . Child cost-effectiveness for FBT was $ 209.17/percent over BMI , compared to $ 1,036.50/percent over BMI for PC-1 and $ 973.98/percent over BMI for PC-2 . Parent cost-effectiveness was $ 132.97/pound ( lb ) for FBT and $ 373.53/lb ( PC-1 ) or $ 351.00/lb ( PC-2 ) . CONCLUSIONS For families with overweight/obese children and parents , FBT presents a lower cost per unit of weight loss for parents and children than treating the parent and child separately . Given the high rates of pediatric and adult obesity , FBT may provide a unique cost-effective platform for obesity intervention that alters weight in overweight/obese parents and their overweight/obese children Objective : To model the health benefits and cost-effectiveness of banning television ( TV ) advertisements in Australia for energy-dense , nutrient-poor food and beverages during children 's peak viewing times . Methods : Benefits were modelled as changes in body mass index ( BMI ) and disability-adjusted life years ( DALYs ) saved . Intervention costs ( AUD$ ) were compared with future health-care cost offsets from reduced prevalence of obesity-related health conditions . Changes in BMI were assumed to be maintained through to adulthood . The comparator was current practice , the reference year was 2001 , and the discount rate for costs and benefits was 3 % . The impact of the withdrawal of non-core food and beverage advertisements on children 's actual food consumption was drawn from the best available evidence ( a r and omized controlled trial of advertisement exposure and food consumption ) . Supporting evidence was found in ecological relationships between TV advertising and childhood obesity , and from the effects of marketing bans on other products . A Working Group of stakeholders provided input into decisions surrounding the modelling assumptions and second-stage filters of ‘ strength of evidence ’ , ‘ equity ’ , ‘ acceptability to stakeholders ’ , ‘ feasibility of implementation ’ , ‘ sustainability ’ and ‘ side-effects ’ . Results : The intervention had a gross incremental cost-effectiveness ratio of AUD$ 3.70 ( 95 % uncertainty interval ( UI ) $ 2.40 , $ 7.70 ) per DALY . Total DALYs saved were 37 000 ( 95 % UI 16 000 , 59 000 ) . When the present value of potential savings in future health-care costs was considered ( AUD$ 300 m ( 95 % UI $ 130 m , $ 480 m ) , the intervention was ‘ dominant ’ , because it result ed in both a health gain and a cost offset compared with current practice . Conclusions : Although recognizing the limitations of the available evidence , restricting TV food advertising to children would be one of the most cost-effective population -based interventions available to governments today . Despite its economic credentials from a public health perspective , the initiative is strongly opposed by food and advertising industries and is under review by the current Australian government PURPOSE To compare the costs of parent-only and family-based group interventions for childhood obesity delivered through Cooperative Extension Services in rural communities . METHODS Ninety-three overweight or obese children ( aged 8 to 14 years ) and their parent(s ) participated in this r and omized controlled trial , which included a 4-month intervention and 6-month follow-up . Families were r and omized to either a behavioral family-based intervention ( n = 33 ) , a behavioral parent-only intervention ( n = 34 ) , or a waitlist control condition ( n = 26 ) . Only program costs data for the parent-only and family-based programs are reported here ( n = 67 ) . Assessment s were completed at baseline , post-treatment ( month 4 ) and follow-up ( month 10 ) . The primary outcome measures were total program costs and cost per child for the parent-only and family interventions . FINDINGS Twenty-six families in the parent-only intervention and 24 families in the family intervention completed all 3 assessment s. As reported previously , both intervention programs led to significantly greater decreases in weight status relative to the control condition at month 10 follow-up . There was no significant difference in weight status change between the parent-only and family interventions . Total program costs for the parent-only and family interventions were 13,546 US dollars and 20,928 , US dollars respectively . Total cost per child for the parent-only and family interventions were 521 US dollars and 872 US dollars , respectively . CONCLUSIONS Parent-only interventions may be a cost-effective alternative treatment for pediatric obesity , especially for families in medically underserved setting BACKGROUND A common policy response to the childhood obesity epidemic is to recommend that primary care physicians screen for and offer counseling to the overweight/obese . As the literature suggests , this approach may be ineffective ; it is important to document the opportunity costs incurred by brief primary care obesity interventions that ultimately may not alter body mass index ( BMI ) trajectory . METHODS Live , Eat and Play ( LEAP ) was a r and omized controlled trial of a brief secondary prevention intervention delivered by family physicians in 2002 - 2003 that targeted overweight/mildly obese children aged 5 to 9 years . Primary care utilization was prospect ively audited via medical records , and parents reported family re source use by written question naire . Outcome measures were BMI ( primary ) and parent-reported physical activity and dietary habits ( secondary ) in intervention compared with control children . RESULTS The cost of LEAP per intervention family was AU $ 4094 greater than for control families , mainly due to increased family re sources devoted to child physical activity . Total health sector costs were AU $ 873 per intervention family and AU $ 64 per control , a difference of AU $ 809 ( P < .001 ) . At 15 months , intervention children did not differ significantly in adjusted BMI or daily physical activity scores compared with the control group , but dietary habits had improved . CONCLUSIONS This brief intervention result ed in higher costs to families and the health care sector , which could have been devoted to other uses that do create benefits to health and /or family well-being . This has implication s for countries such as the United States , the United Kingdom , and Australia , whose current guidelines recommend routine surveillance and counseling for high child BMI in the primary care sector UNLABELLED What is already known about this subject Approximately one-fifth of children in the UK are obese . There are currently few , effective interventions available in the UK . There are very little data on relative cost-effectiveness of childhood obesity interventions , which hampers the commissioning of future services . What this study adds Simple multi-component obesity interventions can be provided at relatively low cost per 0.1 body mass index st and ard deviation score ( BMI SDS ) improvement . More intensive and effective interventions incur greater cost per 0.1 BMI SDS reduction but this may be justified given the improved overall BMI SDS reduction attained . OBJECTIVE To describe the costs and outcomes of three models of care for childhood obesity previously evaluated in two 2-arm pilot r and omized trials in Engl and . The treatments were ( i ) a hospital clinic ( control in both trials ) , comprising a multidisciplinary team of consultant , dietitian and exercise specialist ; ( ii ) a nurse-led primary care clinic replicating the service provided by the hospital and ( iii ) an intensive intervention using M and ometer ® , a behaviour modification tool aim ed at encouraging slower eating and better recognition of satiety . METHOD Patient-level data on re sources used to deliver each intervention were collected during the trials . Apart from the cost of the M and ometer ® the majority of cost was staff time , dependent on discipline and grade . Outcome for both trials was body mass index st and ard deviation score ( BMI SDS ) measured at 12 months . RESULTS Cost and outcome data were available for 143 children in total . Cost per child was £ 1749 ( SD £ 243 ) in the M and ometer ® group , £ 301 ( £ 76 ) in the primary care group , and £ 263 ( £ 88 ) and £ 209 ( £ 81 ) in the hospital groups . Mean reduction in BMI SDS was 0.40 ( 0.35 ) , 0.17 ( 0.26 ) , 0.15 ( 0.25 ) and 0.14 ( 0.32 ) , respectively . CONCLUSION Intensive management using M and ometer ® was effective but costly ( £ 432 per 0.1 reduction in BMI SDS ) compared to conventional care ( range £ 153-£173 ) . A total of 26 % children receiving conventional care achieved a clinical ly meaningful reduction in BMI SDS ; however , use of M and ometer ® training may be justified in children not responding to conventional lifestyle interventions OBJECTIVE To assess the cost-effectiveness a school-based intervention design ed to reduce overweight/obesity and other cardiovascular risk factors in children . METHODS St and ard cost effectiveness analysis methods and two perspectives ( societal and institutional ) were used . A cluster-r and omized controlled trial with 10 intervention schools ( 691 children ) and 10 control schools ( 718 children ) was performed . Net costs were calculated by subtracting the usual after-school care cost from intervention costs . The effectiveness of the intervention was measured as the reduction in health outcomes compared with the control group . RESULTS The intervention costs totaled 125,469.75 € , representing 269.83 € /year/child . The usual after-school care was estimated at 844,56 € /year/child . Intervention children showed a decrease in triceps skinfold thickness ( -1.25 mm , 95 % CI : -1.82 to -0.67 ; P<.001 ) . Intervention children with body mass index ( BMI ) between the percentiles 25 and 75 showed a decrease in the percentage of body fat ( -0.59 % ; 95 % CI : -1.03 to -0.67 ; P<.001 ) , and those with a BMI > P75 showed a decrease in triceps skinfold thickness ( -1.87 mm ; 95%CI : -3.43 to -0.32 ; P<.001 ) , and percentage of body fat ( -0.67 % ; 95%CI : -1.32 to -0.01 ; P<.05 ) . CONCLUSIONS This type of after-school program for recreational physical activity to prevent obesity are likely to be a cost-effective use of public funds and warrant careful consideration by policy makers and program planners BACKGROUND Cost-effectiveness analyses facilitate the allocation of health care re sources . The aim of the study was to compare the cost-effectiveness of group treatment , already known to be more effective , with routine counseling in obese children . METHOD A prospect i ve 6-month intervention assessed family-based group treatment ( 15 separate sessions for parents and children ) and routine counseling ( two appointments for children ) . Children 's weights and heights were measured at baseline , at the end of the intervention and at follow up 6 months later , and the changes in weight for height and body mass index st and ard deviations scores ( BMI -SDS ) were calculated and used as main outcome measures . The mean costs and effects of the programs were analyzed to produce the incremental cost-effectiveness ratio , which is an estimate of the additional costs per 1 % decrease in weight for height or 0.1 decrease in BMI -SDS . Cost-effectiveness analysis was performed from the perspective of the service provider . RESULTS At the end of the intervention , group treatment costs were 1.4-fold ( non-calculable 6 months later ) when counted per 1 % weight for height decrease , and 3.5-fold ( 2.8-fold 6 months later ) when counted per 0.1 BMI -SDS decrease . Incremental cost-effectiveness ratio estimates were euro 53 when calculated for 1 % weight for height decrease , and euro 266 ( euro 275 6 months later ) when calculated for 0.1 BMI -SDS decrease . CONCLUSIONS Family-based group treatment is more costly compared with individual routine counseling . Salaries form most of the total costs OBJECTIVE To determine the costs and cost-effectiveness of an early childhood home visiting program delivered to families in socio-economically disadvantaged areas of Sydney , Australia during 2007 - 2010 . METHODS Economic evaluation of a r and omized controlled trial , the healthy beginnings ( HB ) trial , from the perspective of the health funder . Intervention re sources were determined from local health district records in 2012 $ AUD . Health-care re source utilization was determined through patient-level data linkage . RESULTS The cost of HB intervention in the clinical trial over 2 years was $ 1309 per child ( 2012 $ AUD ) . The incremental cost-effectiveness ratio was $ 4230 per unit BMI avoided and $ 631 per 0.1 reduction in BMI z-score . It was estimated that the program could be delivered in practice for $ 709 per child ; with incremental cost-effectiveness ratios of $ 2697 per unit BMI avoided and $ 376 per 0.1 reduction in BMI z-score . CONCLUSIONS We present the first economic evaluation of an effective obesity prevention initiative in early childhood . HB is a moderately priced intervention with demonstrated effectiveness that offers similar or better value for money than existing obesity prevention or treatment interventions targeted at older children |
13,678 | 31,340,953 | Once-weekly semaglutide was not statistically differentiable than all SGLT-2is in reducing systolic blood pressure .
NMA was not feasible for postpr and ial blood glucose and safety outcomes .
Once-weekly semaglutide demonstrated statistically significant and clinical ly meaningful reductions in HbA1c and body weight in T2D patients inadequately controlled with 1 - 2 OADs compared to all SGLT-2is licensed in Europe and North America | OBJECTIVE To determine the comparative efficacy of once-weekly semaglutide relative to sodium-glucose cotransporter 2 inhibitors ( SGLT-2is ) licensed in Europe and North America among patients with type 2 diabetes ( T2D ) inadequately controlled with 1 - 2 oral antidiabetics ( OADs ) , using a network meta- analysis ( NMA ) . | OBJECTIVE To evaluate the efficacy and safety of dapagliflozin in patients with type 2 diabetes inadequately controlled with metformin and sulfonylurea . RESEARCH DESIGN AND METHODS Patients with HbA1c of 7.0 % ( 53 mmol/mol ) to 10.5 % ( 91 mmol/mol ) receiving sulfonylurea and metformin were r and omized to receive dapagliflozin 10 mg/day ( n = 109 ) or placebo ( n = 109 ) for 24 weeks . RESULTS HbA1c ( baseline : dapagliflozin 8.08 % [ 65 mmol/mol ] ; placebo 8.24 % [ 67 mmol/mol ] ) and fasting plasma glucose ( baseline : dapagliflozin 167.4 mg/dL [ 9.29 mmol/L ] ; placebo 180.5 mg/dL [ 10.02 mmol/L ] ) significantly improved from baseline with dapagliflozin ( placebo-subtracted change –0.69 % [ –7.5 mmol/mol ] , P < 0.0001 ; –33.5 mg/dL [ –1.86 mmol/L ] , P < 0.0001 , respectively ) . More patients achieved a therapeutic glycemic response ( HbA1c < 7.0 % [ 53 mmol/mol ] ) with dapagliflozin ( 31.8 % ) versus placebo ( 11.1 % ) ( P < 0.0001 ) . Body weight and systolic blood pressure were significantly reduced from baseline over 24 and 8 weeks , respectively , with dapagliflozin ( placebo-subtracted change –2.1 kg , P < 0.0001 ; –3.8 mmHg , P = 0.0250 ) . Patients receiving dapagliflozin showed placebo-subtracted increases in total , LDL , and HDL cholesterol ( 11.4 mg/dL , P = 0.0091 ; 11.4 mg/dL , P = 0.0030 ; 2.2 mg/dL , P = 0.0172 , respectively ) with no change in LDL/HDL cholesterol ratio ( 0.1 ; P = 0.2008 ) or triglycerides ( –16.5 mg/dL ; P = 0.1755 ) . Adverse events occurred in 48.6 % of patients receiving dapagliflozin and 51.4 % receiving placebo . Significantly more patients with dapagliflozin compared with placebo experienced hypoglycemia ( 12.8 vs. 3.7 % ; P = 0.024 ) and genital infections ( 5.5 vs. 0 % ; P = 0.029 ) . Events of urinary tract infection were reported by 6.4 % of patients in both groups . CONCLUSIONS Dapagliflozin was well tolerated and effective over 24 weeks as add-on to metformin plus sulfonylurea . Adverse effects included hypoglycemia and genital infections OBJECTIVE To compare the efficacy and safety of once-weekly semaglutide 1.0 mg s.c . with exenatide extended release ( ER ) 2.0 mg s.c . in subjects with type 2 diabetes . RESEARCH DESIGN AND METHODS In this phase 3a , open-label , parallel-group , r and omized controlled trial , 813 subjects with type 2 diabetes taking oral antidiabetic drugs were r and omized ( 1:1 ) to semaglutide 1.0 mg or exenatide ER 2.0 mg for 56 weeks . The primary end point was change from baseline in HbA1c at week 56 . RESULTS Mean HbA1c ( 8.3 % [ 67.7 mmol/mol ] at baseline ) was reduced by 1.5 % ( 16.8 mmol/mol ) with semaglutide and 0.9 % ( 10.0 mmol/mol ) with exenatide ER ( estimated treatment difference vs. exenatide ER [ ETD ] –0.62 % [ 95 % CI –0.80 , –0.44 ] [ –6.78 mmol/mol ( 95 % CI –8.70 , –4.86 ) ] ; P < 0.0001 for noninferiority and superiority ) . Mean body weight ( 95.8 kg at baseline ) was reduced by 5.6 kg with semaglutide and 1.9 kg with exenatide ER ( ETD –3.78 kg [ 95 % CI –4.58 , –2.98 ] ; P < 0.0001 ) . Significantly more subjects treated with semaglutide ( 67 % ) achieved HbA1c < 7.0 % ( < 53 mmol/mol ) versus those taking exenatide ER ( 40 % ) . Both treatments had similar safety profiles , but gastrointestinal adverse events were more common in semaglutide-treated subjects ( 41.8 % ) than in exenatide ER – treated subjects ( 33.3 % ) ; injection-site reactions were more frequent with exenatide ER ( 22.0 % ) than with semaglutide ( 1.2 % ) . CONCLUSIONS Semaglutide 1.0 mg was superior to exenatide ER 2.0 mg in improving glycemic control and reducing body weight after 56 weeks of treatment ; the drugs had comparable safety profiles . These results indicate that semaglutide treatment is highly effective for subjects with type 2 diabetes who are inadequately controlled on oral antidiabetic drugs OBJECTIVE To evaluate the efficacy and safety of combinations of empagliflozin/linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin . RESEARCH DESIGN AND METHODS Subjects were r and omized to a combination of empagliflozin 25 mg/linagliptin 5 mg ( n = 137 ) , empagliflozin 10 mg/linagliptin 5 mg ( n = 136 ) , empagliflozin 25 mg ( n = 141 ) , empagliflozin 10 mg ( n = 140 ) , or linagliptin 5 mg ( n = 132 ) as add-on to metformin for 52 weeks . The primary end point was change from baseline in HbA1c at week 24 . RESULTS At week 24 , reductions in HbA1c ( mean baseline 7.90–8.02 % [ 62.8–64.1 mmol/mol ] ) with empagliflozin/linagliptin were superior to those with empagliflozin or linagliptin alone as add-on to metformin ; adjusted mean ( SE ) changes from baseline were −1.19 % ( 0.06 ) ( −13.1 mmol/mol [ 0.7 ] ) with empagliflozin 25 mg/linagliptin 5 mg , −1.08 % ( 0.06 ) ( −11.8 mmol/mol [ 0.7 ] ) with empagliflozin 10 mg/linagliptin 5 mg , −0.62 % ( 0.06 ) ( −6.8 mmol/mol [ 0.7 ] ) with empagliflozin 25 mg , −0.66 % ( 0.06 ) ( −7.2 mmol/mol [ 0.7 ] ) with empagliflozin 10 mg , and −0.70 % ( 0.06 ) ( −7.6 mmol/mol [ 0.7 ] ) with linagliptin 5 mg ( P < 0.001 for all comparisons ) . In these groups , respectively , 61.8 , 57.8 , 32.6 , 28.0 , and 36.1 % of subjects with baseline HbA1c ≥7 % ( ≥53 mmol/mol ) had HbA1c < 7 % ( < 53 mmol/mol ) at week 24 . Efficacy was maintained at week 52 . The proportion of subjects with adverse events ( AEs ) over 52 weeks was similar across treatment arms ( 68.6–73.0 % ) , with no hypoglycemic AEs requiring assistance . CONCLUSIONS Combinations of empagliflozin/linagliptin as second-line therapy for 52 weeks significantly reduced HbA1c compared with the individual components and were well tolerated CONTEXT Dapagliflozin , a selective sodium-glucose cotransporter 2 ( SGLT2 ) inhibitor , reduces hyperglycemia in patients with type 2 diabetes mellitus ( T2DM ) by increasing urinary glucose excretion , and weight loss is a consistent associated finding . OBJECTIVES Our objectives were to confirm weight loss with dapagliflozin and establish through body composition measurements whether weight loss is accounted for by changes in fat or fluid components . DESIGN AND SETTING This was a 24-wk , international , multicenter , r and omized , parallel-group , double-blind , placebo-controlled study with ongoing 78-wk site- and patient-blinded extension period at 40 sites in five countries . PATIENTS Included were 182 patients with T2DM ( mean values : women 63.3 and men 58.6 yr of age ; hemoglobin A1c 7.17 % , body mass index 31.9 kg/m2 , and body weight 91.5 kg ) inadequately controlled on metformin . INTERVENTION Dapagliflozin 10 mg/d or placebo was added to open-label metformin for 24 wk . MAIN OUTCOME MEASURES Primary endpoint was total body weight ( TBW ) change from baseline at wk 24 . Key secondary endpoints were waist circumference and dual-energy x-ray absorptiometry total-body fat mass ( FM ) changes from baseline at wk 24 , and patient proportion achieving body weight reduction of at least 5 % at wk 24 . In a subset of patients , magnetic resonance assessment of visceral adipose tissue ( VAT ) and sc adipose tissue ( SAT ) volume and hepatic lipid content were also evaluated . RESULTS At wk 24 , placebo-corrected changes with dapagliflozin were as follows : TBW , -2.08 kg [ 95 % confidence interval (CI)=-2.84 to -1.31 ; P<0.0001 ] ; waist circumference , -1.52 cm ( 95 % CI=-2.74 to -0.31 ; P=0.0143 ) ; FM , -1.48 kg ( 95 % CI=-2.22 to -0.74 ; P=0.0001 ) ; proportion of patients achieving weight reduction of at least 5 % , + 26.2 % ( 95 % CI=15.5 to 36.7 ; P<0.0001 ) ; VAT , -258.4 cm3 ( 95 % CI=-448.1 to -68.6 ; nominal P=0.0084 ) ; SAT , -184.9 cm3 ( 95 % CI=-359.7 to -10.1 ; nominal P=0.0385 ) . In the dapagliflozin vs. placebo groups , respectively , serious adverse events were reported in 6.6 vs. 1.1 % ; events suggestive of vulvovaginitis , balanitis , and related genital infection in 3.3 vs. 0 % ; and lower urinary tract infections in 6.6 vs. 2.2 % . CONCLUSIONS Dapagliflozin reduces TBW , predominantly by reducing FM , VAT and SAT in T2DM inadequately controlled with metformin OBJECTIVES : This study examined cross-sectional and prospect i ve relationships between macronutrient intake , behaviors intended to limit fat intake , physical activity and body weight . DESIGN : The overall goal was to identify diet and exercise behaviors that predict and /or accompany weight gain or loss over time . Specific questions addressed included : ( a ) are habitual levels of diet or exercise predictive of weight change ; ( b ) are habitual diet and exercise levels associated cross-sectionally with body weight ; and ( c ) are changes in diet and exercise associated with changes in body weight over time ? PARTICIPANTS : Subjects were a sample of community volunteers ( n=826 women , n=218 men ) taking part in a weight gain prevention project over a 3-year period . MEASURES : Body weight was measured at baseline and annually over the study period . Self-report measures of diet and exercise behavior were also measured annually . RESULTS : Among both men and women , the most consistent results were the positive association between dietary fat intake and weight gain and an inverse association between frequency of physical activity and weight gain . Individuals who weighed more both ate more and exercised less than those who weighed less . Individuals who increased their physical activity level and decreased their food intake over time were protected from weight gain compared to those who did not . Frequency of high-intensity physical activity was particularly important for both men and women . Additionally , women who consistently engaged in higher levels of moderate physical activity gained weight at a slower rate compared to women who were less active . CONCLUSIONS : Overall results indicated that both cross-sectionally and prospect ively , the determinants of weight and weight change are multifactorial . Attention to exercise , fat intake and total energy intake all appear important for successful long term control of body weight OBJECTIVE To investigate the efficacy and tolerability of empagliflozin as add-on to metformin and sulfonylurea in patients with type 2 diabetes . RESEARCH DESIGN AND METHODS Patients inadequately controlled on metformin and sulfonylurea ( HbA1c ≥7 to ≤10 % ) were r and omized and treated with once-daily empagliflozin 10 mg ( n = 225 ) , empagliflozin 25 mg ( n = 216 ) , or placebo ( n = 225 ) for 24 weeks . The primary end point was change from baseline in HbA1c at week 24 . Key secondary end points were changes from baseline in weight and mean daily glucose ( MDG ) at week 24 . RESULTS At week 24 , adjusted mean ( SE ) changes from baseline in HbA1c were −0.17 % ( 0.05 ) for placebo vs. −0.82 % ( 0.05 ) and −0.77 % ( 0.05 ) for empagliflozin 10 and 25 mg , respectively ( both P < 0.001 ) . Empagliflozin significantly reduced MDG , weight , and systolic ( but not diastolic ) blood pressure versus placebo . Adverse events were reported in 62.7 , 67.9 , and 64.1 % of patients on placebo and empagliflozin 10 and 25 mg , respectively . Events consistent with urinary tract infection were reported in 8.0 , 10.3 , and 8.3 % of patients on placebo and empagliflozin 10 and 25 mg , respectively ( females : 13.3 , 18.0 , and 17.5 % , respectively ; males : 2.7 , 2.7 , and 0 % , respectively ) . Events consistent with genital infection were reported in 0.9 , 2.7 , and 2.3 % of patients on placebo and empagliflozin 10 and 25 mg , respectively ( females : 0.9 , 4.5 , and 3.9 % , respectively ; males : 0.9 % in each group ) . CONCLUSIONS Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin plus sulfonylurea improved glycemic control , weight , and systolic blood pressure and were well tolerated This study investigated the long-term efficacy and safety of empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes mellitus ( T2DM ) . Of 666 patients treated with empagliflozin 10 mg , empagliflozin 25 mg or placebo once daily for 24 weeks , 472 patients ( 70.9 % ) were treated in a double-blind extension trial for ≥52 weeks . Pre-specified exploratory endpoints included changes from baseline in HbA(1c ) , weight and blood pressure at week 76 . At week 76 , adjusted mean differences versus placebo in change from baseline in HbA(1c ) were -0.7 % (-8 mmol/mol ) with empagliflozin 10 mg or 25 mg ( both p<0.001 ) , in weight were -1.8 kg and -1.6 kg with empagliflozin 10 mg and 25 mg , respectively ( both p<0.001 ) , and in systolic blood pressure ( SBP ) were -2.2 mmHg with empagliflozin 10 mg ( p=0.021 ) and -2.1 mmHg with empagliflozin 25 mg ( p=0.029 ) . Sensitivity analyses provided consistent results for HbA1c and weight , but showed no significant difference between empagliflozin and placebo in change from baseline in SBP . Adverse events ( AEs ) were reported in 81.7 % , 82.0 % and 81.3 % of patients on empagliflozin 10 mg , 25 mg and placebo , respectively . Confirmed hypoglycaemic AEs ( glucose ≤3.9 mmol/l and /or requiring assistance ) were reported in 23.7 % , 19.4 % and 15.6 % of patients on empagliflozin 10 mg , 25 mg and placebo , respectively ; one patient each on empagliflozin 10 mg and placebo required assistance . In conclusion , empagliflozin as add-on to metformin plus sulphonylurea for 76 weeks was well tolerated and led to sustained reductions in HbA1c and weight versus placebo . CLINICAL TRIALS.GOV : NCT01289990 AIMS Dapagliflozin , a highly selective inhibitor of sodium-glucose cotransporter 2 ( SGLT2 ) , reduces hyperglycaemia and weight in patients with type 2 diabetes mellitus ( T2DM ) by increasing urinary glucose excretion . Long-term glycaemic control , body composition and bone safety were evaluated in patients with T2DM after 102 weeks of dapagliflozin treatment . METHODS This r and omized , double-blind , placebo-controlled study ( NCT00855166 ) enrolled patients with T2DM [ mean : age 60.7 years ; HbA1c 7.2 % ; body mass index ( BMI ) 31.9 kg/m(2 ) ; body weight 91.5 kg ] inadequately controlled on metformin . Patients ( N = 182 ) were r and omly assigned 1 : 1 to receive dapagliflozin 10 mg/day or placebo added to open-label metformin for a 24-week double-blind treatment period followed by a 78-week site- and patient-blinded extension period . At week 102 , changes from baseline in HbA1c , weight , waist circumference , total body fat mass as measured by dual-energy X-ray absorptiometry ( DXA ) , serum markers of bone turnover , bone mineral density ( BMD ) as measured by DXA , and adverse events were evaluated . RESULTS A total of 140 patients ( 76.9 % ) completed the study . Over 102 weeks , dapagliflozin-treated patients showed reductions in HbA1c by -0.3 % , weight by -4.54 kg , waist circumference by -5.0 cm and fat mass by -2.80 kg without increase in rate of hypoglycaemia . Compared with placebo , no meaningful changes from baseline in markers of bone turnover or BMD were identified over 102 weeks . One fracture occurred in each treatment group . The frequency of urinary tract infection ( UTI ) and genital infection was similar in both treatment groups . CONCLUSIONS Over 102 weeks , dapagliflozin improved glycaemic control , and reduced weight and fat mass , without affecting markers of bone turnover or BMD in patients with T2DM inadequately controlled on metformin Abstract Aims / Introduction The aim of the present study was to evaluate the safety and efficacy of luseogliflozin added to liraglutide monotherapy in Japanese individuals with type 2 diabetes . Material s and Methods This 52‐week , multicenter , open‐label , single‐arm clinical study enrolled Japanese patients who had inadequate glycemic control with diet/exercise and liraglutide monotherapy . Major efficacy end‐points included the changes from baseline in glycated hemoglobin , fasting plasma glucose and bodyweight . Body composition was also assessed in individuals who had access to bioelectrical impedance analysis . Safety assessment s included adverse events , clinical laboratory tests , vital signs and 12‐lead electrocardiograms . Results Of 76 patients who received luseogliflozin , 62 completed the study . The changes from baseline in glycated hemoglobin , fasting plasma glucose , and bodyweight ( mean ± SE ) were −0.68 ± 0.10 % , −32.1 ± 3.6 mg/dL and −2.71 ± 0.24 kg at week 52 , respectively ( all , P < 0.001 vs baseline ) . Luseogliflozin was associated with greater reductions in fat mass than lean mass at all measuring points ( n = 22 ) : fat vs lean mass changes ( mean ± SE ) at week 52 were −2.49 ± 0.45 kg ( P < 0.001 vs baseline ) and −0.44 ± 0.26 kg ( P = 0.107 vs baseline ) , respectively . Insulin secretion and Matsuda Index were also improved at weeks 12 and 52 compared with baseline . Adverse events and adverse drug reactions occurred in 65.8 and 27.6 % of patients , respectively . The overall safety profile , including frequency of hypoglycemia , was found to be consistent with those of previous studies and there were no new safety concerns . Conclusions Luseogliflozin added to liraglutide was well tolerated , and improved glycemic control with bodyweight and fat mass reductions in Japanese type 2 diabetes patients BACKGROUND Semaglutide is a novel glucagon-like peptide-1 ( GLP-1 ) analogue , suitable for once-weekly subcutaneous administration , in development for treatment of type 2 diabetes . We assessed the efficacy and safety of semaglutide versus the dipeptidyl peptidase-4 ( DPP-4 ) inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled on metformin , thiazolidinediones , or both . METHODS We did a 56-week , phase 3a , r and omised , double-blind , double-dummy , active-controlled , parallel-group , multinational , multicentre trial ( SUSTAIN 2 ) at 128 sites in 18 countries . Eligible patients were aged at least 18 years ( or at least 20 years in Japan ) and diagnosed with type 2 diabetes , with insufficient glycaemic control ( HbA1c 7·0 - 10·5 % [ 53·0 - 91·0 mmol/mol ] ) despite stable treatment with metformin , thiazolidinediones , or both . We r and omly assigned participants ( 2:2:1:1 ) using an interactive voice or web response system to 56 weeks of treatment with subcutaneous semaglutide 0·5 mg once weekly plus oral sitagliptin placebo once daily , subcutaneous semaglutide 1·0 mg once weekly plus oral sitagliptin placebo once daily , oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 0·5 mg once weekly , or oral sitagliptin 100 mg once daily plus subcutaneous semaglutide placebo 1·0 mg once weekly . The two oral sitagliptin 100 mg groups ( with semaglutide placebo 0·5 mg and 1·0 mg ) were pooled for the analyses . The primary endpoint was change in HbA1c from baseline to week 56 , assessed in the modified intention-to-treat population ( all r and omly assigned participants who received at least one dose of study drug ) ; change in bodyweight from baseline to week 56 was the confirmatory secondary endpoint . Safety endpoints included adverse events and hypoglycaemic episodes . This trial is registered with Clinical Trials.gov , number NCT01930188 . FINDINGS Between Dec 2 , 2013 , and Aug 5 , 2015 , we r and omly assigned 1231 participants ; of the 1225 included in the modified intention-to-treat analysis , 409 received semaglutide 0·5 mg , 409 received semaglutide 1·0 mg , and 407 received sitagliptin 100 mg . Mean baseline HbA1c was 8·1 % ( SD 0·93 ) ; at week 56 , HbA1c was reduced by 1·3 % in the semaglutide 0·5 mg group , 1·6 % in the semaglutide 1·0 mg group , and 0·5 % with sitagliptin ( estimated treatment difference vs sitagliptin -0·77 % [ 95 % CI -0·92 to -0·62 ] with semaglutide 0·5 mg and -1·06 % [ -1·21 to -0·91 ] with semaglutide 1·0 mg ; p<0·0001 for non-inferiority and for superiority , for both semaglutide doses vs sitagliptin ) . Mean baseline bodyweight was 89·5 kg ( SD 20·3 ) ; at week 56 , bodyweight reduced by 4·3 kg with semaglutide 0·5 mg , 6·1 kg with semaglutide 1·0 mg , and 1·9 kg with sitagliptin ( estimated treatment difference vs sitagliptin -2·35 kg [ 95 % CI -3·06 to -1·63 ] with semaglutide 0·5 mg and -4·20 kg [ -4·91 to -3·49 ] with semaglutide 1·0 mg ; p<0·0001 for superiority , for both semaglutide doses vs sitagliptin ) . The proportion of patients who discontinued treatment because of adverse events was 33 ( 8 % ) for semaglutide 0·5 mg , 39 ( 10 % ) for semaglutide 1·0 mg , and 12 ( 3 % ) for sitagliptin . The most frequently reported adverse events in both semaglutide groups were gastrointestinal in nature : nausea was reported in 73 ( 18 % ) who received semaglutide 0·5 mg , 72 ( 18 % ) who received semaglutide 1·0 mg , and 30 ( 7 % ) who received placebo , and diarrhoea was reported in 54 ( 13 % ) who received semaglutide 0·5 mg , 53 ( 13 % ) who received semaglutide 1·0 mg , and 29 ( 7 % ) who received placebo . Seven ( 2 % ) patients in the semaglutide 0·5 mg group , two ( < 1 % ) in the semaglutide 1·0 mg group , and five ( 1 % ) in the sitagliptin group had blood-glucose confirmed hypoglycaemia . There were six fatal events ( two in the semaglutide 0·5 mg group , one in the semaglutide 1·0 mg group , and three in the sitagliptin group ) ; none were considered likely to be related to the trial drugs . INTERPRETATION Once-weekly semaglutide was superior to sitagliptin at improving glycaemic control and reducing bodyweight in participants with type 2 diabetes on metformin , thiazolidinediones , or both , and had a similar safety profile to that of other GLP-1 receptor agonists . Semaglutide seems to be an effective add-on treatment option for this patient population . FUNDING Novo Nordisk OBJECTIVE To examine the safety and efficacy of dapagliflozin , a sodium-glucose cotransporter-2 inhibitor , added on to pioglitazone in type 2 diabetes inadequately controlled on pioglitazone . RESEARCH DESIGN AND METHODS Treatment-naive patients or those receiving metformin , sulfonylurea , or thiazolidinedione entered a 10-week pioglitazone dose-optimization period with only pioglitazone . They were then r and omized , along with patients previously receiving pioglitazone ≥30 mg , to 48 weeks of double-blind dapagliflozin 5 ( n = 141 ) or 10 mg ( n = 140 ) or placebo ( n = 139 ) every day plus open-label pioglitazone . The primary objective compared HbA1c change from baseline with dapagliflozin plus pioglitazone versus placebo plus pioglitazone at week 24 . Primary analysis was based on ANCOVA model using last observation carried forward ; all remaining analyses used repeated- measures analysis . RESULTS At week 24 , the mean reduction from baseline in HbA1c was −0.42 % for placebo versus −0.82 and −0.97 % for dapagliflozin 5 and 10 mg groups , respectively ( P = 0.0007 and P < 0.0001 versus placebo ) . Patients receiving pioglitazone alone had greater weight gain ( 3 kg ) than those receiving dapagliflozin plus pioglitazone ( 0.7–1.4 kg ) at week 48 . Through 48 weeks : hypoglycemia was rare ; more events suggestive of genital infection were reported with dapagliflozin ( 8.6–9.2 % ) than placebo ( 2.9 % ) ; events suggestive of urinary tract infection showed no clear drug effect ( 5.0–8.5 % for dapagliflozin and 7.9 % for placebo ) ; dapagliflozin plus pioglitazone groups had less edema ( 2.1–4.3 % ) compared with placebo plus pioglitazone ( 6.5 % ) ; and congestive heart failure and fractures were rare . CONCLUSIONS In patients with type 2 diabetes inadequately controlled on pioglitazone , the addition of dapagliflozin further reduced HbA1c levels and mitigated the pioglitazone-related weight gain without increasing hypoglycemia risk Aims /hypothesisThe aim of this work was to evaluate the efficacy and safety of canagliflozin vs placebo and sitagliptin in patients with type 2 diabetes who were being treated with background metformin . Methods This r and omised , double-blind , four-arm , parallel-group , Phase 3 study was conducted at 169 centres in 22 countries between April 2010 and August 2012 . Participants ( N = 1,284 ) with type 2 diabetes aged ≥18 and ≤80 years who had inadequate glycaemic control ( HbA1c ≥7.0 % [ 53 mmol/mol ] and ≤10.5 % [ 91 mmol/mol ] ) on metformin therapy received canagliflozin 100 mg or 300 mg , sitagliptin 100 mg , or placebo ( n = 368 , 367 , 366 , 183 , respectively ) for a 26 week , placebo- and active-controlled period followed by a 26 week , active-controlled period ( placebo group switched to sitagliptin [ placebo/sitagliptin ] ) and were included in the modified intent-to-treat analysis set . R and omisation was performed using a computer-generated schedule ; participants , study centres and the sponsor were blinded to group assignment . The primary endpoint was change from baseline in HbA1c at week 26 ; secondary endpoints included changes in HbA1c ( week 52 ) and fasting plasma glucose ( FPG ) , body weight , and systolic blood pressure ( BP ; weeks 26 and 52 ) . Adverse events ( AEs ) were recorded throughout the study . Results At week 26 , canagliflozin 100 mg and 300 mg reduced HbA1c vs placebo ( −0.79 % , –0.94 % , –0.17 % , respectively ; p < 0.001 ) . At week 52 , canagliflozin 100 mg and 300 mg demonstrated non-inferiority , and canagliflozin 300 mg demonstrated statistical superiority , to sitagliptin in lowering HbA1c ( −0.73 % , –0.88%,–0.73 % , respectively ) ; differences ( 95 % CI ) vs sitagliptin were 0 % ( −0.12 , 0.12 ) and −0.15 % ( −0.27 , –0.03 ) , respectively . Canagliflozin 100 mg and 300 mg reduced body weight vs placebo ( week 26 : –3.7 % , –4.2 % , –1.2 % , respectively ; p < 0.001 ) and sitagliptin ( week 52 : –3.8 % , –4.2 % , –1.3 % , respectively ; p < 0.001 ) . Both canagliflozin doses reduced FPG and systolic BP vs placebo ( week 26 ) and sitagliptin ( week 52 ) ( p < 0.001 ) . Overall AE and AE-related discontinuation rates were generally similar across groups , but higher with canagliflozin 100 mg . Genital mycotic infection and osmotic diuresis-related AE rates were higher with canagliflozin ; few led to discontinuations . Hypoglycaemia incidence was higher with canagliflozin . Conclusions /interpretationCanagliflozin improved glycaemia and reduced body weight vs placebo ( week 26 ) and sitagliptin ( week 52 ) and was generally well tolerated in patients with type 2 diabetes on metformin . Clinical trial registry Clinical Trials.gov NCT01106677 Funding This study was supported by Janssen Research & Development , LLC Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed BACKGROUND Correction of hyperglycaemia and prevention of glucotoxicity are important objectives in the management of type 2 diabetes . Dapagliflozin , a selective sodium-glucose cotransporter-2 inhibitor , reduces renal glucose reabsorption in an insulin-independent manner . We assessed the efficacy and safety of dapagliflozin in patients who have inadequate glycaemic control with metformin . METHODS In this phase 3 , multicentre , double-blind , parallel-group , placebo-controlled trial , 546 adults with type 2 diabetes who were receiving daily metformin ( > /=1500 mg per day ) and had inadequate glycaemic control were r and omly assigned to receive one of three doses of dapagliflozin ( 2.5 mg , n=137 ; 5 mg , n=137 ; or 10 mg , n=135 ) or placebo ( n=137 ) orally once daily . R and omisation was computer generated and stratified by site , implemented with a central , telephone-based interactive voice response system . Patients continued to receive their pre- study metformin dosing . The primary outcome was change from baseline in haemoglobin A(1c)(HbA(1c ) ) at 24 weeks . All r and omised patients who received at least one dose of double-blind study medication and who had both a baseline and at least one post-baseline measurement ( last observation carried forward ) were included in the analysis . Data were analysed by use of ANCOVA models . This trial is registered with Clinical Trials.gov , number NCT00528879 . FINDINGS 534 patients were included in analysis of the primary endpoint ( dapagliflozin 2.5 mg , n=135 ; dapagliflozin 5 mg , n=133 ; dapagliflozin 10 mg , n=132 ; placebo , n=134 ) . At week 24 , mean HbA(1c ) had decreased by -0.30 % ( 95 % CI -0.44 to -0.16 ) in the placebo group , compared with -0.67 % ( -0.81 to -0.53 , p=0.0002 ) in the dapagliflozin 2.5 mg group , -0.70 % ( -0.85 to -0.56 , p<0.0001 ) in the dapagliflozin 5 mg group , and -0.84 % ( -0.98 to -0.70 , p<0.0001 ) in the dapagliflozin 10 mg group . Symptoms of hypoglycaemia occurred in similar proportions of patients in the dapagliflozin ( 2 - 4 % ) and placebo groups ( 3 % ) . Signs , symptoms , and other reports suggestive of genital infections were more frequent in the dapagliflozin groups ( 2.5 mg , 11 patients [ 8 % ] ; 5 mg , 18 [ 13 % ] ; 10 mg , 12 [ 9 % ] ) than in the placebo group ( seven [ 5 % ] ) . 17 patients had serious adverse events ( four in each of the dapagliflozin groups and five in the placebo group ) . INTERPRETATION Addition of dapagliflozin to metformin provides a new therapeutic option for treatment of type 2 diabetes in patients who have inadequate glycaemic control with metformin alone . FUNDING Bristol-Myers Squibb and AstraZeneca AIMS This study investigated the efficacy and tolerability of empagliflozin as add-on to pioglitazone ± metformin in patients with type 2 diabetes ( T2DM ) . METHODS Patients with HbA1c ≥7 and ≤10 % were r and omized and treated with once daily empagliflozin 10 mg ( n = 165 ) , empagliflozin 25 mg ( n = 168 ) or placebo ( n = 165 ) as add-on to pioglitazone ± metformin for 24 weeks . Endpoints included changes from baseline in HbA1c ( primary endpoint ) , fasting plasma glucose ( FPG ) and body weight at week 24 . RESULTS Adjusted mean ± st and ard error changes in HbA1c were -0.6 ± 0.07 % and -0.7 ± 0.07 % with empagliflozin 10 mg and 25 mg , respectively , vs. -0.1 ± 0.07 % with placebo ( both p < 0.001 ) . More patients with HbA1c ≥7 % at baseline achieved HbA1c < 7 % with empagliflozin 10 mg ( 23.8 % ) and 25 mg ( 30.0 % ) vs. placebo ( 7.7 % ) ( both p < 0.001 ) . FPG decreased with empagliflozin ( -0.94 mmol/l for 10 mg and -1.22 mmol/l for 25 mg ) and increased with placebo ( + 0.36 mmol/l ; both p < 0.001 ) . Adjusted mean ± st and ard error changes in weight were -1.62 ± 0.21 kg and -1.47 ± 0.21 kg with empagliflozin 10 mg and 25 mg , respectively , vs. + 0.34 ± 0.21 kg with placebo ( both p < 0.001 ) . Similar proportions of patients reported adverse events with empagliflozin ( 67.3 - 71.4 % ) and placebo ( 72.7 % ) . Confirmed hypoglycaemia was reported by 1.2 - 2.4 % of patients on empagliflozin and 1.8 % on placebo . CONCLUSION Empagliflozin 10 mg and 25 mg once daily for 24 weeks as add-on to pioglitazone ± metformin reduced HbA1c , FPG and weight and were well tolerated in patients with T2DM Aims To evaluate the efficacy and safety of titrated canagliflozin , a sodium glucose co‐transporter 2 inhibitor , in patients with type 2 diabetes mellitus ( T2DM ) inadequately controlled on metformin and sitagliptin . Methods In this r and omized , double‐blind study , patients with T2DM ( N = 218 ) on metformin ≥1500 mg/day and sitagliptin 100 mg received canagliflozin 100 mg or placebo . After 6 weeks , the canagliflozin dose was increased from 100 to 300 mg ( or from placebo to matching placebo ) if all of the following criteria were met : baseline estimated glomerular filtration rate ≥70 ml/min/1.73 m2 ; fasting self‐monitored blood glucose ≥5.6 mmol/l ( ≥100 mg/dl ) ; and no volume depletion – related adverse events ( AEs ) within 2 weeks before dose increase . Endpoints included change in glycated haemoglobin ( HbA1c ) at week 26 ( primary ) ; proportion of patients achieving HbA1c < 7.0 % ; and changes in fasting plasma glucose ( FPG ) , body weight and systolic blood pressure ( SBP ) . Safety was assessed using AE reports . Results Overall , 85.4 % of patients were titrated to canagliflozin 300 mg or matching placebo ( mean ± st and ard deviation time to titration 6.2 ± 0.8 weeks ) . At week 26 , canagliflozin ( pooled 100 and 300 mg ) demonstrated superiority in HbA1c reduction versus placebo ( −0.91 % vs. −0.01 % ; p < 0.001 ) . Canagliflozin provided significant reductions in FPG , body weight and SBP compared with placebo ( p < 0.001 ) . The overall AE incidence was 39.8 and 44.4 % for canagliflozin and placebo , respectively . Canagliflozin was associated with an increased incidence of genital mycotic infections . Conclusions Titrated canagliflozin significantly improved HbA1c , FPG , body weight and SBP , and was generally well tolerated over 26 weeks in patients with T2DM as add‐on to metformin and sitagliptin OBJECTIVE Rates of severe obesity ( BMI ≥40 kg/m2 ) are on the rise , and effective treatment options are needed . We examined the effect of an intensive lifestyle intervention ( ILI ) on weight loss , cardiovascular disease ( CVD ) risk , and program adherence in participants with type 2 diabetes who were severely obese compared with overweight ( BMI 25 to < 30 kg/m2 ) , class I ( BMI 30 to < 35 kg/m2 ) , and class II ( BMI 35 to < 40 kg/m2 ) obese participants . RESEARCH DESIGN AND METHODS Participants in the Action for Health in Diabetes ( Look AHEAD ) trial were r and omly assigned to ILI or diabetes support and education ( DSE ) . DSE participants received a less intense educational intervention , whereas ILI participants received an intensive behavioral treatment to increase physical activity ( PA ) and reduce caloric intake . This article focuses on the 2,503 ILI participants ( age 58.6 ± 6.8 years ) . RESULTS At 1 year , severely obese participants in the ILI group lost −9.04 ± 7.6 % of initial body weight , which was significantly greater ( P < 0.05 ) than ILI participants who were overweight ( −7.43 ± 5.6 % ) and comparable to class I ( −8.72 ± 6.4 % ) and class II obese ( −8.64 ± 7.4 % ) participants . All BMI groups had comparable improvements in fitness , PA , LDL cholesterol , triglycerides , blood pressure , fasting glucose , and HbA1c at 1 year . ILI treatment session attendance was excellent and did not differ among weight categories ( severe obese 80 % vs. others 83 % ; P = 0.43 ) . CONCLUSIONS Severely obese participants in the ILI group had similar adherence , percentage of weight loss , and improvement in CVD risk compared with less obese participants . Behavioral weight loss programs should be considered an effective option for this population Aim The efficacy and safety of canagliflozin , a sodium glucose co-transporter 2 inhibitor , was evaluated in patients with type 2 diabetes mellitus ( T2DM ) inadequately controlled with metformin and pioglitazone . Methods In this r and omized , double-blind , phase 3 study , patients ( N = 342 ) received canagliflozin 100 or 300 mg during a 26-week , placebo-controlled , core period and a 26-week , active-controlled extension in which placebo-treated patients were switched to sitagliptin 100 mg . Efficacy comparisons for canagliflozin versus placebo at week 26 are reported , with no comparisons versus sitagliptin at week 52 ( sitagliptin used to maintain double-blind and control for safety ) . Safety data are reported for canagliflozin and placebo/sitagliptin . Results Canagliflozin 100 and 300 mg significantly lowered haemoglobin A1c ( HbA1c ) compared with placebo at week 26 ( −0.89 % , −1.03 % and −0.26 % ; p < 0.001 ) ; reductions with canagliflozin 100 and 300 mg were maintained at week 52 ( −0.92 % and −1.03 % ) . Relative to placebo , both canagliflozin doses significantly reduced body weight ( −2.5 and −3.5 kg ) , fasting plasma glucose and systolic blood pressure ( BP ) at week 26 ( p < 0.05 for all ) , with reductions maintained at week 52 . Overall adverse event ( AE ) incidence over 52 weeks was 69.9 , 76.3 and 76.5 % with canagliflozin 100 and 300 mg and placebo/sitagliptin ; AE-related discontinuation and serious AE rates were low . Incidences of genital mycotic infections and AEs related to osmotic diuresis and volume depletion were higher with canagliflozin than placebo/sitagliptin . Conclusion Canagliflozin improved glycaemic control , reduced body weight and systolic BP , and was generally well tolerated in patients with T2DM on metformin and pioglitazone over 52 weeks Aims Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus ( T2DM ) . This r and omised , double-blind , placebo-controlled , Phase 3 study evaluated the efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2DM . Methods Patients ( N = 469 ) received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period and a 26-week extension . Prespecified primary end-point was change in HbA1c at 26 weeks . Secondary end-points included change in HbA1c at week 52 as well as proportion of patients achieving HbA1c < 7.0 % , change in fasting plasma glucose ( FPG ) and systolic blood pressure , and per cent change in body weight , high-density lipoprotein cholesterol , and triglycerides ( weeks 26 and 52 ) . Results HbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 ( –0.85 % , –1.06 % , and –0.13 % ; p < 0.001 ) ; these reductions were maintained at week 52 ( –0.74 % , –0.96 % , and 0.01 % ) . Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 ( p < 0.001 ) and week 52 . Overall adverse event ( AE ) rates were similar across groups over 52 weeks , with higher rates of genital mycotic infections and osmotic diuresis-related AEs seen with canagliflozin vs. placebo ; these led to few discontinuations . Increased incidence of documented , but not severe , hypoglycaemia episodes was seen with canagliflozin vs. placebo . Conclusions Canagliflozin improved glycaemic control , reduced body weight , and was generally well tolerated in T2DM patients on metformin plus sulphonylurea over 52 weeks PURPOSE To investigate the long-term efficacy and safety of empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus . METHODS Of 498 patients r and omized to empagliflozin 10 mg , empagliflozin 25 mg , or placebo once daily for 24 weeks in the EMPA-REG PIO ™ study , 305 ( 61.2 % ) were treated in a double-blind extension trial for ≥52 weeks ( total duration ≥76 weeks ) . Exploratory end points at week 76 included changes from baseline in glycosylated hemoglobin ( HbA1c ) , weight , and blood pressure assessed using ANCOVA in patients who received ≥1 dose of study drug and had a baseline HbA1c measurement in the initial study . FINDINGS Compared with placebo , adjusted mean ( 95 % CI ) changes from baseline in HbA1c level at week 76 were -0.59 % ( -0.79 % to -0.40 % ; P < 0.001 ) for empagliflozin 10 mg ( -6.5 [ -8.6 to -4.4 ] mmol/mol ) and -0.69 % ( -0.88 % to -0.50 % ; P < 0.001 ) for empagliflozin 25 mg ( -7.5 [ -9.6 to -5.4 ] mmol/mol ) . Compared with placebo , adjusted mean ( 95 % CI ) changes from baseline in weight at week 76 were -2.0 kg ( -2.7 to -1.2 kg ; P < 0.001 ) and -1.7 kg ( -2.4 -1.0 kg ; P < 0.001 ) for empagliflozin 10 mg and 25 mg , respectively . Compared with placebo , only empagliflozin 25 mg led to significant reductions in systolic blood pressure ( adjusted mean [ 95 % CI ] change : -3.7 mmHg [ -6.1 to -1.3 mmHg ] ; P = 0.003 ) and diastolic blood pressure ( adjusted mean [ 95 % CI ] change : -2.2 mmHg [ -3.7 to -0.7 mmHg ] ; P = 0.004 ) . Sensitivity analyses were consistent with these results for HbA1c level , fasting plasma glucose concentration , and weight , but revealed no significant difference between empagliflozin and placebo in change from baseline in systolic or diastolic blood pressure at week 76 . Confirmed hypoglycemic adverse events ( glucose ≤3.9 mmol/L and /or requiring assistance ) were reported in 4.2 % , 1.8 % , and 3.0 % of patients treated with placebo , empagliflozin 10 mg , and empagliflozin 25 mg , respectively ; 1 patient each taking placebo and empagliflozin 25 mg required assistance . Adverse events consistent with urinary tract infection were reported in 26.7 % , 22.4 % , and 22.0 % of patients treated with placebo , empagliflozin 10 mg , and empagliflozin 25 mg , respectively . Adverse events consistent with genital infection were reported in 3.0 % , 10.3 % , and 4.2 % of patients treated with placebo , empagliflozin 10 mg , and empagliflozin 25 mg , respectively . IMPLICATION S Empagliflozin 10 mg or 25 mg as add-on therapy to pioglitazone with or without metformin for 76 weeks was well tolerated and led to sustained reductions in HbA1c and weight compared with placebo in patients with type 2 diabetes . Clinical Trials.gov identifier : NCT01210001 The American Diabetes Association ’s ( ADA ’s ) St and ards of Medical Care in Diabetes are published each year in a supplement to the January issue of Diabetes Care . The ADA ’s Professional Practice Committee develops the St and ards and up date s them annually , or more frequently online should it determine that new evidence or regulatory changes ( e.g. , drug approvals , label changes ) merit immediate incorporation . The St and ards include the most current evidence -based recommendations for diagnosing and treating adults and children with diabetes . ADA ’s grading system uses A , B , C , or E to show the evidence level that supports each recommendation . • A — Clear evidence from wellconducted , generalizable r and omized controlled trials that are adequately powered • B — Supportive evidence from well-conducted cohort studies • C — Supportive evidence from poorly controlled or uncontrolled studies • E — Expert consensus or clinical OBJECTIVE This study compared the efficacy and safety of dual add-on of saxagliptin plus dapagliflozin versus saxagliptin and dapagliflozin added on alone in patients with type 2 diabetes poorly controlled with metformin . RESEARCH DESIGN AND METHODS This was a double-blind trial in adults with HbA1c ≥8.0 % and ≤12.0 % ( 64–108 mmol/mol ) , r and omized to saxagliptin ( SAXA ) ( 5 mg/day ) plus dapagliflozin ( DAPA ) ( 10 mg/day ; n = 179 ) , or SAXA ( 5 mg/day ) and placebo ( n = 176 ) , or DAPA ( 10 mg/day ) and placebo ( n = 179 ) on background metformin extended release ( MET ) ≥1,500 mg/day . Primary objective compared changes from baseline in HbA1c with SAXA+DAPA+MET versus SAXA+MET and DAPA+MET . RESULTS Patients had a mean baseline HbA1c of 8.9 % ( 74 mmol/mol ) , diabetes duration of 7.6 years , and a BMI of 32 kg/m2 . At week 24 , the adjusted mean change from the baseline HbA1c was –1.5 % ( –16.1 mmol/mol ) with SAXA+DAPA+MET versus –0.9 % ( –9.6 mmol/mol ) with SAXA+MET ( difference −0.59 % [ –6.4 mmol/mol ] , P < 0.0001 ) and –1.2 % ( –13.1 mmol/mol ) with DAPA+MET ( difference −0.27 % [ 3.0 mmol/mol ] , P < 0.02 ) . The proportion of patients achieving HbA1c < 7 % ( 53 mmol/mol ) was 41 % with SAXA+DAPA+MET versus 18 % with SAXA+MET and 22 % with DAPA+MET . Urinary and genital infections occurred in ≤1 % of patients receiving SAXA+DAPA+MET . Hypoglycemia was infrequent , with no episodes of major hypoglycemia . CONCLUSIONS In this first report of adding a well-tolerated combination of saxagliptin plus dapagliflozin to background metformin therapy in patients poorly controlled with metformin , greater improvements in glycemic control were obtained with triple therapy by the dual addition of saxagliptin and dapagliflozin than dual therapy with the addition of saxagliptin or dapagliflozin alone AIMS Progressive deterioration of glycaemic control in type 2 diabetes mellitus ( T2DM ) often requires treatment intensification . Dapagliflozin increases urinary glucose excretion by selective inhibition of renal sodium-glucose cotransporter 2 ( SGLT2 ) . We assessed the efficacy , safety and tolerability of dapagliflozin added to glimepiride in patients with uncontrolled T2DM . METHODS This 24-week , r and omized , double-blind , placebo-controlled , parallel-group , international , multicentre trial ( Clinical Trials.gov NCT00680745 ) enrolled patients with uncontrolled T2DM [ haemoglobin A1c ( HbA1c ) 7 - 10 % ] receiving sulphonylurea monotherapy . Adult patients ( n = 597 ) were r and omly assigned to placebo or dapagliflozin ( 2.5 , 5 or 10 mg/day ) added to open-label glimepiride 4 mg/day for 24 weeks . Primary endpoint was HbA1c mean change from baseline at 24 weeks . Secondary endpoints included change in body weight and other glycaemic parameters . RESULTS At 24 weeks , HbA1c adjusted mean changes from baseline for placebo versus dapagliflozin 2.5/5/10 mg groups were -0.13 versus -0.58 , -0.63 , -0.82 % , respectively ( all p < 0.0001 vs. placebo by Dunnett 's procedure ) . Corresponding body weight and fasting plasma glucose values were -0.72 , -1.18 , -1.56 , -2.26 kg and -0.11 , -0.93 , -1.18 , -1.58 mmol/l , respectively . In placebo versus dapagliflozin groups , serious adverse events were 4.8 versus 6.0 - 7.1 % ; hypoglycaemic events 4.8 versus 7.1 - 7.9 % ; events suggestive of genital infection 0.7 versus 3.9 - 6.6 % ; and events suggestive of urinary tract infection 6.2 versus 3.9 - 6.9 % . No kidney infections were reported . CONCLUSIONS Dapagliflozin added to glimepiride in patients with T2DM uncontrolled on sulphonylurea monotherapy significantly improved HbA1c , reduced weight and was generally well tolerated , although events suggestive of genital infections were reported more often in patients receiving dapagliflozin Abstract Assessment of the benefits of anti-diabetic drugs for type 2 diabetes requires analysis of composite end-points , taking HbA1c , bodyweight , hypoglycemia and other metabolic parameters into consideration ; continuous , optimal glycemic control as well as bodyweight , blood pressure and lipid levels are critical to prevent micro- and macro-vascular complications . Glucagon-like peptide-1 receptor agonists ( GLP-1RAs ) are now established as an important total treatment strategy for type 2 diabetes , exerting glucose-lowering effects with little hypoglycemia risk and also ameliorating bodyweight , blood pressure and lipid levels , which are therapeutic targets for prevention of complications of the disease . The available data strongly suggest only beneficial effects of GLP-1RAs ; however , long-term evaluation of the relevant composite end-points including health-related quality of life and cost-effectiveness remain to be investigated in adequately powered , prospect i ve , controlled clinical trials . In the meantime , healthcare professionals need to be scrupulously attentive for potential , rare adverse events in patients using GLP-1RAs BACKGROUND Sodium-glucose cotransporter 2 ( SGLT2 ) inhibitors improve glycaemia in patients with type 2 diabetes by enhancing urinary glucose excretion . We compared the efficacy and safety of canagliflozin , an SGLT2 inhibitor , with glimepiride in patients with type 2 diabetes inadequately controlled with metformin . METHODS We undertook this 52 week , r and omised , double-blind , active-controlled , phase 3 non-inferiority trial at 157 centres in 19 countries between Aug 28 , 2009 , and Dec 21 , 2011 . Patients aged 18 - 80 years with type 2 diabetes and glycated haemoglobin A1c ( HbA1c ) of 7·0 - 9·5 % on stable metformin were r and omly assigned ( 1:1:1 ) by computer-generated r and om sequence via an interactive voice or web response system to receive canagliflozin 100 mg or 300 mg , or glimepiride ( up-titrated to 6 mg or 8 mg per day ) orally once daily . Patients , study investigators , and local sponsor personnel were masked to treatment . The primary endpoint was change in HbA1c from baseline to week 52 , with a non-inferiority margin of 0·3 % for the comparison of each canagliflozin dose with glimepiride . If non-inferiority was shown , we assessed superiority on the basis of an upper bound of the 95 % CI for the difference of each canagliflozin dose versus glimepiride of less than 0·0 % . Analysis was done in a modified intention-to-treat population , including all r and omised patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT00968812 . FINDINGS 1450 of 1452 r and omised patients received at least one dose of glimepiride ( n=482 ) , canagliflozin 100 mg ( n=483 ) , or canagliflozin 300 mg ( n=485 ) . For lowering of HbA1c at 52 weeks , canagliflozin 100 mg was non-inferior to glimepiride ( least-squares mean difference -0·01 % [ 95 % CI -0·11 to 0·09 ] ) , and canagliflozin 300 mg was superior to glimepiride ( -0·12 % [ -0·22 to -0·02 ] ) . 39 ( 8 % ) patients had serious adverse events in the glimepiride group versus 24 ( 5 % ) in the canagliflozin 100 mg group and 26 ( 5 % ) in the 300 mg group . In the canagliflozin 100 mg and 300 mg groups versus the glimepiride group , we recorded a greater number of genital mycotic infections ( women : 26 [ 11 % ] and 34 [ 14 % ] vs five [ 2 % ] ; men : 17 [ 7 % ] and 20 [ 8 % ] vs three [ 1 % ] ) , urinary tract infections ( 31 [ 6 % ] for both canagliflozin doses vs 22 [ 5 % ] ) , and osmotic diuresis-related events ( pollakiuria : 12 [ 3 % ] for both doses vs one [ < 1 % ] ; polyuria : four [ < 1 % ] for both doses vs two [ < 1 % ] ) . INTERPRETATION Canagliflozin provides greater HbA1c reduction than does glimepiride , and is well tolerated in patients with type 2 diabetes receiving metformin . These findings support the use of canagliflozin as a viable treatment option for patients who do not achieve sufficient glycaemic control with metformin therapy . FUNDING Janssen Research & Development , LLC BACKGROUND Despite common mechanisms of actions , glucagon-like peptide-1 receptor agonists differ in structure , pharmacokinetic profile , and clinical effects . This head-to-head trial compared semaglutide with dulaglutide in patients with inadequately controlled type 2 diabetes . METHODS This was an open-label , parallel-group , phase 3b trial done at 194 hospitals , clinical institutions or private practice s in 16 countries . Eligible patients were aged 18 years or older and had type 2 diabetes with HbA1c 7·0 - 10·5 % ( 53·0 - 91·0 mmol/mol ) on metformin monotherapy . Patients were r and omly assigned ( 1:1:1:1 ) by use of an interactive web-response system to once a week treatment with either semaglutide 0·5 mg , dulaglutide 0·75 mg , semaglutide 1·0 mg , or dulaglutide 1·5 mg subcutaneously . The primary endpoint was change from baseline in percentage HbA1c ; the confirmatory secondary endpoint was change in bodyweight , both at week 40 . The primary analysis population included all r and omly assigned patients exposed to at least one dose of trial product obtained while on treatment and before the onset of rescue medication . The safety population included all r and omly assigned patients exposed to at least one dose of trial product obtained while on treatment . The trial was powered for HbA1c non-inferiority ( margin 0·4 % ) and bodyweight superiority . This trial is registered with Clinical Trials.gov , number NCT02648204 . FINDINGS Between Jan 6 , 2016 , and June 22 , 2016 , 1201 patients were r and omly assigned to treatment ; of these , 301 were exposed to semaglutide 0·5 mg , 299 to dulaglutide 0·75 mg , 300 to semaglutide 1·0 mg , and 299 to dulaglutide 1·5 mg . 72 ( 6 % ) patients withdrew from the trial ( 22 receiving semaglutide 0·5 mg , 13 receiving dulaglutide 0·75 mg , 21 receiving semaglutide 1·0 mg , and 16 receiving dulaglutide 1·5 mg ) . From overall baseline mean , mean percentage HbA1c was reduced by 1·5 ( SE 0·06 ) percentage points with semaglutide 0·5 mg versus 1·1 ( 0·05 ) percentage points with dulaglutide 0·75 mg ( estimated treatment difference [ ETD ] -0·40 percentage points [ 95 % CI -0·55 to -0·25 ] ; p<0·0001 ) and by 1·8 ( 0·06 ) percentage points with semaglutide 1·0 mg versus 1·4 ( 0·06 ) percentage points with dulaglutide 1·5 mg ( ETD -0·41 percentage points [ -0·57 to -0·25 ] ; p<0·0001 ) . From overall baseline mean , mean bodyweight was reduced by 4·6 kg ( SE 0·28 ) with semaglutide 0·5 mg compared with 2·3 kg ( 0·27 ) with dulaglutide 0·75 mg ( ETD -2·26 kg [ -3·02 to -1·51 ] ; p<0·0001 ) and by 6·5 kg ( 0·28 ) with semaglutide 1·0 mg compared with 3·0 kg ( 0·27 ) with dulaglutide 1·5 mg ( ETD -3·55 kg [ -4·32 to -2·78 ] ; p<0·0001 ) . Gastrointestinal disorders were the most frequently reported adverse event , occurring in 129 ( 43 % ) of 301 patients receiving semaglutide 0·5 mg , 133 ( 44 % ) of 300 patients receiving semaglutide 1·0 mg , 100 ( 33 % ) of 299 patients receiving dulaglutide 0·75 mg , and in 143 ( 48 % ) of 299 patients receiving dulaglutide 1·5 mg . Gastrointestinal disorders were also the most common reason for discontinuing treatment with semaglutide and dulaglutide . There were six fatalities : one in each semaglutide group and two in each dulaglutide group . INTERPRETATION At low and high doses , semaglutide was superior to dulaglutide in improving glycaemic control and reducing bodyweight , enabling a significantly greater number of patients with type 2 diabetes to achieve clinical ly meaningful glycaemic targets and weight loss , with a similar safety profile . FUNDING Novo Nordisk Patients with type 2 diabetes ( T2DM ) and inadequate glycaemic control on combination metformin ( MET ) and sulphonylurea ( SU ) were enrolled in a 24‐week , double‐blind , r and omized , placebo‐controlled study with a 28‐week extension . The five‐dimension EuroQol question naire ( EQ‐5D ) , SHIELD Weight Question naire‐9 ( WQ‐9 ) , Impact of Weight on Quality of Life‐Lite ( IWQOL‐Lite ) question naire and the Diabetes Treatment Satisfaction Question naire ( DTSQ ) were used to evaluate health status and health‐related quality of life ( HRQoL ) at baseline and week 52 . Patients with dapagliflozin 10 mg + MET + SU ( n = 108 ) were compared with patients treated with placebo + MET + SU ( n = 108 ) , using a repeated‐ measures mixed model . EQ‐5D visual analogue scale scores , IWQOL‐Lite and DTSQ scores improved in the dapagliflozin and placebo groups from baseline to week 52 ; however , there was no significant difference between groups ( p > 0.20 ) . EQ‐5D index scores remained the same from baseline to week 52 for dapagliflozin and placebo ( p = 0.54 ) . A numerically greater proportion of the dapagliflozin group reported improvement in all nine SHIELD WQ‐9 items compared with placebo , and the difference was statistically significant for physical health ( p = 0.017 ) . Over 52 weeks of therapy , patients maintained their health status and HRQoL when dapagliflozin was added to the treatment BACKGROUND Glucagon-like peptide-1 ( GLP-1 ) receptor agonists and sodium-glucose co-transporter-2 ( SGLT2 ) inhibitors reduce glycaemia and weight , and improve cardiovascular risk factors via different mechanisms . We aim ed to compare the efficacy and safety of co-initiation of the GLP-1 receptor agonist exenatide and the SGLT2 inhibitor dapagliflozin with exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled by metformin . METHODS DURATION -8 was a 28 week , multicentre , double-blind , r and omised , active-controlled phase 3 trial done at 109 sites in six countries . Adults ( aged ≥18 years ) with type 2 diabetes and inadequate glycaemic control ( HbA1c 8 - 12 % [ 64 - 108 mmol/mol ] ) despite stable metformin monotherapy ( ≥1500 mg/day ) were r and omly assigned ( 1:1:1 ) , via an interactive voice and web-response system , to receive once-weekly exenatide 2 mg by subcutaneous injection plus once-daily dapagliflozin 10 mg oral tablets , exenatide with dapagliflozin-matched oral placebo , or dapagliflozin with exenatide-matched placebo injections . R and omisation was stratified by baseline HbA1c ( < 9·0 % vs ≥9·0 % [ < 75 mmol/mol vs ≥75 mmol/mol ] ) . The primary endpoint was change in HbA1c from baseline to week 28 . Secondary endpoints were the change from baseline in fasting plasma glucose at week 2 and week 28 , and 2 h postpr and ial glucose at week 28 ; the proportion of patients with an HbA1c less than 7·0 % ( < 53 mmol/mol ) at week 28 ; change in weight at week 28 ; the proportion of patients with weight loss of 5 % or more at week 28 ; and change in systolic blood pressure at week 28 . Analyses were by intention to treat . This trial is registered with Clinical Trials.gov , number NCT02229396 . FINDINGS Between Sept 4 , 2014 , and Oct 15 , 2015 , we r and omly assigned 695 patients to receive exenatide plus dapagliflozin ( n=231 ) , exenatide alone ( n=231 ; n=1 untreated ) , or dapagliflozin alone ( n=233 ) . The intention-to-treat population comprised 685 participants ( mean HbA1c 9·3 % [ SD 1·1 ] ; 78 mmol/mol [ 12 ] ) , of whom 611 ( 88 % ) completed the study . After 28 weeks , the change in baseline HbA1c was -2·0 % ( 95 % CI -2·1 to -1·8 ) in the exenatide plus dapagliflozin group , -1·6 % ( -1·8 to -1·4 ) in the exenatide group , and -1·4 % ( -1·6 to -1·2 ) in the dapagliflozin group . Exenatide plus dapagliflozin significantly reduced HbA1c from baseline to week 28 compared with exenatide alone ( -0·4 % [ 95 % CI -0·6 to -0·1 ] ; p=0·004 ) or dapagliflozin alone ( -0·6 % [ -0·8 to -0·3 ] ; p<0·001 ) . Exenatide plus dapagliflozin was significantly superior to either drug alone for all secondary efficacy endpoints , with greater reductions in fasting plasma and postpr and ial glucose , more patients with an HbA1c less than 7·0 % ( < 53 mmol/mol ) , greater weight loss , a greater proportion of patients with weight loss of 5 % or more , and greater reductions in systolic blood pressure ( all p≤0·025 ) . Adverse events were recorded in 131 ( 57 % ) of 231 patients in the exenatide plus dapagliflozin group , 124 ( 54 % ) of 230 patients in the exenatide group , and 121 ( 52 % ) of 233 patients in the dapagliflozin group . The most common adverse events ( ≥5 % of patients in any group ) were diarrhoea , injection-site nodules , nausea , and urinary tract infections . No episodes of major hypoglycaemia or minor hypoglycaemia were reported . INTERPRETATION Co-initiation of exenatide and dapagliflozin improved various glycaemic measures and cardiovascular risk factors in patients with type 2 diabetes inadequately controlled by metformin monotherapy . The dual treatment regimen was well tolerated , with the expected safety profile for this combination . Additional data from an ongoing study ( eg , AWARD-10 ; NCT02597049 ) will further inform the use of these drug classes in combination . FUNDING AstraZeneca OBJECTIVE To compare the efficacy and safety of treatment with dapagliflozin versus that with placebo add-on to saxagliptin plus metformin in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin treatment . RESEARCH DESIGN AND METHODS Patients receiving treatment with stable metformin ( stratum A ) ( screening HbA1c level 8.0–11.5 % [ 64–102 mmol/mol ] ) or stable metformin and a dipeptidyl peptidase-4 ( DPP-4 ) inhibitor ( stratum B ) ( HbA1c 7.5–10.5 % [ 58–91 mmol/mol ] ) for ≥8 weeks received open-label saxagliptin 5 mg/day and metformin for 16 weeks ( stratum A ) or 8 weeks ( stratum B ) ( saxagliptin replaced any DPP-4 inhibitor ) . Patients with inadequate glycemic control ( HbA1c 7–10.5 % [ 53–91 mmol/mol ] ) were r and omized to receive placebo or dapagliflozin 10 mg/day plus saxagliptin and metformin . The primary end point was the change in HbA1c from baseline to week 24 . Secondary end points included fasting plasma glucose ( FPG ) level , 2-h postpr and ial glucose ( PPG ) level , body weight , and proportion of patients achieving an HbA1c level of < 7 % ( 53 mmol/mol ) . RESULTS Treatment with dapagliflozin add-on to saxagliptin plus metformin result ed in a greater mean HbA1c reduction than placebo ( −0.82 vs. −0.10 % [ −9 vs. −1.1 mmol/mol ] , P < 0.0001 ) . Significantly greater reductions in FPG level , 2-h PPG level , and body weight were observed , and more patients achieved an HbA1c level of < 7 % ( 53 mmol/mol ) with treatment with dapagliflozin versus placebo . Adverse events were similar across treatment groups , with a low overall risk of hypoglycemia ( ∼1 % ) . Genital infections developed in more patients with dapagliflozin treatment ( 5 % ) than with placebo ( 0.6 % ) . CONCLUSIONS Triple therapy with dapagliflozin add-on to saxagliptin plus metformin improves glycemic control and is well tolerated in patients whose type 2 diabetes is inadequately controlled with saxagliptin plus metformin therapy |
13,679 | 31,464,026 | Improvements in mindfulness skills were associated with greater reductions in psychological distress at post-intervention .
MBIs appear efficacious in reducing psychological distress and other symptoms in cancer patients and -survivors . | OBJECTIVE Mindfulness-based interventions ( MBIs ) are increasingly used within psycho-oncology .
Since the publication of the most recent comprehensive meta- analysis on MBIs in cancer in 2012 , the number of published trials has more than doubled .
We therefore conducted a systematic review and meta- analysis of r and omized controlled trials ( RCTs ) , testing the efficacy of MBIs on measures of psychological distress ( primary outcome ) and other health outcomes in cancer patients and -survivors . | PURPOSE The purpose of this r and omized trial was to evaluate the efficacy of the Mindfulness-Based Stress Reduction for Breast Cancer ( MBSR[BC ] ) program in improving psychological and physical symptoms and quality of life among breast cancer survivors ( BCSs ) who completed treatment . Outcomes were assessed immediately after 6 weeks of MBSR(BC ) training and 6 weeks later to test efficacy over an extended timeframe . PATIENTS AND METHODS A total of 322 BCSs were r and omly assigned to either a 6-week MBSR(BC ) program ( n = 155 ) or a usual care group ( n = 167 ) . Psychological ( depression , anxiety , stress , and fear of recurrence ) and physical symptoms ( fatigue and pain ) and quality of life ( as related to health ) were assessed at baseline and at 6 and 12 weeks . Linear mixed models were used to assess MBSR(BC ) effects over time , and participant characteristics at baseline were also tested as moderators of MBSR(BC ) effects . RESULTS Results demonstrated extended improvement for the MBSR(BC ) group compared with usual care in both psychological symptoms of anxiety , fear of recurrence overall , and fear of recurrence problems and physical symptoms of fatigue severity and fatigue interference ( P < .01 ) . Overall effect sizes were largest for fear of recurrence problems ( d = 0.35 ) and fatigue severity ( d = 0.27 ) . Moderation effects showed BCSs with the highest levels of stress at baseline experienced the greatest benefit from MBSR(BC ) . CONCLUSION The MBSR(BC ) program significantly improved a broad range of symptoms among BCSs up to 6 weeks after MBSR(BC ) training , with generally small to moderate overall effect sizes Purpose Advanced prostate cancer ( PC ) is associated with substantial psychosocial morbidity . We sought to determine whether mindfulness-based cognitive therapy ( MBCT ) reduces distress in men with advanced PC . Methods Men with advanced PC ( proven metastatic and /or castration-resistant biochemical progression ) were r and omly assigned to an 8-week , group-based MBCT intervention delivered by telephone ( n = 94 ) or to minimally enhanced usual care ( n = 95 ) . Primary intervention outcomes were psychological distress , cancer-specific distress , and prostate-specific antigen anxiety . Mindfulness skills were assessed as potential mediators of effect . Participants were assessed at baseline and were followed up at 3 , 6 , and 9 months . Main statistical analyses were conducted on the basis of intention to treat . Results Fourteen MBCT groups were conducted in the intervention arm . Facilitator adherence ratings were high ( > 93 % ) . Using r and om-effects mixed-regression models , intention-to-treat analyses indicated no significant changes in intervention outcomes or in engagement with mindfulness for men in MBCT compared with those receiving minimally enhanced usual care . Per- protocol analyses also found no differences between arms in outcomes or engagement , with the exception of the mindfulness skill of observing , which increased over time for men in MBCT compared with usual care ( P = .032 ) . Conclusion MBCT in this format was not more effective than minimally enhanced usual care in reducing distress in men with advanced PC . Future intervention research for these men should consider approaches that map more closely to masculinity Background There is increasing recognition of mindfulness and mindfulness training as a way to decrease stress and increase psychological functioning . Purpose The aims of this study were to examine the effects of mindfulness stress reduction training on perceived stress and psychological well-being and to examine if changes in mindfulness mediate intervention effects on these outcomes . Methods Seventy women and one man with a previous cancer diagnosis ( mean age 51.8 years , st and ard deviation = 9.86 ) were r and omized into an intervention group or a wait-list control group . The intervention consisted of an 8-week mindfulness training course . Results Compared to participants in the control group , participants in the mindfulness training group had significantly decreased perceived stress and posttraumatic avoidance symptoms and increased positive states of mind . Those who participated in the intervention reported a significant increase in scores on the five-facet mindfulness question naire ( FFMQ ) when compared to controls . The increase in FFMQ score mediated the effects of the intervention on perceived stress , posttraumatic avoidance symptoms , and positive states of mind . Conclusions This study indicates that the improvements in psychological well-being result ing from mindfulness stress reduction training can potentially be explained by increased levels of mindfulness as measured with the FFMQ . The importance of these findings for future research in the field of mindfulness is discussed Background Approximately one third of all patients who have been successfully treated for cancer suffer from chronic cancer-related fatigue ( CCRF ) . Effective and easily accessible interventions are needed for these patients . Objective The current paper reports on the results of a 3-armed r and omized controlled trial investigating the clinical effectiveness of two different guided Web-based interventions for reducing CCRF compared to an active control condition . Methods Severely fatigued cancer survivors were recruited via online and offline channels , and self-registered on an open-access website . After eligibility checks , 167 participants were r and omized via an embedded automated r and omization function into : ( 1 ) physiotherapist-guided Ambulant Activity Feedback ( AAF ) therapy encompassing the use of an accelerometer ( n=62 ) ; ( 2 ) psychologist-guided Web-based mindfulness-based cognitive therapy ( eMBCT ; n=55 ) ; or ( 3 ) an unguided active control condition receiving psycho-educational emails ( n=50 ) . All interventions lasted nine weeks . Fatigue severity was self-assessed using the Checklist Individual Strength - Fatigue Severity subscale ( primary outcome ) six times from baseline ( T0b ) to six months ( T2 ) . Mental health was self-assessed three times using the Hospital Anxiety and Depression Scale and Positive and Negative Affect Schedule ( secondary outcome ) . Treatment dropout was investigated . Results Multiple group latent growth curve analysis , corrected for individual time between assessment s , showed that fatigue severity decreased significantly more in the AAF and eMBCT groups compared to the psycho-educational group . The analyses were checked by a research er who was blind to allocation . Clinical ly relevant changes in fatigue severity were observed in 66 % ( 41/62 ) of patients in AAF , 49 % ( 27/55 ) of patients in eMBCT , and 12 % ( 6/50 ) of patients in psycho-education . Dropout was 18 % ( 11/62 ) in AAF , mainly due to technical problems and poor usability of the accelerometer , and 38 % ( 21/55 ) in eMBCT , mainly due to the perceived high intensity of the program . Conclusions Both the AAF and eMBCT interventions are effective for managing fatigue severity compared to receiving psycho-educational emails . Trial Registration Trialregister.nl NTR3483 ; http://www.trialregister.nl/trialreg/admin/ rct view.asp?TC=3483 ( Archived by WebCite at http://www.webcitation.org/6NWZqon3o Purpose Cancer-related fatigue ( CRF ) is a disruptive symptom for many survivors . Despite promising evidence for efficacy of mindfulness-based stress reduction ( MBSR ) in reducing CRF , no trials comparing it to an active comparator for fatigued survivors have been published . The purpose of this trial was to compare MBSR to psychoeducation for CRF and associated symptoms . Methods Breast ( n = 60 ) and colorectal ( n = 11 ) cancer survivors ( stage 0–III ) with clinical ly significant CRF after completing chemotherapy and /or radiation therapy an average of 28 months prior to enrollment were r and omized to MBSR or psychoeducation/support groups ( PES ) . MBSR focused on mindfulness training ; PES focused on CRF self-management . Outcomes included CRF interference ( primary ) , CRF severity and global improvement , vitality , depression , anxiety , sleep disturbance , and pain . Outcomes were assessed at baseline ( T1 ) , post-intervention ( T2 ) , and 6-month follow-up ( T3 ) using intent-to-treat analysis . Results Between-group differences in CRF interference were not significant at any time point ; however , there was a trend favoring MBSR ( d = −0.46 , p = 0.073 ) at T2 . MBSR participants reported significantly greater improvement in vitality ( d = 0.53 , p = 0.003 ) and were more likely to report CRF as moderately to completely improved compared to the PES group ( χ2 ( 1 ) = 4.1765 , p = 0.041 ) at T2 . MBSR participants also reported significantly greater reductions in pain at T2 ( d = 0.53 , p = 0.014 ) . In addition , both MBSR and PES produced moderate-to-large and significant within-group improvements in all fatigue outcomes , depression , anxiety , and sleep at T2 and T3 compared to T1 . Conclusion MBSR and PES appear efficacious for CRF and related symptoms . Larger trials including a usual care arm are warranted . Trial Registration Clinical Trials.gov Identifier : NCT01724333 Objective : Mindfulness meditation reduces psychological distress among individuals with cancer . However , mechanisms for intervention effects have not been fully determined . This study tested emotion regulation strategies as mediators of intervention effects in a sample of younger women treated for breast cancer , a group at risk for psychological distress . We focused on two distinct strategies targeted by the intervention — rumination and self-kindness— and further examined the broader construct of mindfulness as a potential mediator . Method : Women ( n = 71 ) with Stage 0-III breast cancer diagnosed at or before age 50 who had completed cancer treatment were r and omly assigned to a 6-week mindfulness intervention or wait-list control group . Assessment s occurred at study entry , postintervention , and a 3-month follow-up . Results : In single mediator analyses , increases in self-kindness ( CIB [ −7.83 , −1.93 ] ) , decreases in rumination ( CIB [ −5.05 , −.31 ] ) , and increases in mindfulness ( CIB [ −6.58 , −.82 ] ) each mediated reductions in depressive symptoms from pre- to postintervention . Increases in self-kindness also mediated reductions in perceived stress ( CIB [ −5.37 , −.62 ] ) from pre- to postintervention , and increases in self-kindness ( CIB [ −5.67 , −.22 ] ) and in mindfulness ( CIB [ −5.51 , −.16 ] ) each mediated intervention effects on perceived stress from preintervention to 3-month follow-up . In multiple mediator analysis , only self-kindness mediated intervention effects on depressive symptoms from pre- to postintervention ( CIB [ −6.41 , −.61 ] ) , and self-kindness and mindfulness together mediated intervention effects on perceived stress from preintervention to follow-up ( CIB [ −6.77 , −.35 ] ) . Conclusions : Self-kindness played a consistent role in reducing distress in younger women with breast cancer . The efficacy of this understudied emotion regulation strategy should be evaluated in other clinical population Abstract Breast cancer ( BC ) patients in China suffered from a variety of psychology stress such as perceived stress and anxiety , posttraumatic growth ( PTG ) as a positive factor could promote their psychology health and quality of life . This study aim ed to investigate the efficacy of mindfulness-based stress reduction ( MBSR ) on promoting PTG , decreasing perceived stress and anxiety of Chinese BC patients . A r and omized controlled trial of 60 BC patients ( Stages I – III ) was conducted . They were r and omly divided to the 8-week MBSR group or usual care ( UC ) group . PTG inventory , Perceived Stress Scale of Chinese version ( CPSS ) and State Trait Anxiety Inventory ( STAI ) evaluated the PTG level , perceived stress and anxiety at three times(before intervention-T1 , after intervention-T2 and follow up at 3 months-T3 ) . A repeated- measures analysis of variance model was used to compare each outcome measure of two groups at the three times . There was one patient discontinued the intervention and one lose to follow up in MBSR group , finally 58 BC patients completed the research . There was no difference between two groups before the intervention . The results showed significant improvements in MBSR group comparing with the UC group that PTG level was much higher after the 8-week intervention and the follow up ( F = 34.73 , p < .00 ) . At the same time , CPSS ( F = 14.41 , p < .00 ) and STAI ( F = 15.24 , p < .00 ) scores were significant decreased at T2 and T3 . The results showed that MBSR promoted the level of PTG and decreased perceived stress and anxiety state of Chinese BC patients , and the results persisted at three months after intervention . The research preliminary proved that MBSR was suitable to Chinese BC patients . MBSR should be recommending to BC survivors in China OBJECTIVES While mindfulness-based stress reduction ( MBSR ) and mindfulness-based cognitive therapy ( MBCT ) have demonstrated efficacy in clinical population s , the potential therapeutic benefit of mindfulness in the context of cancer is less clear . The aim of this review was to critically appraise mindfulness intervention reporting and study methodology . METHODS Studies using r and omized control trial design and /or a control arm were included . PubMed , Medline , PsycINFO , CINAHL , and Embase data bases between January 1999 and April 2017 were search ed . Studies were assessed on ( 1 ) reported theoretical framework , ( 2 ) intervention description , and ( 3 ) justification of modifications to st and ardized MBSR/MBCT . The overall quality of study design and research methodology were also assessed . RESULTS Of 30 studies identified , none adhered to MBSR . Modified versions of MBSR were reported in 19 studies . Five studies reported variants of MBCT , 1 used a combination of MBSR/MBCT , and 5 inadequately documented the intervention/ theoretical framework . Overall , component and timeline modifications were poorly documented and justified . Mean intervention contact time was less than st and ardized MBSR/MBCT protocol s. Target outcomes were poorly justified , and 12 studies failed to identify a primary aim , reporting multiple outcomes . Only 9 of 15 studies recruiting clinical population s included clinical cutoffs , and an active therapeutic control was included in 4 studies . CONCLUSIONS Mindfulness is increasingly considered a st and ard therapy in psycho-oncology . While many studies procl aim benefits , considerable variability , modification to st and ardized protocol s , and cl aims of benefit often reflect decreases in sub- clinical supportive care symptomology rather than therapeutic relief of clinical ly significant psychological disorders OBJECTIVE Lung cancer patients report among the highest distress rates of all cancer patients . Partners report similar distress rates . The present study examined the effectiveness of additional mindfulness-based stress reduction ( care as usual [ CAU ] + MBSR ) versus solely CAU to reduce psychological distress in lung cancer patients and /or their partners . METHODS We performed a multicentre , parallel-group , r and omized controlled trial . Mindfulness-based stress reduction is an 8-week group-based intervention , including mindfulness practice and teachings on stress . Care as usual included anticancer treatment , medical consultations , and supportive care . The primary outcome was psychological distress . Secondary outcomes included quality of life , caregiver burden , relationship satisfaction , mindfulness skills , self-compassion , rumination , and posttraumatic stress symptoms . Outcomes were assessed at baseline , post-intervention , and 3-month follow-up . Linear mixed modeling was conducted on an intention-to-treat sample . Moderation ( gender , disease stage , baseline distress , participation with/without partner ) and mediation analyses were performed . RESULTS A total of 31 patients and 21 partners were r and omized to CAU + MBSR and 32 patients and 23 partners to CAU . After CAU + MBSR patients reported significantly less psychological distress ( p = .008 , d = .69 ) than after CAU . Baseline distress moderated outcome : those with more distress benefitted most from MBSR . Additionally , after CAU + MBSR patients showed more improvements in quality of life , mindfulness skills , self-compassion , and rumination than after CAU . In partners , no differences were found between groups . CONCLUSION Our findings suggest that psychological distress in lung cancer patients can be effectively treated with MBSR . No effect was found in partners , possibly because they were more focused on patients ' well-being rather than their own OBJECTIVES Considerable morbidity persists among survivors of breast cancer ( BC ) including high levels of psychological stress , anxiety , depression , fear of recurrence , and physical symptoms including pain , fatigue , and sleep disturbances , and impaired quality of life . Effective interventions are needed during this difficult transitional period . METHODS We conducted a r and omized controlled trial of 84 female BC survivors ( Stages 0-III ) recruited from the H. Lee Moffitt Cancer and Research Institute . All subjects were within 18 months of treatment completion with surgery and adjuvant radiation and /or chemotherapy . Subjects were r and omly assigned to a 6-week Mindfulness-Based Stress Reduction ( MBSR ) program design ed to self-regulate arousal to stressful circumstances or symptoms ( n=41 ) or to usual care ( n=43 ) . Outcome measures compared at 6 weeks by r and om assignment included vali date d measures of psychological status ( depression , anxiety , perceived stress , fear of recurrence , optimism , social support ) and psychological and physical subscales of quality of life ( SF-36 ) . RESULTS Compared with usual care , subjects assigned to MBSR(BC ) had significantly lower ( two-sided p<0.05 ) adjusted mean levels of depression ( 6.3 vs 9.6 ) , anxiety ( 28.3 vs 33.0 ) , and fear of recurrence ( 9.3 vs 11.6 ) at 6 weeks , along with higher energy ( 53.5 vs 49.2 ) , physical functioning ( 50.1 vs 47.0 ) , and physical role functioning ( 49.1 vs 42.8 ) . In stratified analyses , subjects more compliant with MBSR tended to experience greater improvements in measures of energy and physical functioning . CONCLUSIONS Among BC survivors within 18 months of treatment completion , a 6-week MBSR(BC ) program result ed in significant improvements in psychological status and quality of life compared with usual care Many breast cancer survivors have to deal with a variety of psychological and physiological sequelae including impaired immune responses . The primary purpose of this r and omized controlled trial was to determine the efficacy of a mindfulness‐based stress reduction ( MBSR ) intervention for mood disorders in women with breast cancer . Secondary outcomes were symptom experience , health status , coping capacity , mindfulness , posttraumatic growth , and immune status . This RTC assigned 166 women with breast cancer to one of three groups : MBSR ( 8 weekly group sessions of MBSR ) , active controls ( self‐instructing MBSR ) and non‐MBSR . The primary outcome measure was the Hospital Anxiety and Depression Scale . Secondary outcome measures were : Memorial Symptom Assessment Scale , SF‐36 , Sense of Coherence , Five Facets of Mindfulness Question naire , and Posttraumatic Growth Index . Blood sample s were analyzed using flow cytometry for NK‐cell activity ( FANKIA ) and lymphocyte phenotyping ; concentrations of cytokines were determined in sera using commercial high sensitivity IL‐6 and IL‐8 ELISA ( enzyme‐linked immunosorbent assay ) kits . Results provide evidence for beneficial effects of MBSR on psychological and biological responses . Women in the MBSR group experienced significant improvements in depression scores , with a mean pre‐MBSR HAD‐score of 4.3 and post‐MBSR score of 3.3 ( P = 0.001 ) , and compared to non‐MBSR ( P = 0.015 ) . Significant improvements on scores for distress , symptom burden , and mental health were also observed . Furthermore , MBSR facilitated coping capacity as well as mindfulness and posttraumatic growth . Significant benefits in immune response within the MBSR group and between groups were observed . MBSR have potential for alleviating depression , symptom experience , and for enhancing coping capacity , mindfulness and posttraumatic growth , which may improve breast cancer survivorship . MBSR also led to beneficial effect on immune function ; the clinical implication s of this finding merit further research Background Surgeons , along with the Centers for Disease Control and Prevention , emphasize the importance of managing symptoms and improving the quality of life of cancer survivors . A 2008 meta- analysis of mindfulness-based stress reduction ( MBSR ) concluded that this technique might improve patients ’ adjustment to their disease . However , r and omized controlled trials using st and ardized measures for evaluating MBSR are limited . The primary objective of this study was to evaluate , using valid and reliable measures , the effects of a unique , interactive , 8-week cancer recovery and wellness program on symptoms and quality of life of female cancer survivors . Methods Sixty-eight female cancer patients were r and omized into either an intervention or waitlisted control group . Patients were evaluated using the Symptoms Checklist ( SCL-90-R ) , the European Organization for Research and Treatment of Cancer Quality of Life Question naire ( EORTC QLQ-30 ) , and the Symptoms of Stress Inventory ( SOSI ) . Results Of the participants , 70.6 % were breast cancer survivors . Mean age was 57.5 years ( treatment group ) and 56.4 years ( control group ) . Between-group demographic differences were not significant ( P > 0.6 ) . The treatment group improved significantly on the EORTC QLQ-30 ( P = 0.005 ) , on six of the eight SOSI subscales ( P ≤ 0.049 ) , and on both SCL-90-R subscales ( P ≤ 0.023 ) , while the control group did not improve on any of these measures ( P > 0.2 ) . Conclusion The MBSR-based cancer recovery and wellness intervention improved the symptoms and quality of life of this largely breast cancer survivor population across a variety of cancer symptoms and quality -of-life measures Purpose Cancer-related cognitive impairment ( CRCI ) is a common , fatigue-related symptom that disrupts cancer survivors ’ quality of life . Few interventions for CRCI exist . As part of a r and omized pilot study targeting cancer-related fatigue , the effects of mindfulness-based stress reduction ( MBSR ) on survivors ’ cognitive outcomes were investigated . Methods Breast and colorectal cancer survivors ( n = 71 ) with moderate-to-severe fatigue were r and omized to MBSR ( n = 35 ) or a fatigue education and support ( ES ; n = 36 ) condition . The Attentional Function Index ( AFI ) and the Stroop test were used to assess survivors ’ cognitive function at baseline ( T1 ) , after the 8-week intervention period ( T2 ) , and 6 months later ( T3 ) using intent-to-treat analysis . Mediation analyses were performed to explore mechanisms of intervention effects on cognitive functioning . Results MBSR participants reported significantly greater improvement on the AFI total score compared to ES participants at T2 ( d = 0.83 , p = 0.001 ) and T3 ( d = 0.55 , p = 0.021 ) . MBSR also significantly outperformed ES on most AFI subscales , although both groups improved over time . MBSR produced greater Stroop accuracy rates relative to ES at T2 ( r = 0.340 , p = 0.005 ) and T3 ( r = 0.280 , p = 0.030 ) , with improved accuracy over time only for the MBSR group . There were no significant differences in Stroop reaction time between groups . Improvements in mindfulness mediated the effect of group ( e.g. , MBSR vs. ES ) on AFI total score at T2 and T3 . Conclusions Additional r and omized trials with more comprehensive cognitive measures are warranted to definitively assess the efficacy of MBSR for CRCI . Implication s for Cancer SurvivorsThis pilot study has important implication s for all cancer survivors as it is the first published trial to show that MBSR offers robust and durable improvements in CRCI PURPOSE To compare the efficacy of the following two empirically supported group interventions to help distressed survivors of breast cancer cope : mindfulness-based cancer recovery ( MBCR ) and supportive-expressive group therapy ( SET ) . PATIENTS AND METHODS This multisite , r and omized controlled trial assigned 271 distressed survivors of stage I to III breast cancer to MBCR , SET , or a 1-day stress management control condition . MBCR focused on training in mindfulness meditation and gentle yoga , whereas SET focused on emotional expression and group support . Both intervention groups included 18 hours of professional contact . Measures were collected at baseline and after intervention by assessors blind to study condition . Primary outcome measures were mood and diurnal salivary cortisol slopes . Secondary outcomes were stress symptoms , quality of life , and social support . RESULTS Using linear mixed-effects models , in intent-to-treat analyses , cortisol slopes were maintained over time in both SET ( P = .002 ) and MBCR ( P = .011 ) groups relative to the control group , whose cortisol slopes became flatter . Women in MBCR improved more over time on stress symptoms compared with women in both the SET ( P = .009 ) and control ( P = .024 ) groups . Per- protocol analyses showed greater improvements in the MBCR group in quality of life compared with the control group ( P = .005 ) and in social support compared with the SET group ( P = .012 ) . CONCLUSION In the largest trial to date , MBCR was superior for improving stress levels , quality of life and social support [ CORRECTED ] for distressed survivors of breast cancer . Both SET and MBCR also result ed in more normative diurnal cortisol profiles than the control condition . The clinical implication s of this finding require further investigation Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND Mindfulness-based cancer recovery ( MBCR ) and supportive-expressive therapy ( SET ) are well-vali date d psycho-oncological interventions , and we have previously reported health benefits of both programs . However , little is known about patients ' characteristics or program preferences that may influence outcomes . Therefore , this study examined moderators of the effects of MBCR and SET on psychological well-being among breast cancer survivors . METHODS A multi-site r and omized controlled trial was conducted between 2007 and 2012 in two Canadian cities ( Calgary and Vancouver ) . A total of 271 distressed stage I-III breast cancer survivors were r and omized into MBCR , SET or a 1-day stress management seminar ( SMS ) . Baseline measures of moderator variables included program preference , personality traits , emotional suppression , and repressive coping . Outcome measures of mood , stress symptoms , quality of life , spiritual well-being , post-traumatic growth , social support , and salivary cortisol were measured pre- and post intervention . Hierarchical regression analyses were used to assess moderator effects on outcomes . RESULTS The most preferred program was MBCR ( 55 % ) . Those who were r and omized to their preference improved more over time on quality of life and spiritual well-being post-intervention regardless of the actual intervention type received . Women with greater psychological morbidity at baseline showed greater improvement in stress symptoms and quality of life if they received their preferred versus nonpreferred program . CONCLUSIONS Patients ' program preference and baseline psychological functioning , rather than personality , were predictive of program benefits . These results suggest incorporating program preference can maximize the efficacy of integrative oncology interventions , and emphasize the method ological importance of assessing and accommodating for preferences when conducting mind-body clinical trials The purpose of this study was to gather data on the efficacy of a newly developed psychosocial group intervention for cancer patients , called mindfulness-based art therapy ( MBAT ) . One hundred and eleven women with a variety of cancer diagnoses were paired by age and r and omized to either an eight-week MBAT intervention group or a wait-list control group . Ninety-three participants ( 84 % ) completed both the pre- and post- study measurements . As compared to the control group , the MBAT group demonstrated a significant decrease in symptoms of distress ( as measured by the Symptoms Checklist-90-Revised ) and significant improvements in key aspects of health-related quality of life ( as measured by the Medical Outcomes Study Short-Form Health Survey ) . This investigation of MBAT provides initial encouraging data that support a possible future role for the intervention as a psychosocial treatment option for cancer patients Abstract Background . Women with breast cancer experience different symptoms related to surgical or adjuvant therapy . Previous findings and theoretical models of mind – body interactions suggest that psychological wellbeing , i.e. levels of distress , influence the subjective evaluation of symptoms , which influences or determines functioning . The eight-week mindfulness-based stress reduction ( MBSR ) program significantly reduced anxiety and depression in breast cancer patients in a r and omized controlled trial ( NCT00990977 ) . In this study we tested the effect of MBSR on the burden of breast cancer related somatic symptoms , distress , mindfulness and spiritual wellbeing and evaluated possible effect modification by adjuvant therapy and baseline levels of , distress , mindfulness and spiritual wellbeing . Material and methods . A population -based sample of 336 women Danish women operated for breast cancer stages I – III were r and omized to MBSR or usual care and were followed up for somatic symptoms , distress , mindfulness skills and spiritual wellbeing post-intervention and after six and 12 months . Effect was tested by general linear regression models post-intervention , and after six and 12 months follow-up and by mixed effects models for repeated measures of continuous outcomes . Effect size ( Cohen 's d ) was calculated to explore clinical significance of effects among intervention group . Finally , modification of effect of MBSR on burden of somatic symptoms after 12 months ’ follow-up by adjuvant therapy and baseline levels of , distress , mindfulness and spiritual wellbeing were estimated . Results . General linear regression showed a significant effect of MBSR on the burden of somatic symptoms post-intervention and after 6 months ’ follow-up . After 12 months ’ follow-up , no significant effect of MBSR on the burden of somatic symptoms was found in mixed effect models . A statistically significant effect of MBSR on distress was found at all time-points and in the mixed effect models . Significant effects on mindfulness were seen after six and 12 months and no significant effect was observed for spiritual wellbeing . No significant modification of MBSR effect on somatic symptom burden was identified . Conclusion . This first report from a r and omized clinical trial on the long-term effect of MBSR finds an effect on somatic symptom burden related to breast cancer after six but not 12 months follow-up providing support for MBSR in this patient group Despite growing evidence in support of mindfulness as an underlying mechanism of mindfulness-based interventions ( MBIs ) , it has been suggested that nonspecific therapeutic factors , such as the experience of social support , may contribute to the positive effects of MBIs . In the present study , we examined whether change in mindfulness and /or social support mediated the effect of Mindfulness-Based Cancer Recovery ( MBCR ) compared to another active intervention ( i.e. Supportive Expressive Group Therapy ( SET ) ) , on change in mood disturbance , stress symptoms and quality of life . A secondary analysis was conducted of a multi-site r and omized clinical trial investigating the impacts of MBCR and SET on distressed breast cancer survivors ( MINDSET ) . We applied the causal steps approach with bootstrapping to test mediation , using pre- and post-intervention question naire data of the participants who were r and omised to MBCR ( n = 69 ) or SET ( n = 70 ) . MBCR participants improved significantly more on mood disturbance , stress symptoms and social support , but not on quality of life or mindfulness , compared to SET participants . Increased social support partially mediated the impact of MBCR versus SET on mood disturbance and stress symptoms . Because no group differences on mindfulness and quality of life were observed , no mediation analyses were performed on these variables . Findings showed that increased social support was related to more improvement in mood and stress after MBCR compared to support groups , whereas changes in mindfulness were not . This suggests a more important role for social support in enhancing outcomes in MBCR than previously thought INTRODUCTION As the incidence of and survival from breast cancer continue to raise , interventions to reduce anxiety and depression before , during and after treatment are needed . Previous studies have reported positive effects of a structured 8-week group mindfulness-based stress reduction program ( MBSR ) among patients with cancer and other conditions . PURPOSE To test the effect of such a programme on anxiety and depression among women with breast cancer in a population -based r and omised controlled study . METHODS A total of 336 women who had been operated on for breast cancer ( stage I-III ) were r and omised to usual care or MBSR+usual care . Question naires including the Symptom Checklist-90r anxiety and depression subscales and the Center for Epidemiological Studies -Depression scale were administered before r and omisation and immediately , 6 and 12 months after the intervention . RESULTS Intention-to-treat analyses showed differences between groups in levels of anxiety ( p=0.0002 ) and depression ( SCL-90r , p<0.0001 ; CES-D , p=0.0367 ) after 12 months . Graphical comparisons of participants with higher levels of anxiety and depression at baseline showed a significantly greater decrease in the intervention group throughout follow-up and no differences among least affected participants . Medium-to-large effects were found for all outcomes in the intervention group in analyses of change scores after 12 months ' follow-up . CONCLUSION The 8-week group based MBSR intervention had clinical ly meaningful , statistically significant effects on depression and anxiety after 12 months ' follow-up , and medium-to-large effect sizes . Our findings support the dissemination of MBSR among women with breast cancer . ( Clintrials.gov No. : NCT00990977 ) OBJECTIVE This study evaluated the effectiveness of mindfulness-based cognitive therapy ( MBCT ) for individuals with a diagnosis of cancer . METHOD Participants ( N = 115 ) diagnosed with cancer , across site and stage , were r and omly allocated to either the treatment or the wait-list condition . Treatment was conducted at 1 site , by a single therapist , and involved participation in 8 weekly 2-hr sessions that focused on mindfulness . Participants meditated for up to 1 hr daily and attended an additional full-day session during the course . Participants were assessed before treatment and 10 weeks later ; this second assessment occurred immediately after completion of the program for the treatment condition . The treatment condition was also assessed at 3 months postintervention . All postinitial assessment s were completed by assessors who were blind to treatment allocation . RESULTS There were large and significant improvements in mindfulness ( effect size [ ES ] = 0.55 ) , depression ( ES = 0.83 ) , anxiety ( ES = 0.59 ) , and distress ( ES = 0.53 ) as well as a trend for quality of life ( ES = 0.30 ) for MBCT participants compared to those who had not received the training . The wait-list group was assessed before and after receiving the intervention and demonstrated similar change . CONCLUSIONS These improvements represent clinical ly meaningful change and provide evidence for the provision of MBCT within oncology setting Background There is increasing evidence showing beneficial effects of mindfulness and mindfulness training on various indicators of mental and physical health . Purpose This paper reports the 6-month follow-up effects of a mindfulness stress reduction training program among patients treated for cancer on perceived stress , depression , anxiety , post-traumatic stress symptoms , positive states of mind , coping self-efficacy , and mindfulness . Methods Patients with a previous cancer diagnosis were recruited and r and omized into an intervention group or a waiting list control group . The intervention consisted of an 8-week mindfulness training course . Results Compared to participants in the control group , the intervention group showed a larger increase in mindfulness at 6-month follow-up . However , there were no differences on any of the other outcomes between the intervention and control groups . Continued meditation practice was associated with a significant reduction in post-traumatic stress symptoms of avoidance . Conclusions The study draws attention to the need to better underst and the mechanisms behind the effect of mindfulness training and to potential modification of mindfulness interventions to promote sustained benefits over time Objective A treatment-as-usual r and omized wait-list controlled trial was conducted to investigate the feasibility and impact of an online synchronous Mindfulness-Based Cancer Recovery ( MBCR ) group program for underserved distressed cancer survivors . Methods Sixty-two men and women exhibiting moderate to high distress within 3 years of completing primary cancer treatment without access to in-person MBCR were r and omized to either immediate online MBCR ( n = 30 ) or to wait for the next available program ( n = 32 ) . Participants completed question naires preintervention and postintervention or wait period online . Program evaluations were completed after MBCR . Feasibility was tracked through monitoring eligibility and participation through the protocol . Intent-to-treat mixed-model analyses for repeated measures were conducted . Results Feasibility targets for recruitment and retention were achieved , and participants were satisfied and would recommend online MBCR . There were significant improvements and moderate Cohen d effect sizes in the online MBCR group relative to controls after MBCR for total scores of mood disturbance ( d = 0.44 , p = .049 ) , stress symptoms ( d = 0.49 , p = .021 ) , spirituality ( d = 0.37 , p = .040 ) , and mindfully acting with awareness ( d = 0.50 , p = .026 ) . Main effects of time were observed for posttraumatic growth and remaining mindfulness facets . Conclusions Results provide evidence for the feasibility and efficacy of an online adaptation of MBCR for the reduction of mood disturbance and stress symptoms , as well as an increase in spirituality and mindfully acting with awareness compared with a treatment-as-usual wait-list . Future study using larger active control RCT design s is warranted . Trial Registration : Clinical Trials.gov : NCT01476891 Background Following publication of the PRISMA statement , the UK Centre for Review s and Dissemination ( CRD ) at the University of York in Engl and began to develop an international prospect i ve register of systematic review s with health-related outcomes . The objectives were to reduce unplanned duplication of review s and provide transparency in the review process , with the aim of minimizing reporting bias . Methods An international advisory group was formed and a consultation undertaken to establish the key items necessary for inclusion in the register and to gather views on various aspects of functionality . This article describes the development of the register , now called PROSPERO , and the process of registration . Results PROSPERO offers free registration and free public access to a unique prospect i ve register of systematic review s across all areas of health from all around the world . The dedicated web-based interface is electronically search able and available to all prospect i ve registrants . At the moment , inclusion in PROSPERO is restricted to systematic review s of the effects of interventions and strategies to prevent , diagnose , treat , and monitor health conditions , for which there is a health-related outcome .Ideally , registration should take place before the research ers have started formal screening against inclusion criteria but review s are eligible as long as they have not progressed beyond the point of completing data extraction .The required data set captures the key attributes of review design as well as the administrative details necessary for registration .Su bmi tted registration forms are checked against the scope for inclusion in PROSPERO and for clarity of content before being made publicly available on the register , rejected , or returned to the applicant for clarification . The public records include an audit trail of major changes to planned methods , details of when the review has been completed , and links to result ing publications when provided by the authors . Conclusions There has been international support and an enthusiastic response to the principle of prospect i ve registration of protocol s for systematic review s and to the development of PROSPERO .In October 2011 , PROSPERO contained 200 records of systematic review s being undertaken in 26 countries around the world on a diverse range of interventions Objectives : The aim of this study was to investigate possible statistical mediators in a r and omized controlled trial of mindfulness-based cognitive therapy ( MBCT ) on pain intensity in women treated for primary breast cancer . Material s and Methods : The sample consisted of 129 women treated for breast cancer , presenting with persistent pain , who were r and omly assigned to MBCT or a wait-list control . We previously reported a statistically significant and robust effect of MBCT on pain intensity ( 11-point numeric rating scale ) , which was included as the primary outcome . The proposed mediators were mindfulness ( the Five Facet Mindfulness Question naire ) , self-compassion ( the Short-Form Self-Compassion Scale ) , and pain catastrophizing ( the Pain Catastrophizing Scale ) . Measurement points included baseline ( T1 ) , postintervention ( T2 ) , and 3- ( T3 ) and 6-month ( T4 ) follow-ups . All indirect effects of the mediators were tested in separate Multilevel Models , using the product-of-coefficients approach with bias-corrected confidence intervals ( 95 % BSCI ) . The statistically significant mediators were then included in a multiple mediator model . Results : Statistically significant indirect effects were found for mindfulness nonreactivity ( B=−0.17 , BSCI [ −0.32 to −0.04 ] ) and pain catastrophizing ( B=−0.76 , BSCI [ −1.25 to −0.47 ] ) . No statistically significant indirect effect was found for self-compassion ( B=−0.09 , BSCI [ −0.30 to 0.04 ] ) . In a multiple mediator model , including mindfulness nonreactivity and pain catastrophizing , only pain catastrophizing remained statistically significant ( B=−0.72 , BSCI [ −1.19 to −0.33 ] ) , explaining 78 % of the effect . Discussion : The results of the present study may have clinical implication s. An increased focus on the proposed mediators may optimize the clinical use of MBCT for persistent pain in women treated for breast cancer Objective The objective of this study was to assess the effects of participation in a mindfulness meditation – based stress reduction program on mood disturbance and symptoms of stress in cancer out patients . Methods A r and omized , wait-list controlled design was used . A convenience sample of eligible cancer patients enrolled after giving informed consent and were r and omly assigned to either an immediate treatment condition or a wait-list control condition . Patients completed the Profile of Mood States and the Symptoms of Stress Inventory both before and after the intervention . The intervention consisted of a weekly meditation group lasting 1.5 hours for 7 weeks plus home meditation practice . Results Ninety patients ( mean age , 51 years ) completed the study . The group was heterogeneous in type and stage of cancer . Patients ’ mean preintervention scores on dependent measures were equivalent between groups . After the intervention , patients in the treatment group had significantly lower scores on Total Mood Disturbance and subscales of Depression , Anxiety , Anger , and Confusion and more Vigor than control subjects . The treatment group also had fewer overall Symptoms of Stress ; fewer Cardiopulmonary and Gastrointestinal symptoms ; less Emotional Irritability , Depression , and Cognitive Disorganization ; and fewer Habitual Patterns of stress . Overall reduction in Total Mood Disturbance was 65 % , with a 31 % reduction in Symptoms of Stress . Conclusions This program was effective in decreasing mood disturbance and stress symptoms in both male and female patients with a wide variety of cancer diagnoses , stages of illness , and ages BACKGROUND AND OBJECTIVE Publication bias and other sample size effects are issues for meta-analyses of test accuracy , as for r and omized trials . We investigate limitations of st and ard funnel plots and tests when applied to meta-analyses of test accuracy and look for improved methods . METHODS Type I and type II error rates for existing and alternative tests of sample size effects were estimated and compared in simulated meta-analyses of test accuracy . RESULTS Type I error rates for the Begg , Egger , and Macaskill tests are inflated for typical diagnostic odds ratios ( DOR ) , when disease prevalence differs from 50 % and when thresholds favor sensitivity over specificity or vice versa . Regression and correlation tests based on functions of effective sample size are valid , if occasionally conservative , tests for sample size effects . Empirical evidence suggests that they have adequate power to be useful tests . When DORs are heterogeneous , however , all tests of funnel plot asymmetry have low power . CONCLUSION Existing tests that use st and ard errors of odds ratios are likely to be seriously misleading if applied to meta-analyses of test accuracy . The effective sample size funnel plot and associated regression test of asymmetry should be used to detect publication bias and other sample size related effects OBJECTIVE It is well documented that stress is associated with negative health outcomes in cancer patients . The purpose of this study was to assess the effects of a novel mindfulness intervention called mindfulness-based art therapy ( MBAT ) versus st and ard educational support , on indices of stress and quality of life in breast cancer patients with high stress levels . METHODS A total of 191 women were enrolled , stratified by age and stress level , and r and omized to receive either an 8-week MBAT intervention or a breast cancer educational support program of equal time and duration . Psychosocial stress was measured using the Symptoms Checklist-90-Revised , and quality of life was measured using the Medical Outcomes Study Short-Form Health Survey at baseline , immediately post-intervention , and at 6 months . RESULTS Results showed overall significant improvements in psychosocial stress and quality of life in both the MBAT and educational support groups immediately post-intervention ; however , participants with high stress levels at baseline had significantly improved overall outcomes only in the MBAT group , both immediately post-intervention and at 6 months . In addition , at 6 months follow-up , participants attending five or more sessions trended toward retaining treatment effects better in the MBAT than in the control group . Finally , black women and white women were similar in terms of how they benefited from the MBAT intervention , even though white participants tended to have higher educational level and marital status . CONCLUSIONS In conclusion , MBAT is associated with significant , sustained benefits across a diverse range of breast cancer patients , particularly those with high stress levels The aim of this study was determine the effectiveness of a mindfulness-based stress-reduction ( MBSR ) program on quality of life ( QOL ) and psychosocial outcomes in women with early-stage breast cancer , using a three-arm r and omized controlled clinical trial ( RCT ) . This RCT consisting of 172 women , aged 20–65 with stage I or II breast cancer consisted of the 8-week MBSR , which was compared to a nutrition education program ( NEP ) and usual supportive care ( UC ) . Follow-up was performed at three post-intervention points : 4 months , 1 , and 2 years . St and ardized , vali date d self-administered question naires were adopted to assess psychosocial variables . Statistical analysis included descriptive and regression analyses incorporating both intention-to-treat and post hoc multivariable approaches of the 163 women with complete data at baseline , those who were r and omized to MBSR experienced a significant improvement in the primary measures of QOL and coping outcomes compared to the NEP , UC , or both , including the spirituality subscale of the FACT-B as well as dealing with illness scale increases in active behavioral coping and active cognitive coping . Secondary outcome improvements result ing in significant between-group contrasts favoring the MBSR group at 4 months included meaningfulness , depression , paranoid ideation , hostility , anxiety , unhappiness , and emotional control . Results tended to decline at 12 months and even more at 24 months , though at all times , they were as robust in women with lower expectation of effect as in those with higher expectation . The MBSR intervention appears to benefit psychosocial adjustment in cancer patients , over and above the effects of usual care or a credible control condition . The universality of effects across levels of expectation indicates a potential to utilize this stress reduction approach as complementary therapy in oncologic practice PURPOSE To assess the efficacy of mindfulness-based cognitive therapy ( MBCT ) for late post-treatment pain in women treated for primary breast cancer . METHODS A r and omized wait list-controlled trial was conducted with 129 women treated for breast cancer reporting post-treatment pain ( score ≥ 3 on pain intensity or pain burden assessed with 10-point numeric rating scales ) . Participants were r and omly assigned to a manualized 8-week MBCT program or a wait-list control group . Pain was the primary outcome and was assessed with the Short Form McGill Pain Question naire 2 ( SF-MPQ-2 ) , the Present Pain Intensity subscale ( the McGill Pain Question naire ) , and perceived pain intensity and pain burden ( numeric rating scales ) . Secondary outcomes were quality of life ( World Health Organization-5 Well-Being Index ) , psychological distress ( the Hospital Depression and Anxiety Scale ) , and self-reported use of pain medication . All outcome measures were assessed at baseline , postintervention , and 3-month and 6-month follow-up . Treatment effects were evaluated with mixed linear models . RESULTS Statistically significant time × group interactions were found for pain intensity ( d = 0.61 ; P = .002 ) , the Present Pain Intensity subscale ( d = 0.26 ; P = .026 ) , the SF-MPQ-2 neuropathic pain subscale ( d = 0.24 ; P = .036 ) , and SF-MPQ-2 total scores ( d = 0.23 ; P = .036 ) . Only pain intensity remained statistically significant after correction for multiple comparisons . Statistically significant effects were also observed for quality of life ( d = 0.42 ; P = .028 ) and nonprescription pain medication use ( d = 0.40 ; P = .038 ) . None of the remaining outcomes reached statistical significance . CONCLUSION MBCT showed a statistically significant , robust , and durable effect on pain intensity , indicating that MBCT may be an efficacious pain rehabilitation strategy for women treated for breast cancer . In addition , the effect on neuropathic pain , a pain type reported by women treated for breast cancer , further suggests the potential of MBCT but should be considered preliminary PURPOSE To assess the effectiveness of mindfulness-based stress reduction ( MBSR ) for mood , breast- and endocrine-specific quality of life , and well-being after hospital treatment in women with stage 0 to III breast cancer . PATIENTS AND METHODS A r and omized , wait-listed , controlled trial was carried out in 229 women after surgery , chemotherapy , and radiotherapy for breast cancer . Patients were r and omly assigned to the 8-week MBSR program or st and ard care . Profile of Mood States ( POMS ; primary outcome ) , Functional Assessment of Cancer Therapy-Breast ( FACT-B ) , Functional Assessment of Cancer Therapy-Endocrine Symptoms ( FACT-ES ) scales and the WHO five-item well-being question naire ( WHO-5 ) evaluated mood , quality of life , and well-being at weeks 0 , 8 , and 12 . For each outcome measure , a repeated- measures analysis of variance model , which incorporated week 0 measurements as a covariate , was used to compare treatment groups at 8 and 12 weeks . RESULTS There were statistically significant improvements in outcome in the experimental group compared with control group at both 8 and 12 weeks ( except as indicated ) for POMS total mood disturbance ( and its subscales of anxiety , depression [ 8 weeks only ] , anger [ 12 weeks only ] , vigor , fatigue , and confusion [ 8 weeks only ] ) , FACT-B , FACT-ES , ( and Functional Assessment of Cancer Therapy subscales of physical , social [ 8 weeks only ] , emotional , and functional well-being ) , and WHO-5 . CONCLUSION MSBR improved mood , breast- and endocrine-related quality of life , and well-being more effectively than st and ard care in women with stage 0 to III breast cancer , and these results persisted at three months . To our knowledge , this study provided novel evidence that MBSR can help alleviate long-term emotional and physical adverse effects of medical treatments , including endocrine treatments . MBSR is recommended to support survivors of breast cancer BACKGROUND Insomnia is an important but often overlooked side effect of cancer . Dysfunctional sleep beliefs have been identified as an important perpetuating factor for insomnia . Mindfulness practice has been demonstrated to improve sleep quality but it is unknown whether these effects relate to changes in dysfunctional sleep beliefs . PURPOSE This study is a secondary analysis of a r and omized controlled trial comparing mindfulness-based cancer recovery ( MBCR ) to cognitive behavior therapy for insomnia ( CBT-I ) in cancer patients with insomnia . This present analysis compares program impact on mindfulness , dysfunctional sleep beliefs , and insomnia severity clinical cutoffs . METHODS Patients ( MBCR , n = 32 ; CBT-I , n = 40 ) were assessed at baseline , post-program , and 3-month follow-up . RESULTS Across both groups , patients showed improvements over time in acting with awareness ( P = .021 ) and not judging experiences ( P = .023 ) . Changes in dysfunctional sleep beliefs produced by the CBT-I group exceeded those produced by MBCR at post-program and follow-up ( P < .001 ) . Acting with awareness , non-judging , and non-reacting were the facets of mindfulness associated with an overall reduction in dysfunctional sleep beliefs . There were no significant differences between the MBCR and CBT-I groups in the percentage of patients exceeding insomnia severity clinical cutoffs at post-program or follow-up . CONCLUSIONS This study supports the use of both CBT-I and MBCR to reduce insomnia severity and suggests the development of mindfulness facets as a method of reducing dysfunctional sleep beliefs BACKGROUND Mindfulness-based art therapy ( MBAT ) induces emotional relaxation in cancer patients and is a treatment known to improve psychological stability . The objective of this research was to evaluate the treatment effects of MBAT for breast cancer patients . METHODS Overall , 24 breast cancer patients were selected as subjects of the study . Two groups , the MBAT group and control group with 12 patients each , were r and omly assigned . The patients in the MBAT group were given 12 sessions of treatments . To measure depression and anxiety , low scales of the personality assessment inventory ( PAI ) was used . Health-related quality of life was evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Question naire ( EORTCQLQ-C30 ) . The treatment results were analyzed using analysis of covariance ( ANCOVA ) and two-way repeated measures analysis of variance ( ANOVA ) . RESULTS The results showed that depression and anxiety decreased significantly and health-related quality of life improved significantly in the MBAT group . In the control group , however , there was no significant change . CONCLUSIONS MBAT can be seen as an effective treatment method that improves breast cancer patients ׳ psychological stability and quality of life . Evaluation of treatment effects using program development and large-scale research for future clinical application is needed Purpose Mindfulness-based cognitive therapy ( MBCT ) has been shown to alleviate psychological distress in patients with cancer . However , patients experience barriers to participating in face-to-face MBCT . Individual Internet-based MBCT ( eMBCT ) could be an alternative . The study aim was to compare MBCT and eMBCT with treatment as usual ( TAU ) for psychological distress in patients with cancer . Patients and Methods We obtained ethical and safety approval to include 245 patients with cancer with psychological distress ( ≥ 11 on the Hospital Anxiety and Depression Scale ) in the study . They were r and omly allocated to MBCT ( n = 77 ) , eMBCT ( n = 90 ) , or TAU ( n = 78 ) . Patients completed baseline ( T0 ) and postintervention ( T1 ) assessment s. The primary outcome was psychological distress on the Hospital Anxiety and Depression Scale . Secondary outcomes were psychiatric diagnosis , fear of cancer recurrence , rumination , health-related quality of life , mindfulness skills , and positive mental health . Continuous outcomes were analyzed using linear mixed modeling on the intention-to-treat sample . Because both interventions were compared with TAU , the type I error rate was set at P < .025 . Results Compared with TAU , patients reported significantly less psychological distress after both MBCT ( Cohen 's d , .45 ; P < .001 ) and eMBCT ( Cohen 's d , .71 ; P < .001 ) . In addition , post-treatment prevalence of psychiatric diagnosis was lower with both MBCT ( 33 % improvement ; P = .030 ) and eMBCT ( 29 % improvement ; P = .076 ) in comparison with TAU ( 16 % ) , but these changes were not statistically significant . Both interventions reduced fear of cancer recurrence and rumination , and increased mental health-related quality of life , mindfulness skills , and positive mental health compared with TAU ( all Ps < .025 ) . Physical health-related quality of life did not improve ( P = .343 ) . Conclusion Compared with TAU , MBCT and eMBCT were similarly effective in reducing psychological distress in a sample of distressed heterogeneous patients with cancer OBJECTIVES Mindfulness-based cognitive therapy ( MBCT ) is a group-based intervention similar to mindfulness-based stress reduction , but which includes cognitive therapy techniques . This study investigates its usefulness in the treatment of depressive , anxiety and stress/distress symptoms in cancer patients referred to a psycho-oncology service . It also examines whether effect on depression is mediated by self-compassion . METHOD In phase 1 of this study , 16 cancer patients with mild/moderate psychological distress were r and omised to MBCT ( n=8 ) or treatment as usual ( TAU ; n=8 ) , and assessed pre- and post-treatment . Analysis of variance was performed to examine the effect of treatment on anxiety and depression . In phase 2 , the TAU group received the intervention , and results of pre- and post-MBCT assessment s were combined with those receiving MBCT in phase 1 . Finally , both groups were followed up at 3 months . RESULTS In phase 1 , the MBCT group had a significant improvement in mindfulness and a decrease in anxiety . Statistically significant improvements in both depression and anxiety were found at 3 month follow-up . Self-compassion appeared to mediate the effect on anxiety/depression . CONCLUSION This small pilot study suggests that MBCT may have a beneficial effect on psychological variables often adversely affected in cancer in a heterogeneous cancer population CONTEXT Breast cancer survivors ( BCS ) face adverse physical and psychological symptoms , often co-occurring . Biologic and psychological factors may link symptoms within clusters , distinguishable by prevalence and /or severity . Few studies have examined the effects of behavioral interventions or treatment of symptom clusters . OBJECTIVES The aim of this study was to identify symptom clusters among post-treatment BCS and determine symptom cluster improvement following the Mindfulness-Based Stress Reduction for Breast Cancer ( MBSR(BC ) ) program . METHODS Three hundred twenty-two Stage 0-III post-treatment BCS were r and omly assigned to either a six-week MBSR(BC ) program or usual care . Psychological ( depression , anxiety , stress , and fear of recurrence ) , physical ( fatigue , pain , sleep , and drowsiness ) , and cognitive symptoms and quality of life were assessed at baseline , six , and 12 weeks , along with demographic and clinical history data at baseline . A three-step analytic process included the error-accounting models of factor analysis and structural equation modeling . RESULTS Four symptom clusters emerged at baseline : pain , psychological , fatigue , and cognitive . From baseline to six weeks , the model demonstrated evidence of MBSR(BC ) effectiveness in both the psychological ( anxiety , depression , perceived stress and QOL , emotional well-being ) ( P = 0.007 ) and fatigue ( fatigue , sleep , and drowsiness ) ( P < 0.001 ) clusters . Results between six and 12 weeks showed sustained effects , but further improvement was not observed . CONCLUSION Our results provide clinical effectiveness evidence that MBSR(BC ) works to improve symptom clusters , particularly for psychological and fatigue symptom clusters , with the greatest improvement occurring during the six-week program with sustained effects for several weeks after MBSR(BC ) training . TRIAL REGISTRATION Name and URL of Registry : Clinical Trials.gov . Registration number : NCT01177124 OBJECTIVE Cancer-related fatigue ( CRF ) is one of the most common , persistent , and disabling symptoms associated with cancer and its treatment . Evidence -based treatments that are acceptable to patients are critically needed . This study examined the efficacy of mindfulness-based stress reduction ( MBSR ) for CRF and related symptoms . METHOD A sample of 35 cancer survivors with clinical ly significant CRF was r and omly assigned to a 7-week MBSR-based intervention or wait-list control group . The intervention group received training in mindfulness meditation , yoga , and self-regulatory responses to stress . Fatigue interference ( primary outcome ) and a variety of secondary outcomes ( e.g. , fatigue severity , vitality , disability , depression , anxiety , and sleep disturbance ) were assessed at baseline , post-intervention , and 1-month follow-up . Bonferroni correction was employed to account for multiple comparisons . Controls received the intervention after the 1-month follow-up . Participants in both groups were followed for 6 months after completing their respective MBSR courses to assess maintenance of effects . RESULTS Compared to controls , the MBSR group reported large post-intervention reductions as assessed by effect sizes ( d ) in the primary outcome , fatigue interference ( d = -1.43 , p < 0.001 ) , along with fatigue severity ( d = -1.55 , p < 0.001 ) , vitality ( d = 1.29 , p < 0.001 ) , depression ( d = -1.30 , p < 0.001 ) , and sleep disturbance ( d = -0.74 , p = 0.001 ) . Results were maintained or strengthened at 1-month follow-up , the point at which significant improvements in disability ( d = -1.22 , p < 0.002 ) and anxiety ( d = -0.98 , p = 0.002 ) occurred . Improvements in all outcomes were maintained 6 months after completing the course . MBSR adherence was high , with 90 % attendance across groups and high rates of participant-reported home practice of mindfulness . CONCLUSIONS Mindfulness-based stress reduction is a promising treatment for CRF and associated symptoms PURPOSE Our study examined whether mindfulness-based stress reduction ( MBSR ) is noninferior to cognitive behavioral therapy for insomnia ( CBT-I ) for the treatment of insomnia in patients with cancer . PATIENTS AND METHODS This was a r and omized , partially blinded , noninferiority trial involving patients with cancer with insomnia recruited from a tertiary cancer center in Calgary , Alberta , Canada , from September 2008 to March 2011 . Assessment s were conducted at baseline , after the program , and after 3 months of follow-up . The noninferiority margin was 4 points measured by the Insomnia Severity Index . Sleep diaries and actigraphy measured sleep onset latency ( SOL ) , wake after sleep onset ( WASO ) , total sleep time ( TST ) , and sleep efficiency . Secondary outcomes included sleep quality , sleep beliefs , mood , and stress . RESULTS Of 327 patients screened , 111 were r and omly assigned ( CBT-I , n = 47 ; MBSR , n = 64 ) . MBSR was inferior to CBT-I for improving insomnia severity immediately after the program ( P = .35 ) , but MBSR demonstrated noninferiority at follow-up ( P = .02 ) . Sleep diary-measured SOL was reduced by 22 minutes in the CBT-I group and by 14 minutes in the MBSR group at follow-up . Similar reductions in WASO were observed for both groups . TST increased by 0.60 hours for CBT-I and 0.75 hours for MBSR . CBT-I improved sleep quality ( P < .001 ) and dysfunctional sleep beliefs ( P < .001 ) , whereas both groups experienced reduced stress ( P < .001 ) and mood disturbance ( P < .001 ) . CONCLUSION Although MBSR produced a clinical ly significant change in sleep and psychological outcomes , CBT-I was associated with rapid and durable improvement and remains the best choice for the nonpharmacologic treatment of insomnia Abstract The prevalence of sleep disturbance is high among cancer patients , and the sleep problems tend to last for years after the end of treatment . As part of a large r and omized controlled clinical trial ( the MICA trial , NCT00990977 ) of the effect of mindfulness-based stress reduction ( MBSR ) on psychological and somatic symptoms among breast cancer patients , the aim of the current study was to evaluate the effect of MBSR on the secondary outcome , ‘ sleep quality ’ . Material and methods . A total of 336 women operated on for breast cancer stage I – III 3–18 months previously were r and omized to MBSR ( n = 168 ) or treatment as usual ( n = 168 ) ; both groups received st and ard clinical care . The intervention consisted of an eight-week MBSR program ( psycho-education , meditation and gentle yoga ) . Sleep quality was assessed on the Medical Outcome Study sleep scale at baseline , after the intervention and at six- and 12-months ’ follow-up . Results . The mean sleep problem scores were significantly lower in the MBSR group than in controls immediately after the intervention . Quantile regression analyses showed that the effect was statistically significant only for the participants represented by the lower percentile of change between baseline and post-intervention , i.e. those who had more sleep problems ; the MBSR group had a significantly smaller increase in sleep problems than the control group . After the 12-month follow-up , there was no significant between-group effect of MBSR on sleep quality in intention-to-treat analyses . Conclusion . MBSR had a statistically significant effect on sleep quality just after the intervention but no long-term effect among breast cancer patients . Future trials in which participation is restricted to patients with significant sleep problems are recommended for evaluating the effect of MBSR on sleep quality |
13,680 | 18,254,066 | Women with recurrent genital herpes simplex virus should be informed that the risk of neonatal herpes is low .
There is insufficient evidence to determine if antiviral prophylaxis reduces the incidence of neonatal herpes .
Antenatal antiviral prophylaxis reduces viral shedding and recurrences at delivery and reduces the need for cesarean delivery for genital herpes .
Limited information exists regarding the neonatal safety of prophylaxis . | BACKGROUND Genital herpes simplex virus ( HSV ) infection is one of the most common viral sexually transmitted infections .
The majority of women with genital herpes will have a recurrence during pregnancy .
Transmission of the virus from mother to fetus typically occurs by direct contact with virus in the genital tract during birth .
OBJECTIVES To assess the effectiveness of antenatal antiviral prophylaxis for recurrent genital herpes on neonatal herpes and maternal recurrences at delivery . | The pharmacokinetics and safety of the L‐valyl ester pro‐drug of acyclovir , valaciclovir ( 256U87 ) , were investigated in two phase I , placebo‐controlled trials in normal volunteers . These included a single‐dose study with doses from 100 to 1000 mg ( single cohort ) and a multiple‐dose investigation with doses from 250 to 2000 mg ( five separate cohorts ) . In each cohort , eight subjects received valaciclovir and four subjects received placebo . Pharmacokinetic findings for valaciclovir and acyclovir were consistent in the two studies . Valaciclovir was rapidly and extensively converted to acyclovir , result ing in significantly greater acyclovir bioavailability ( ~ threefold to fivefold ) compared with that historically observed with high‐dose ( 800 mg ) oral acyclovir . At the higher valaciclovir doses , acyclovir maximum concentration and daily area under the concentration‐time curve approximated those obtained with intravenous acyclovir . The favorable safety profile and enhanced acyclovir bioavailability from valaciclovir administration has prompted additional clinical evaluations for zoster and herpes simplex virus treatment , as well as cytomegalovirus suppression in immunocompromised patients OBJECTIVE : To determine if suppressive acyclovir near term decreased the frequency of clinical recurrences at delivery in women with recurrent genital herpes simplex virus ( HSV ) infection . METHODS : We conducted a prospect i ve , double-blind , r and omized trial in 234 women with recurrent genital herpes . Women with genital infection of any frequency were enrolled . Patients received either suppressive oral acyclovir 400 mg three times daily or an identical placebo after 36 weeks ' gestation . Clinical lesions were identified , and HSV cultures were obtained at delivery . The frequencies of clinical and sub clinical HSV recurrences at delivery were evaluated . RESULTS : Six percent of patients treated with acyclovir , and 14 % of patients treated with placebo had clinical HSV at delivery ( p = 0.046 ) . No patients in the acyclovir group had positive HSV cultures , compared with 6 % of placebo-treated patients ( p = 0.029 ) . There was no significant difference in sub clinical HSV shedding in the acyclovir group ( 0 % ) compared with the placebo-treated group ( 3 % ) ( p = 0.102 ) . CONCLUSIONS : Suppressive acyclovir therapy significantly decreased the incidence of clinical genital herpes and the overall incidence of HSV excretion at delivery in patients with previous herpes infection We compared the clinical presentation of 95 newborns with herpes simplex virus ( HSV ) infection from 1973 through 1981 ( first period ) with data from 196 newborns evaluated from 1982 through 1987 ( second period ) . There was a significant change in the presentation of infection in these infants . From the first to the second period , the frequency of disseminated disease decreased from 50.5 % to 22.9 % , whereas the frequency of skin , eye , and mouth ( SEM ) diseases increased from 17.9 % to 43.4 % ( P less than .001 ) . The frequency of infants with central nervous system ( CNS ) disease remained relatively unchanged--31.6 % versus 33.7 % . We also compared the demographic and clinical characteristics of the infants and their mothers . For neonates with CNS or disseminated infection , disease duration and frequency of prematurity were significantly decreased in the second period , as was the frequency of skin vesicles for newborns with SEM or disseminated infection . These changes are most likely the consequence of recognizing and treating SEM infection before its progression to more-severe disease A r and omized , double-blind study of valaciclovir for suppression of recurrent genital herpes was conducted among 1479 immunocompetent patients . Patients were r and omized to receive valaciclovir ( 250 mg , 500 mg , or 1 g once daily , or 250 mg twice daily ) , acyclovir ( 400 mg twice daily ) , or placebo , for 1 year . All valaciclovir dosages were significantly more effective than placebo at preventing or delaying recurrences ( P < .0001 ) . There was a dose-response relationship ( P < .0001 ) across the once-daily valaciclovir regimens . Twice-daily valaciclovir and acyclovir were similar in effectiveness . Subgroup analysis showed that patients with a history of < 10 recurrences per year were effectively managed with 500 mg of valaciclovir once daily . One gram of valaciclovir once daily , 250 mg of valaciclovir twice daily , or 400 mg of acyclovir twice daily were more effective in patients with > or = 10 recurrences per year . Safety profiles of all treatments were comparable . Thus , valaciclovir is highly effective and well tolerated for suppression of recurrent genital herpes . Once-daily regimens offer a useful option for patients who require suppressive therapy for management of genital herpes Normal adults with six or more episodes of genital herpes in the previous year were enrolled in a one-year , multicenter , double-blind trial comparing placebo with 400 mg of acyclovir administered orally twice daily . Patients with episodes during the study were offered 200 mg of acyclovir administered orally five times daily for five days ; this allowed comparison of suppressive and episodic treatment . After one year , 227 ( 44 % ) of 519 patients receiving suppressive treatment and seven ( 2 % ) of 431 receiving placebo ( episodic ) treatment remained free of recurrences , and the mean numbers of recurrences per year were 1.8 and 11.4 , respectively . Among 67 patients who had received suppressive therapy for one year , the mean duration of lesions in the first episode following the discontinuation of treatment was 9.3 days compared with 7.3 days among 45 patients who had received episodic therapy for one year . Treatment was well tolerated , and no changes were noted in the in vitro susceptibility to acyclovir of herpes simplex virus cultured during or after the one-year trial . Continuous or episodic oral acyclovir therapy for one year remained safe and effective Objective To evaluate the efficacy and safety of a suppressive course of acyclovir in late pregnancy in women with recurrent genital herpes infection on the incidence of viral shedding , herpes lesion development and caesarean section for recurrent genital herpes BACKGROUND Nucleoside analogues against herpes simplex virus ( HSV ) have been shown to suppress shedding of HSV type 2 ( HSV-2 ) on genital mucosal surfaces and may prevent sexual transmission of HSV . METHODS We followed 1484 immunocompetent , heterosexual , monogamous couples : one with clinical ly symptomatic genital HSV-2 and one susceptible to HSV-2 . The partners with HSV-2 infection were r and omly assigned to receive either 500 mg of valacyclovir once daily or placebo for eight months . The susceptible partner was evaluated monthly for clinical signs and symptoms of genital herpes . Source partners were followed for recurrences of genital herpes ; 89 were enrolled in a sub study of HSV-2 mucosal shedding . Both partners were counseled on safer sex and were offered condoms at each visit . The predefined primary end point was the reduction in transmission of symptomatic genital herpes . RESULTS Clinical ly symptomatic HSV-2 infection developed in 4 of 743 susceptible partners who were given valacyclovir , as compared with 16 of 741 who were given placebo ( hazard ratio , 0.25 ; 95 percent confidence interval , 0.08 to 0.75 ; P=0.008 ) . Overall , acquisition of HSV-2 was observed in 14 of the susceptible partners who received valacyclovir ( 1.9 percent ) , as compared with 27 ( 3.6 percent ) who received placebo ( hazard ratio , 0.52 ; 95 percent confidence interval , 0.27 to 0.99 ; P=0.04 ) . HSV DNA was detected in sample s of genital secretions on 2.9 percent of the days among the HSV-2-infected ( source ) partners who received valacyclovir , as compared with 10.8 percent of the days among those who received placebo ( P<0.001 ) . The mean rates of recurrence were 0.11 per month and 0.40 per month , respectively ( P<0.001 ) . CONCLUSIONS Once-daily suppressive therapy with valacyclovir significantly reduces the risk of transmission of genital herpes among heterosexual , HSV-2-discordant couples Objective To determine if suppressive acyclovir therapy given to term gravidas experiencing a first episode of genital herpes simplex virus ( HSV ) infection during pregnancy decreases the need for cesarean delivery for that indication . Methods Forty-six pregnant women with first episodes of genital herpes during pregnancy were r and omly assigned to receive oral acyclovir 400 mg or placebo , three times per day , from 36 weeks ' gestation until delivery as part of a prospect i ve , double-blind trial . Herpes simplex virus cultures were obtained when patients presented for delivery . Vaginal delivery was permitted if no clinical recurrence was present ; otherwise , a cesarean was performed . Neonatal HSV cultures were obtained and infants were followed-up clinical ly . Results None of the 21 patients treated with acyclovir and nine of 25 ( 36 % ) treated with placebo had clinical evidence of recurrent genital herpes at delivery ( odds ratio [ OR ] 0.04 , 95 % confidence interval [ CI ] 0.002 - 0.745 ; P = .002 ) . No woman treated with acyclovir had a cesarean for herpes , compared with nine of 25 ( 36 % ) of those treated with placebo ( OR 0.04 , CI 0.002–0.0745 ; P = .002 ) . No patient in either treatment group experienced asymptomatic genital viral shedding at delivery . No neonate had evidence of herpes infection or adverse effects from acyclovir . Conclusion Suppressive acyclovir therapy reduced the need for cesarean for recurrent herpes in women whose first clinical episode of genital HSV occurred during pregnancy . Suppressive acyclovir treatment did not increase asymptomatic viral shedding and was not harmful to the term fetus OBJECTIVE : To measure the efficacy of valacyclovir suppression in late pregnancy to reduce the incidence of recurrent genital herpes in labor and subsequent cesarean delivery . METHODS : A total of 350 pregnant women with a history of genital herpes were assigned r and omly to oral valacyclovir 500 mg twice a day or an identical placebo from 36 weeks of gestation until delivery . In labor , vulvovaginal herpes simplex virus ( HSV ) culture and polymerase chain reaction ( PCR ) specimens were collected . Vaginal delivery was permitted if no clinical recurrence or prodromal symptoms were present . Neonatal HSV cultures and laboratory tests were obtained , and infants were followed up for 1 month after delivery . Data were analyzed using & khgr;2 and Student t tests . RESULTS : One hundred seventy women treated with valacyclovir and 168 women treated with placebo were evaluated . Eighty-two percent of the women had recurrent genital herpes ; 12 % had first episode , non primary genital herpes ; and 6 % had first episode , primary genital herpes . At delivery , 28 women ( 8 % ) had recurrent genital herpes requiring cesarean delivery : 4 % in the valacyclovir group and 13 % in the placebo group ( P = .009 ) . Herpes simplex virus was detected by culture in 2 % of the valacyclovir group and 24 % of the placebo group ( P = .02 ) . No infants were diagnosed with neonatal HSV , and there were no significant differences in neonatal complications . There were no significant differences in maternal or obstetric complications in either group . CONCLUSION : Valacyclovir suppression after 36 weeks of gestation significantly reduces HSV shedding and recurrent genital herpes requiring cesarean delivery . LEVEL OF EVIDENCE : OBJECTIVE The objective was to obtain preliminary pharmacokinetic data for acyclovir from gravid women receiving herpes simplex virus suppressive therapy with the acyclovir prodrug valacyclovir . STUDY DESIGN In a prospect i ve , double-blind trial , 20 women with a history of recurrent genital herpes simplex virus infection and positive herpes simplex virus 2 serologic results were r and omly assigned at 36 weeks ' gestation to receive oral valacyclovir ( 500 mg twice daily ) or acyclovir ( 400 mg 3 times daily ) . Acyclovir pharmacokinetic profiles were obtained after the initial dose ( 36 weeks ) and at steady state ( 38 weeks ) . Amniotic fluid sample s were obtained during labor and simultaneous umbilical cord and maternal plasma sample s were collected at delivery . Laboratory studies were performed to screen for laboratory evidence of toxicity in mothers and infants . RESULTS Peak acyclovir plasma concentrations ( mean + /- st and ard deviation ) were higher in valacyclovir recipients than in acyclovir recipients after the initial dose ( 3.14 + /- 0.7 microg/mL vs 0.74 + /- 0.6 microg/mL , P < .0001 ) and at steady state ( 3.03 + /- 1.0 microg/mL vs 0.94 + /- 0.7 microg/mL , P < .001 ) . The daily area under the curve values were higher in valacyclovir recipients than acyclovir recipients after the initial dose ( 17.8 + /- 3.6 h x microg/mL vs 7.71 + /- 2.5 h x microg/mL , P < .001 ) and at steady state ( 19.65 + /- 6.4 h x microg/mL versus 11.0 + /- 4.5 h x microg/mL , P = .009 ) . There was no significant difference in drug elimination half-life or in time to peak concentration between valacyclovir and acyclovir recipients at either sampling interval . Acyclovir was concentrated in the amniotic fluid ; however , there was no evidence of preferential fetal drug accumulation ( mean maternal/umbilical vein plasma ratios at delivery were 1.7 for valacyclovir and 1.3 for acyclovir ) . Valacyclovir was well tolerated , and no significant laboratory or clinical evidence of toxicity was detected . CONCLUSION In this phase I trial maternal valacyclovir therapy result ed in higher plasma acyclovir levels , with significantly higher peak concentrations and daily area under the curve values , than did acyclovir therapy . Additional trials are needed to further evaluate the safety and efficacy of suppressive valacyclovir therapy during late pregnancy OBJECTIVE To evaluate the efficacy and safety of oral famciclovir in the suppression of genital herpes . METHODS In this r and omized , double-blind , placebo-controlled trial that was performed at 11 university and 9 private ambulatory care referral centers , 375 women who were 18 years of age or older and had a history of 6 or more episodes of genital herpes during 12 of the last 24 months in the absence of suppressive therapy were treated for 4 months with oral famciclovir , 125 mg once daily or twice daily , 250 mg once daily or twice daily , 500 mg once daily , or placebo . The primary outcome measures included the time to first clinical ly and virologically confirmed recurrences , and safety as measured by clinical laboratory tests and adverse experiences . RESULTS The median time to first recurrence was 82 days in the placebo group , 114 days in those receiving famciclovir , 125 mg once daily , and more than 120 days in the other treatment groups . When compared with placebo recipients , the time to the first clinical recurrence was significantly prolonged in subjects who received famciclovir , 125 mg twice daily ( hazard ratio , 1.8 ; 95 % confidence interval , 1.0 - 3.0 ; P = .03 ) , and in those who received famciclovir , 250 mg twice daily ( hazard ratio , 3.6 ; 95 % confidence interval , 1.9 - 6.9 ; P < .001 ) . Treatment was well tolerated , and there was no evidence of emergence of resistance during or after suppressive famciclovir therapy . CONCLUSIONS Oral famciclovir , 250 mg , given twice daily for 4 months is an effective , well-tolerated treatment for the suppression of genital herpes in women with frequent recurrences , but single daily doses produced less complete suppression of genital herpes OBJECTIVE The purpose of this study was to assess the efficacy of acyclovir in the reduction of herpes simplex virus culture and polymerase chain reaction positivity and cesarean delivery . STUDY DESIGN Women with recurrent genital herpes simplex virus were r and omized to acyclovir 400 mg three times daily or placebo from 36 weeks of gestation until delivery . A subset of daily specimens for herpes simplex virus culture and DNA polymerase chain reaction was self-collected . Analyses used chi(2 ) , Fisher exact , and Mann-Whitney U tests . RESULTS Lesions occurred at delivery among 11 of 78 women ( 14 % ) who received placebo and 4 of 84 women ( 5 % ) who received acyclovir ( P = .08 ) . Herpes simplex virus culture and polymerase chain reaction positivity near delivery occurred in 7 % and 34 % women in the placebo group and 0 and 2 % in the acyclovir group ( P = .03 and < .01 , respectively ) . Cesarean delivery for herpes simplex virus occurred in 8 of the women ( 10 % ) in the placebo group and in 3 of the women ( 4 % ) in the acyclovir group ( P = .17 ) . Despite reductions in herpes simplex virus detection , 6 % of the women who received acyclovir had herpes simplex virus detected by polymerase chain reaction on > 20 % of days . Neonatal outcomes were similar between groups . CONCLUSION Acyclovir significantly reduced , but did not eliminate , herpes simplex virus lesions and detection in late pregnancy CONTEXT Neonatal herpes most commonly results from fetal exposure to infected maternal genital secretions at the time of delivery . The risk of transmission from mother to infant as it relates to maternal herpes simplex virus ( HSV ) serologic status and exposure to HSV in the maternal genital tract at the time of labor has not been quantified . Furthermore , no data exist on whether cesarean delivery , the st and ard of care for women with genital herpes lesions at the time of delivery , reduces HSV transmission . OBJECTIVE To determine the effects of viral shedding , maternal HSV serologic status , and delivery route on the risk of transmission of HSV from mother to infant . DESIGN Prospect i ve cohort of pregnant women enrolled between January 1982 and December 1999 . SETTING S A university medical center , a US Army medical center , and 5 community hospitals in Washington State . PATIENTS A total of 58 362 pregnant women , of whom 40 023 had HSV cultures obtained from the cervix and external genitalia and 31 663 had serum sample s tested for HSV . MAIN OUTCOME MEASURE Rates of neonatal HSV infection . RESULTS Among the 202 women from whom HSV was isolated at the time of labor , 10 ( 5 % ) had neonates with HSV infection ( odds ratio [ OR ] , 346 ; 95 % confidence interval [ CI ] , 125 - 956 for neonatal herpes when HSV was isolated vs not isolated ) . Cesarean delivery significantly reduced the HSV transmission rate among women from whom HSV was isolated ( 1 [ 1.2 % ] of 85 cesarean vs 9 [ 7.7 % ] of 117 vaginal ; OR , 0.14 ; 95 % CI , 0.02 - 1.08 ; P = .047 ) . Other risk factors for neonatal HSV included first-episode infection ( OR , 33.1 ; 95 % CI , 6.5 - 168 ) , HSV isolation from the cervix ( OR , 32.6 ; 95 % CI , 4.1 - 260 ) , HSV-1 vs HSV-2 isolation at the time of labor ( OR , 16.5 ; 95 % CI , 4.1 - 65 ) , invasive monitoring ( OR , 6.8 ; 95 % CI , 1.4 - 32 ) , delivery before 38 weeks ( OR , 4.4 ; 95 % CI , 1.2 - 16 ) , and maternal age less than 21 years ( OR , 4.1 ; 95 % CI , 1.1 - 15 ) . Neonatal HSV infection rates per 100 000 live births were 54 ( 95 % CI , 19.8 - 118 ) among HSV-seronegative women , 26 ( 95 % CI , 9.3 - 56 ) among women who were HSV-1-seropositive only , and 22 ( 95 % CI , 4.4 - 64 ) among all HSV-2-seropositive women . CONCLUSION Neonatal HSV infection rates can be reduced by preventing maternal acquisition of genital HSV-1 and HSV-2 infection near term . It can also be reduced by cesarean delivery and limiting the use of invasive monitors among women shedding HSV at the time of labor OBJECTIVE The objective of this investigation was to establish the safety of high-dose ( HD ) acyclovir for the treatment of neonatal herpes simplex virus ( HSV ) disease . In addition , an estimate of therapeutic efficacy was sought , both with respect to mortality and to morbidity . Virologic efficacy of HD acyclovir was also assessed . PARTICIPANTS Infants who were < /=28 days old and whose disease was considered to be caused by HSV were enrolled in this study . Patients with central nervous system ( CNS ; N = 28 ) or disseminated ( N = 41 ) HSV infection were offered participation in the trial . A small number of patients with HSV disease limited to the skin , eyes , or mouth ( SEM ; N = 10 ) or whose disease was clinical ly consistent with HSV but who did not have virologic confirmation of infection ( N = 9 ) also were enrolled on a compassionate basis . Only patients with virologically confirmed HSV disease were included in efficacy analyses . All enrolled patients were included in safety analyses . METHODS The study was an open-label evaluation of intravenous acyclovir at dosages higher than the 30 mg/kg/d st and ard dosage approved by the US Food and Drug Administration . The first 16 patients enrolled received intermediate-dose ( ID ) acyclovir ( 45 mg/kg/d ) , and the next 72 patients received HD acyclovir ( 60 mg/kg/d ) . Acyclovir was administered in 3 divided daily doses for 21 days . Neonates were assessed prospect ively throughout treatment and at scheduled follow-up visits for the first 4 years of life . Data were compared with those of a previous National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group trial in which patients received st and ard-dose ( SD ) acyclovir for 10 days and in which identical methods ( with the exception of acyclovir dosage and duration of therapy ) were used . RESULTS Six ( 21 % ) of 29 HD acyclovir recipients whose HSV disease remained localized to the SEM or CNS experienced neutropenia . One of the 6 had an absolute neutrophil count < 500/mm(3 ) , and 5 patients had an absolute neutrophil count ( ANC ) between 500/mm(3 ) and 1000/mm(3 ) . In all 6 cases , the ANC recovered during continuation of acyclovir at the same dosage or after completion of acyclovir therapy , and there were no apparent adverse sequelae of the transient neutropenia . No other drug-related adverse events were reported among ID or HD recipients , and no other laboratory aberrations could be correlated specifically with antiviral therapy . The survival rate for the patients with disseminated HSV disease treated with HD acyclovir was significantly higher than for those in the previous study treated with SD acyclovir , with an odds ratio ( OR ) of 3.3 ( 95 % confidence interval [ CI ] : 1.4 - 7.9 ) . For patients with CNS disease , however , survival rates were similar for the HD and SD groups . To assess the effect of HD acyclovir on survival for the entire population with neonatal HSV disease , the Cox proportional hazards regression analysis was performed with stratification for disease category ( CNS versus disseminated ) . In performing this analysis , differences in mortality for each disease category were weighted to allow statistical comparison of the treatment dosage groups ( HD , ID , and SD ) . This analysis indicated that the survival rate for patients treated with HD acyclovir was statistically significantly higher than for patients treated with SD acyclovir ( OR : 3.3 ; 95 % CI : 1.5 - 7.3 ) . Recipients of HD acyclovir had a borderline significant decrease in morbidity compared with SD recipients , after stratification for the extent of disease ( SEM vs CNS vs disseminated ) and controlling for the potential confounding factors of HSV type ( HSV-1 vs. HSV-2 ) , prematurity , and disease severity ( seizures ) . Patients treated with HD acyclovir were 6.6 times ( adjusted OR ; 95 % CI : 0.8 - 113.6 ) as likely to be developmentally normal at 12 months of age as patients treated with SD therapy . CONCLUSION These data support the use of a 21-day course of HD ( 60 mg/kg/d ) intravenous acyclovir to treat neonatal CNS and disseminated HSV disease . Throughout the course of HD acyclovir therapy , serial ANC determination should be made at least twice weekly . Decreasing the acyclovir dosage or administering granulocyte colony-stimulating factor should be considered if the ANC remains below 500/mm(3 ) for a prolonged period OBJECTIVE The purpose of this study was to estimate the efficacy of valacyclovir suppressive therapy in pregnant women with recurrent genital herpes . STUDY DESIGN At 36 weeks ' gestation , herpes simplex virus (HSV)-2 seropositive women were r and omized to receive oral valacyclovir 500 mg or placebo twice daily until delivery . Genital tract and neonatal specimens were collected weekly for HSV culture and qualitative polymerase chain reaction ( PCR ) assay to detect viral DNA from the time of r and omization to delivery . Both maternal and neonatal toxicity measures were obtained . RESULTS The 112 enrolled women ( 57 valacyclovir , 55 placebo ) had similar HSV recurrence risks , including mean number of active HSV recurrences before r and omization during the index pregnancy ( 1.1 + /- 1.9 vs 1.5 + /- 2.1 , P = .308 ) and days between r and omization and delivery ( 20.3 + /- 10.2 vs 22.0 + /- 8.9 , P = .344 ) . The number of women with clinical HSV recurrences between the time of r and omization and delivery was significantly lower in the valacyclovir versus placebo group ( 10.5 % vs 27.3 % ; P = .023 , RR 0.4 , 95 % CI 0.2 - 0.9 ) . Shedding of HSV within 7 days of delivery was similar in the valacyclovir and placebo group ( 10.4 % vs 12.0 % , P = .804 ; RR 0.9 , 95 % CI 0.3 - 2.7 ) , as was the number of women with clinical HSV lesions at delivery ( 5.3 % vs 14.6 % , P = .121 ; RR 0.4 , 95 % CI 0.1 - 1.3 ) . No neonates had symptomatic congenital HSV infection before discharge or up to 2 weeks ' postpartum , and no clinical or laboratory safety concerns were identified . CONCLUSION Administration of valacyclovir beginning at 36 weeks ' gestation to women with a history of recurrent genital HSV reduced the number of women with subsequent clinical HSV recurrences |
13,681 | 28,258,686 | Remote ischaemic preconditioning by cuff inflation appears to be a safe method , and probably leads to little or no difference in serum creatinine , adverse effects , need for dialysis , length of hospital stay , death and in the incidence of acute kidney injury .
Overall we had moderate-high certainty evidence however the available data does not confirm the efficacy of remote ischaemic preconditioning in reducing renal ischaemia reperfusion injury in patients undergoing major cardiac and vascular surgery in which renal ischaemia reperfusion injury may occur | BACKGROUND Ischaemia reperfusion injury can lead to kidney dysfunction or failure .
Ischaemic preconditioning is a short period of deprivation of blood supply to particular organs or tissue , followed by a period of reperfusion .
It has the potential to protect kidneys from ischaemia reperfusion injury .
OBJECTIVES This review aim ed to look at the benefits and harms of local and remote ischaemic preconditioning to reduce ischaemia and reperfusion injury among people with renal ischaemia reperfusion injury . | OBJECTIVES This study sought to evaluate whether remote ischemic post-conditioning ( RIPC ) could reduce enzymatic infa rct size in patients with anterior ST-segment elevation myocardial infa rct ion undergoing primary percutaneous coronary intervention ( pPCI ) . BACKGROUND Myocardial reperfusion injury may attenuate the benefit of pPCI . In animal models , RIPC mitigates myocardial reperfusion injury . METHODS One hundred patients with anterior ST-segment elevation myocardial infa rct ion and occluded left anterior descending artery were r and omized to pPCI + RIPC ( n = 50 ) or conventional pPCI ( n = 50 ) . RIPC consisted of 3 cycles of 5 min/5 min ischemia/reperfusion by cuff inflation/deflation of the lower limb . The primary endpoint was infa rct size assessed by the area under the curve of creatinine kinase-myocardial b and release ( CK-MB ) . Secondary endpoints included the following : infa rct size assessed by cardiac magnetic resonance delayed enhancement volume ; T2-weighted edema volume ; ST-segment resolution > 50 % ; TIMI ( Thrombolysis In Myocardial Infa rct ion ) frame count ; and myocardial blush grading . RESULTS Four patients ( 2 RIPC , 2 controls ) were excluded due to missing sample s of CK-MB . A total of 96 patients were analyzed ; median area under the curve CK-MB was 8,814 ( interquartile range [ IQR ] : 5,567 to 11,325 ) arbitrary units in the RIPC group and 10,065 ( IQR : 7,465 to 14,004 ) arbitrary units in control subjects ( relative reduction : 20 % , 95 % confidence interval : 0.2 % to 28.7 % ; p = 0.043 ) . Seventy-seven patients underwent a cardiac magnetic resonance scan 3 to 5 days after r and omization , and 66 patients repeated a second scan after 4 months . T2-weighted edema volume was 37 ± 16 cc in RIPC patients and 47 ± 22 cc in control subjects ( p = 0.049 ) . ST-segment resolution > 50 % was 66 % in RIPC and 37 % in control subjects ( p = 0.015 ) . We observed no significant differences in TIMI frame count , myocardial blush grading , and delayed enhancement volume . CONCLUSIONS In patients with anterior ST-segment elevation myocardial infa rct ion , RIPC at the time of pPCI reduced enzymatic infa rct size and was also associated with an improvement of T2-weighted edema volume and ST-segment resolution > 50 % . ( Remote Postconditioning in Patients With Acute Myocardial Infa rct ion Treated by Primary Percutaneous Coronary Intervention [ PCI ] [ RemPostCon ] ; NCT00865722 ) BACKGROUND Whether remote ischemic preconditioning ( transient ischemia and reperfusion of the arm ) can improve clinical outcomes in patients undergoing coronary-artery bypass graft ( CABG ) surgery is not known . We investigated this question in a r and omized trial . METHODS We conducted a multicenter , sham-controlled trial involving adults at increased surgical risk who were undergoing on-pump CABG ( with or without valve surgery ) with blood cardioplegia . After anesthesia induction and before surgical incision , patients were r and omly assigned to remote ischemic preconditioning ( four 5-minute inflations and deflations of a st and ard blood-pressure cuff on the upper arm ) or sham conditioning ( control group ) . Anesthetic management and perioperative care were not st and ardized . The combined primary end point was death from cardiovascular causes , nonfatal myocardial infa rct ion , coronary revascularization , or stroke , assessed 12 months after r and omization . RESULTS We enrolled a total of 1612 patients ( 811 in the control group and 801 in the ischemic-preconditioning group ) at 30 cardiac surgery centers in the United Kingdom . There was no significant difference in the cumulative incidence of the primary end point at 12 months between the patients in the remote ischemic preconditioning group and those in the control group ( 212 patients [ 26.5 % ] and 225 patients [ 27.7 % ] , respectively ; hazard ratio with ischemic preconditioning , 0.95 ; 95 % confidence interval , 0.79 to 1.15 ; P=0.58 ) . Furthermore , there were no significant between-group differences in either adverse events or the secondary end points of perioperative myocardial injury ( assessed on the basis of the area under the curve for the high-sensitivity assay of serum troponin T at 72 hours ) , inotrope score ( calculated from the maximum dose of the individual inotropic agents administered in the first 3 days after surgery ) , acute kidney injury , duration of stay in the intensive care unit and hospital , distance on the 6-minute walk test , and quality of life . CONCLUSIONS Remote ischemic preconditioning did not improve clinical outcomes in patients undergoing elective on-pump CABG with or without valve surgery . ( Funded by the Efficacy and Mechanism Evaluation Program [ a Medical Research Council and National Institute of Health Research partnership ] and the British Heart Foundation ; ERICCA Clinical Trials.gov number , NCT01247545 . ) Background : Two preconditioning stimuli should induce a more consistent overall cell protection . We hypothesized that remote ischemic preconditioning ( RIPC , second preconditioning stimulus ) applied during isoflurane inhalation ( first preconditioning stimulus ) would provide more protection to the myocardium of patients undergoing on-pump coronary artery bypass grafting . Methods : In this placebo-controlled r and omized controlled study , patients in the RIPC group received four 5-min cycles of 300 mmHg cuff inflation/deflation of the leg before aortic cross-clamping . Anesthesia consisted of opioids and propofol for induction and isoflurane for maintenance . The primary outcome was high-sensitivity cardiac troponin T release . Secondary endpoints were plasma levels of N-terminal pro-brain natriuretic peptide , high-sensitivity C-reactive protein , S100 protein , and short- and long-term clinical outcomes . Gene expression profiles were obtained from atrial tissue using microarrays . Results : RIPC ( n = 27 ) did not reduce high-sensitivity cardiac troponin T release when compared with placebo ( n = 28 ) . Likewise , N-terminal pro-brain natriuretic peptide , a marker of myocardial dysfunction ; high-sensitivity C-reactive protein , a marker of perioperative inflammatory response ; and S100 , a marker of cerebral injury , were not different between the groups . The incidence for the perioperative composite endpoint combining new arrhythmias and myocardial infa rct ions was higher in the RIPC group than the placebo group ( 14/27 vs. 6/28 , P = 0.036 ) . However , there was no difference in the 6-month cardiovascular outcome . N-terminal pro-brain natriuretic peptide release correlated with isoflurane-induced transcriptional changes in fatty-acid metabolism ( P = 0.001 ) and DNA-damage signaling ( P < 0.001 ) , but not with RIPC-induced changes in gene expression . Conclusions : RIPC applied during isoflurane inhalation provides no benefit to the myocardium of patients undergoing on-pump coronary artery bypass grafting Background and Purpose — Remote ischemic preconditioning is neuroprotective in models of acute cerebral ischemia . We tested the effect of prehospital rPerC as an adjunct to treatment with intravenous alteplase in patients with acute ischemic stroke . Methods — Open-label blinded outcome proof-of-concept study of prehospital , paramedic-administered rPerC at a 1:1 ratio in consecutive patients with suspected acute stroke . After neurological examination and MRI , patients with verified stroke receiving alteplase treatment were included and received MRI at 24 hours and 1 month and clinical re-examination after 3 months . The primary end point was penumbral salvage , defined as the volume of the perfusion – diffusion mismatch not progressing to infa rct ion after 1 month . Results — Four hundred forty-three patients were r and omized after provisional consent , 247 received rPerC and 196 received st and ard treatment . Patients with a nonstroke diagnosis ( n=105 ) were excluded from further examinations . The remaining patients had transient ischemic attack ( n=58 ) , acute ischemic stroke ( n=240 ) , or hemorrhagic stroke ( n=37 ) . Transient ischemic attack was more frequent ( P=0.006 ) , and National Institutes of Health Stroke Scale score on admission was lower ( P=0.016 ) in the intervention group compared with controls . Penumbral salvage , final infa rct size at 1 month , infa rct growth between baseline and 1 month , and clinical outcome after 3 months did not differ among groups . After adjustment for baseline perfusion and diffusion lesion severity , voxelwise analysis showed that rPerC reduced tissue risk of infa rct ion ( P=0.0003 ) . Conclusions — Although the overall results were neutral , a tissue survival analysis suggests that prehospital rPerC may have immediate neuroprotective effects . Future clinical trials should take such immediate effects , and their duration , into account . Clinical Trial Registration — URL : http://www . clinical trials.gov . Unique identifier : NCT00975962 BACKGROUND Remote ischemic preconditioning ( RIPC ) is reported to reduce biomarkers of ischemic and reperfusion injury in patients undergoing cardiac surgery , but uncertainty about clinical outcomes remains . METHODS We conducted a prospect i ve , double-blind , multicenter , r and omized , controlled trial involving adults who were scheduled for elective cardiac surgery requiring cardiopulmonary bypass under total anesthesia with intravenous propofol . The trial compared upper-limb RIPC with a sham intervention . The primary end point was a composite of death , myocardial infa rct ion , stroke , or acute renal failure up to the time of hospital discharge . Secondary end points included the occurrence of any individual component of the primary end point by day 90 . RESULTS A total of 1403 patients underwent r and omization . The full analysis set comprised 1385 patients ( 692 in the RIPC group and 693 in the sham-RIPC group ) . There was no significant between-group difference in the rate of the composite primary end point ( 99 patients [ 14.3 % ] in the RIPC group and 101 [ 14.6 % ] in the sham-RIPC group , P=0.89 ) or of any of the individual components : death ( 9 patients [ 1.3 % ] and 4 [ 0.6 % ] , respectively ; P=0.21 ) , myocardial infa rct ion ( 47 [ 6.8 % ] and 63 [ 9.1 % ] , P=0.12 ) , stroke ( 14 [ 2.0 % ] and 15 [ 2.2 % ] , P=0.79 ) , and acute renal failure ( 42 [ 6.1 % ] and 35 [ 5.1 % ] , P=0.45 ) . The results were similar in the per- protocol analysis . No treatment effect was found in any subgroup analysis . No significant differences between the RIPC group and the sham-RIPC group were seen in the level of troponin release , the duration of mechanical ventilation , the length of stay in the intensive care unit or the hospital , new onset of atrial fibrillation , and the incidence of postoperative delirium . No RIPC-related adverse events were observed . CONCLUSIONS Upper-limb RIPC performed while patients were under propofol-induced anesthesia did not show a relevant benefit among patients undergoing elective cardiac surgery . ( Funded by the German Research Foundation ; RIPHeart Clinical Trials.gov number , NCT01067703 . ) Background Remote ischemic preconditioning ( RIPC ) harnesses an innate defensive mechanism that protects against inflammatory activation and ischemia‐reperfusion injury , known sequelae of cardiac surgery with cardiopulmonary bypass . We sought to determine the impact of RIPC on clinical outcomes and physiological markers related to ischemia‐reperfusion injury and inflammatory activation after cardiac surgery in children . Methods and Results Overall , 299 children ( aged neonate to 17 years ) were r and omized to receive an RIPC stimulus ( inflation of a blood pressure cuff on the left thigh to 15 mm Hg above systolic for four 5‐minute intervals ) versus a blinded sham stimulus during induction with a st and ardized anesthesia protocol . Primary outcome was duration of postoperative hospital stay , with serial clinical and laboratory measurements for the first 48 postoperative hours and clinical follow‐up to discharge . There were no significant baseline differences between RIPC ( n=148 ) and sham ( n=151 ) . There were no in‐hospital deaths . No significant difference in length of postoperative hospital stay was noted ( sham 5.4 versus RIPC 5.6 days ; difference + 0.2 ; adjusted P=0.91 ) , with the 95 % confidence interval ( −0.7 to + 0.9 ) excluding a prespecified minimal clinical ly significant differences of 1 or 1.5 days . There were few significant differences in other clinical outcomes or values at time points or trends in physiological markers . Benefit was not observed in specific subgroups when explored through interactions with categories of age , sex , surgery type , Aristotle score , or first versus second half of recruitment . Adverse events were similar ( sham 5 % , RIPC 6 % ; P=0.68 ) . Conclusions RIPC is not associated with important improvements in clinical outcomes and physiological markers after cardiac surgery in children . Clinical Trial Registration URL : clinical trials.gov . Unique identifier : NCT00650507 Background Remote ischemic preconditioning ( RIPC ) induced by transient limb ischemia confers multi-organ protection and improves exercise performance in the setting of tissue hypoxia . We aim ed to evaluate the effect of RIPC on exercise capacity in heart failure patients . Methods We performed a r and omized crossover trial of RIPC ( 4 × 5-minutes limb ischemia ) compared to sham control in heart failure patients undergoing exercise testing . Patients were r and omly allocated to either RIPC or sham prior to exercise , then crossed over and completed the alternate intervention with repeat testing . The primary outcome was peak VO2 , RIPC versus sham . A mechanistic sub study was performed using dialysate from study patient blood sample s obtained after sham and RIPC . This dialysate was used to test for a protective effect of RIPC in a mouse heart Langendorff model of infa rct ion . Mouse heart infa rct size with RIPC or sham dialysate exposure was also compared with historical control data . Results Twenty patients completed the study . RIPC was not associated with improvements in peak VO2 ( 15.6+/−4.2 vs 15.3+/−4.6 mL/kg/min ; p = 0.53 , sham and RIPC , respectively ) . In our Langendorff sub- study , infa rct size was similar between RIPC and sham dialysate groups from our study patients , but was smaller than expected compared to healthy controls ( 29.0 % , 27.9 % [ sham , RIPC ] vs 51.2 % [ controls ] . We observed less preconditioning among the subgroup of patients with increased exercise performance following RIPC ( p<0.04 ) . Conclusion In this pilot study of RIPC in heart failure patients , RIPC was not associated with improvements in exercise capacity overall . However , the degree of effect of RIPC may be inversely related to the degree of baseline preconditioning . These data provide the basis for a larger r and omized trial to test the potential benefits of RIPC in patients with heart failure . Trial Registration Clinical Trials.gov + + + + + BACKGROUND Although remote ischemic preconditioning ( RIPC ) has emerged as an attractive strategy to reduce cardiac injury in patients undergoing diverse cardiac surgical procedures , it is unclear whether RIPC has protective effects in patients undergoing aortic valve replacement surgery without coronary artery bypass grafting ( CABG ) . METHODS Hence , 100 adult patients undergoing elective aortic valve replacement for aortic valve stenosis , without combined surgery with CABG , were prospect ively r and omly assigned in a 1:1 ratio to either the RIPC group or the control group . The RIPC group underwent three cycles of 5-min inflation to 200mmHg and 5-min deflation of an automated upper-arm cuff inflator after induction of anesthesia . The control group had a deflated cuff placed on upper arm for 30min . The primary endpoint was 72-h area under curve ( AUC ) for troponin I ( cTnI ) . Secondary endpoints were 72-h AUC for creatine kinase-MB isoenzyme ( CK-MB ) release , incidence of acute kidney injury , extubation time , length of stay in intensive care unit , and simplified acute physiology score ( SAPS II ) . RESULTS There were no significant differences in cTnI AUC [ 195±190 arbitrary units ( a.u . ) in RIPC group vs. 169±117 a.u . in the control group ; p=0.41 ] and CK-MB AUC between groups . None of the other secondary endpoints differed between groups . Acute kidney injury occurred in 12 patients ( 24.5 % ) in the control group and in 13 ( 26.0 % ) in the RIPC group ( p=0.86 ) . CONCLUSIONS RIPC did not exhibit significant cardiac or kidney protective effects in patients undergoing aortic valve replacement surgery without CABG Background One or more brief episodes of coronary artery occlusion protect or “ precondition ” the myocardium perfused by that artery from a subsequent episode of sustained ischemia . We sought to determine whether ischemic preconditioning protects only those myocytes subjected to brief coronary occlusion or whether brief occlusions in one vascular bed also limit infa rct size and for attenuate contractile dysfunction in remote virgin myocardium subjected to subsequent sustained coronary occlusion . Methods and Results In the preliminary limb of the study , six anesthetized dogs underwent four episodes of 5-minute circumflex branch occlusion plus 5-minute reperfusion , followed by 1 hour of sustained left anterior descending coronary artery occlusion and 4.5 hours of reflow . Subendocardial blood flow during left anterior descending coronary artery occlusion ( measured by injection of radiolabeled microspheres ) was 0.07±0.03 mL. min-1 . g tissue-1 , similar to the value of 0.07±0.02 mL. min-1 . g-1 observed in a group of eight concurrent control dogs . However , infa rct size ( assessed by triphenyltetrazolium staining ) in the circumflex preconditioned group averaged 4±1 % of the myocardium at risk , significantly less ( p<0.05 ) than the value of 13 + 4 % observed in the concurrent controls . An additional 18 dogs were then r and omized to undergo either four episodes of circumflex branch occlusion ( n=8 ) or no intervention ( n=10 ) before 1 hour of left anterior descending coronary artery occlusion and 4.5 hours of reflow . Subendocardial blood flow averaged 0.08±0.02 versus 0.08±0.03 mL. min-1 . g-1 in the control versus circumflex preconditioned groups , yet infa rct size was significantly smaller in circumflex preconditioned dogs than in the controls ( 6±2 % versus 16±5 % of the risk region ; p<0.05 ) . At 4.5 hours following reperfusion , segment shortening in the left anterior descending coronary artery bed ( assessed by sonomicrometry ) averaged -21 + 19%o of baseline in control animals versus 13±12 % of baseline in the preconditioned group ( p = NS ) . Circumflex preconditioning did not , however , have an independent beneficial effect on contractile function : Regression analysis revealed that the trend toward improved function in circumflex preconditioned dogs reflected the smaller infa rct sizes in this group . Conclusions Brief episodes of ischemia in one vascular bed protect remote , virgin myocardium from subsequent sustained coronary artery occlusion in this canine model . These data imply that preconditioning may be mediated by factor(s ) activated , produced , or transported throughout the heart during brief ischemia/reperfusion Background — Myocardial and renal injury commonly contribute to perioperative morbidity and mortality after abdominal aortic aneurysm repair . Remote ischemic preconditioning ( RIPC ) is a phenomenon whereby brief periods of ischemia followed by reperfusion in one organ provide systemic protection from prolonged ischemia . To investigate whether remote preconditioning reduces the incidence of myocardial and renal injury in patients undergoing elective open abdominal aortic aneurysm repair , we performed a r and omized trial . Method and Results — Eighty-two patients were r and omized to abdominal aortic aneurysm repair with RIPC or conventional abdominal aortic aneurysm repair ( control ) . Two cycles of intermittent crossclamping of the common iliac artery with 10 minutes ischemia followed by 10 minutes reperfusion served as the RIPC stimulus . Myocardial injury was assessed by cardiac troponin I ( > 0.40 ng/mL ) , myocardial infa rct ion by the American College of Cardiology/American Heart Association definition and renal injury by serum creatinine ( > 177 & mgr;mol/L ) according to American Heart Association guidelines for risk stratification in major vascular surgery . The groups were well matched for baseline characteristics . RIPC reduced the incidence of myocardial injury by 27 % ( 39 % versus 12 % [ 95 % CI : 8.8 % to 45 % ] ; P=0.005 ) , myocardial infa rct ion by 22 % ( 27 % versus 5 % [ 95 % CI : 7.3 % to 38 % ] ; P=0.006 ) , and renal impairment by 23 % ( 30 % versus 7 % ; [ 95 % CI : 6.4 to 39 ] ; P=0.009 ) . Multivariable analysis revealed the protective effect of RIPC on myocardial injury ( OR : 0.22 , 95 % CI : 0.07 to 0.67 ; P=0.008 ) , myocardial infa rct ion ( OR : 0.18 , 95 % CI : 0.04 to 0.75 ; P=0.006 ) and renal impairment were independent of other covariables . Conclusions — In patients undergoing elective open abdominal aortic aneurysm repair , RIPC reduces the incidence of postoperative myocardial injury , myocardial infa rct ion , and renal impairment Background Novel cardioprotective strategies are required to improve clinical outcomes in high risk patients undergoing coronary artery bypass graft ( CABG ) ± valve surgery . Remote ischemic preconditioning ( RIC ) , in which brief episodes of non-lethal ischemia and reperfusion are applied to the arm or leg , has been demonstrated to reduce perioperative myocardial injury following CABG ± valve surgery . Whether RIC can improve clinical outcomes in this setting is unknown and is investigated in the effect of remote ischemic preconditioning on clinical outcomes ( ERICCA ) trial in patients undergoing CABG surgery . ( Clinical Trials.gov Identifier : NCT01247545 ) . Methods The ERICCA trial is a multicentre r and omized double-blinded controlled clinical trial which will recruit 1,610 high-risk patients ( Additive Euroscore ≥ 5 ) undergoing CABG ± valve surgery using blood cardioplegia via 27 tertiary centres over 2 years . The primary combined endpoint will be cardiovascular death , non-fatal myocardial infa rct ion , coronary revascularization and stroke at 1 year . Secondary endpoints will include peri-operative myocardial and acute kidney injury , intensive care unit and hospital stay , inotrope score , left ventricular ejection fraction , changes of quality of life and exercise tolerance . Patients will be r and omized to receive after induction of anesthesia either RIC ( 4 cycles of 5 min inflation to 200 mmHg and 5 min deflation of a blood pressure cuff placed on the upper arm ) or sham RIC ( 4 cycles of simulated inflations and deflations of the blood pressure cuff ) . Implication sThe findings from the ERICCA trial have the potential to demonstrate that RIC , a simple , non-invasive and virtually cost-free intervention , can improve clinical outcomes in higher-risk patients undergoing CABG ± valve surgery Background Novel treatment strategies are required to reduce the development of acute kidney injury ( AKI ) in patients undergoing cardiac surgery . In this respect , remote ischemic preconditioning ( RIPC ) , a phenomenon in which transient nonlethal ischemia applied to an organ or tissue protects another organ or tissue from subsequent lethal ischemic injury , is a potential renoprotective strategy . Study Design Secondary analysis of 2 r and omized trials . Setting & Participants 78 consenting selected nondiabetic patients in a university teaching hospital undergoing elective coronary artery bypass graft ( CABG ) surgery recruited to 2 previously reported r and omized studies . Intervention RIPC consisted of three 5-minute cycles of right forearm ischemia , induced by inflating a blood pressure cuff on the upper arm to 200 mm Hg , with an intervening 5 minutes of reperfusion , during which time the cuff was deflated . The control consisted of placing an uninflated cuff on the arm for 30 minutes . Outcomes AKI measured using Acute Kidney Injury Network ( AKIN ) criteria , duration of hospital stay , in-hospital and 30-day mortality . Results Numbers of participants with AKI stages 1 , 2 , and 3 were 1 ( 3 % ) , 3 ( 8 % ) , and 0 in the intervention group compared with 10 ( 25 % ) , 0 , and 0 in the control group , respectively ( P = 0.005 ) . The decrease in AKI was independent of the effect of concomitant aortic valve replacement and cross-clamp times , which were distributed unevenly between the 2 groups . Limitations Retrospective analysis of data . More patients in the RIPC group underwent concomitant aortic valve replacement with CABG ; although we have corrected statistically for this imbalance , it remains an important confounding variable . Conclusions RIPC induced using transient forearm ischemia decreased the incidence of AKI in nondiabetic patients undergoing elective CABG surgery in this retrospective analysis . A large prospect i ve clinical trial is required to study this effect and clinical outcomes in patients undergoing cardiac surgery Background — We assessed whether remote ischemic preconditioning ( RIPC ) improves myocardial , renal , and lung protection after on-pump coronary surgery . Methods and Results — This was a single-center , prospect i ve , r and omized ( 1:1 ) , placebo-controlled trial . Patients , investigators , anesthetists , surgeons , and critical care teams were blinded to group allocation . Subjects received RIPC ( or placebo ) stimuli ( ×3 upper limb ( or dummy arm ) , 5-minute cycles of 200 mm Hg cuff inflation/deflation ) before aortic clamping . Anesthesia , perfusion , cardioplegia , and surgical techniques were st and ardized . The primary end point was 48-hour area under the curve ( AUC ) troponin T ( cTnT ) release . Secondary end points were 6-hour and peak cTnT , ECG changes , cardiac index , inotrope and vasoconstrictor use , renal dysfunction , and lung injury . Hospital survival was 99.4 % . Comparing placebo and RIPC , median ( interquartile range ) AUC 48-hour cTnT ( ng/mL−1/48 h−1 ) ; 28 ( 19 , 39 ) versus 30 ( 22 , 38 ) , 6-hour cTnT ( ng/mL−1 ) ; 0.93(0.59 , 1.35 ) versus 1.01(0.72 , 1.43 ) , peak cTnT ( ng/mL−1 ) ; 1.02 ( 0.74 , 1.44 ) versus 1.04 ( 0.78 , 1.51 ) , de novo left bundle-branch block ( 4 % versus 0 % ) and Q waves ( 5.3 % versus 5.5 % ) , serial cardiac indices , intraaortic balloon pump usage ( 8.5 % versus 7.5 % ) , inotrope ( 39 % versus 50 % ) and vasoconstrictor usage ( 66 % versus 64 % ) were not different . Dialysis requirement ( 1.2 % versus 3.8 % ) , peak creatinine ( median [ interquartile range ] , 1.2 mg/dL−1 ( 1.1 , 1.4 ) versus 1.2 ( 1.0 , 1.4 ) ) , and AUC urinary albumin-creatinine ratios 69 ( 40 , 112 ) versus 58 ( 32 , 85 ) were not different . Intubation times ; median ( interquartile range ) , 937 minutes(766 , 1402 ) versus 895(675 , 1180 ) , 6-hour ; 278 ( 210 , 338 ) versus 270 ( 218 , 323 ) and 12-hour pO2:FiO2 ratios 255 ( 195 , 323 ) versus 263 ( 210 , 308 ) were similar . Conclusions — In contrast to prior smaller studies , RIPC did not reduce troponin release , improve hemodynamics , or enhance renal or lung protection . Clinical Trial Registration — URL : http://www.ukcrn.org.uk . Unique identifier : 4659 Background — Myocyte necrosis as a result of elective percutaneous coronary intervention ( PCI ) occurs in approximately one third of cases and is associated with subsequent cardiovascular events . This study assessed the ability of remote ischemic preconditioning ( IPC ) to attenuate cardiac troponin I ( cTnI ) release after elective PCI . Methods and Results — Two hundred forty-two consecutive patients undergoing elective PCI with undetectable preprocedural cTnI were recruited . Subjects were r and omized to receive remote IPC ( induced by three 5-minute inflations of a blood pressure cuff to 200 mm Hg around the upper arm , followed by 5-minute intervals of reperfusion ) or control ( an uninflated cuff around the arm ) before arrival in the catheter laboratory . The primary outcome was cTnI at 24 hours after PCI . Secondary outcomes included renal dysfunction and major adverse cardiac and cerebral event rate at 6 months . The median cTnI at 24 hours after PCI was lower in the remote IPC compared with the control group ( 0.06 versus 0.16 ng/mL ; P=0.040 ) . After remote IPC , cTnI was < 0.04 ng/mL in 44 patients ( 42 % ) compared with 24 in the control group ( 24 % ; P=0.01 ) . Subjects who received remote IPC experienced less chest discomfort ( P=0.0006 ) and ECG ST-segment deviation ( P=0.005 ) than control subjects . At 6 months , the major adverse cardiac and cerebral event rate was lower in the remote IPC group ( 4 versus 13 events ; P=0.018 ) . Conclusion — Remote IPC reduces ischemic chest discomfort during PCI , attenuates procedure-related cTnI release , and appears to reduce subsequent cardiovascular events Rationale : Remote ischemic preconditioning ( RIPC ) has been suggested to induce cardioprotection during cardiac surgery . Maintaining proper atrial function is imperative in preventing arrhythmia and thrombus formation . Mitochondria have been proposed as key targets in conveying RIPC mechanisms and effects . MicroRNA ( miR ) is emerging as an important regulator of mitochondrial function , arrhythmia , and protection from ischemia and reperfusion . Objective : This study aim ed to evaluate the effect of RIPC on mitochondrial respiration and miR expression in human atrial tissue . Methods and Results : Sixty patients undergoing coronary artery bypass graft surgery were r and omized to RIPC ( n=30 ) or control ( n=30 ) . RIPC was performed preoperatively by inflating a blood pressure cuff on the upper arm to 200 mm Hg for 3 × 5 minutes , with 5 minutes reperfusion intervals . Biopsies were obtained from the right atrial appendage before and after aortic cross-clamping . Mitochondrial respiration was measured in situ and miR assessed by commercial miR array and quantitative reverse transcription polymerase chain reaction . Postoperative atrial fibrillation occurrence was monitored by biotelemetry . Maximal mitochondrial respiration was preserved throughout surgery after RIPC but significantly reduced ( −28 % ; P<0.05 ) after aortic cross-clamping in control . Incidence of postoperative atrial fibrillation was lower after RIPC versus control ( 14 % versus 50 % ; P<0.01 ) . Myocardial expression of miR-133a and miR-133b increased after aortic cross-clamping in both RIPC and control , whereas miR-1 was upregulated in control only . MiR-338 - 3p expression was higher in RIPC versus control after aortic cross-clamping . Conclusions : RIPC preserves mitochondrial respiration and prevents upregulation of miR-1 in the right atrium during coronary artery bypass graft . Clinical Trial Registration : URL : http://www . clinical trials.gov . Unique identifier : Background Ischemic or volatile anesthetic preconditioning is defined as tissue protection from impending ischemic cell damage by repetitive short periods of tissue exposure to ischemia or volatile anesthetics . Objective of this study was to eluci date , if ischemic preconditioning and pharmacological preconditioning with sevoflurane have effects on muscle tissue oxygen saturation in patients undergoing surgical revascularization of the lower limb . Methods In this prospect i ve r and omized pilot study ischemic and pharmacological ( sevoflurane ) preconditioning was performed in 40 patients with lower limb arterial occlusive disease undergoing surgical revascularization . Sevoflurane preconditioning was performed in one group ( N = 20 ) by repetitive application of sevoflurane for six minutes interspersed by six minutes of washout . Thereafter , ischemic preconditioning was performed in all patients ( N = 40 ) by repetitive clamping of the femoral artery for six minutes interspersed by six minutes of reperfusion . The effect of both procedures on leg muscle tissue oxygen saturation ( rSO2 ) was measured by near-infrared spectroscopy during both procedures and during surgery and reperfusion ( INVOS ® 5100C Oxymeter with Small Adult SomaSensor ® SAFB-SM , Somanetics , Troy , Michigan , USA ) . Results Repetitive clamping and reperfusion of the femoral artery result ed in significant cyclic decrease and increase of muscle rSO2 ( p < 0.0001 ) . Pharmacological preconditioning with sevoflurane result ed in a faster and higher increase of rSO2 during postoperative reperfusion ( Maximal 111 % baseline ± 20 versus 103 % baseline ± 14 , p = 0.008 ) consistent with an additional effect of pharmacological preconditioning on leg perfusion . Conclusions Ischemic preconditioning of lower limb muscle tissue and pharmacological preconditioning with sevoflurane have an effect on tissue oxygenation in patients with lower limb occlusive arterial disease . Trial registration The trial has been registrated at http://www . Clinical Trial.gov , Trial Number : NCT02038062 at 14 January 2014 Objectives Remote ischaemic preconditioning ( RIPC ) , using brief cycles of limb ischaemia/reperfusion , is a non-invasive , low-cost intervention that may reduce perioperative myocardial injury ( PMI ) in patients undergoing cardiac surgery . We investigated whether RIPC can also improve short-term clinical outcomes . Methods One hundred and eighty patients undergoing elective coronary artery bypass graft ( CABG ) surgery and /or valve surgery were r and omised to receive either RIPC ( 2–5 min cycles of simultaneous upper arm and thigh cuff inflation/deflation ; N=90 ) or control ( uninflated cuffs placed on the upper arm and thigh ; N=90 ) . The study primary end point was PMI , measured by 72 h area under the curve ( AUC ) serum high-sensitive troponin-T ( hsTnT ) ; secondary end point included short-term clinical outcomes . Results RIPC reduced PMI magnitude by 26 % ( −9.303 difference ( CI −15.618 to −2.987 ) 72 h hsTnT-AUC ; p=0.003 ) compared with control . There was also evidence that RIPC reduced the incidence of postoperative atrial fibrillation by 54 % ( 11 % RIPC vs 24 % control ; p=0.031 ) and decreased the incidence of acute kidney injury by 48 % ( 10.0 % RIPC vs 21.0 % control ; p=0.063 ) , and intensive care unit stay by 1 day ( 2.0 days RIPC ( CI 1.0 to 4.0 ) vs 3.0 days control ( CI 2.0 to 4.5 ) ; p=0.043 ) . In a post hoc analysis , we found that control patients administered intravenous glyceryl trinitrate ( GTN ) intraoperatively sustained 39 % less PMI compared with those not receiving GTN , and RIPC did not appear to reduce PMI in patients given GTN . Conclusions RIPC reduced the extent of PMI in patients undergoing CABG and /or valve surgery . RIPC may also have beneficial effects on short-term clinical outcomes , although this will need to be confirmed in future studies . Trial registration number Clinical Trials.gov ID : NCT00397163 There is conflicting evidence regarding the effectiveness of remote ischemic preconditioning ( RIPC ) in patients undergoing elective percutaneous coronary intervention ( PCI ) . Therefore , we prospect ively enrolled elderly patients with coronary heart disease ( CHD ) with diabetes mellitus ( DM ) undergoing elective drug-eluting stent ( DES ) implantation . They were r and omized to receive RIPC within 2 hours before PCI ( n = 102 ) or not ( controls , n = 98 ) . Baseline clinical characteristics were similar between the 2 groups . Despite a trend toward decline , the median high-sensitivity cardiac troponin I ( hscTnI ) level ( P = .256 ) and the incidence of myocardial infa rct ion ( MI ) type 4a ( P = .106 ) in the RIPC group 16 hours after PCI procedure was not significantly different from the control group . The RIPC could attenuate the release of a myocardial biomarker but failed to show a significant effect on hscTnI level or MI type 4a incidence after PCI procedure in elderly patients with CHD having DM undergoing elective DES implantation Background Our previous r and omized controlled trial demonstrated cardiorespiratory protection by remote ischemic preconditioning ( RIPC ) in children before cardiac surgery . However , the impact of RIPC on myocardial prosurvival intracellular signaling remains unknown in cyanosis . RIPC may augment phosphorylated protein signaling in myocardium and circulating leukocytes during tetralogy of Fallot ( ToF ) repair . Methods and Results Children ( n=40 ) undergoing ToF repair were double‐blind r and omized to RIPC ( n=11 boys , 9 girls ) or control ( sham RIPC : n=9 boys , 11 girls ) . Blood sample s were taken before , immediately after , and 24 hours after cardiopulmonary bypass . Resected right ventricular outflow tract muscle and leukocytes were processed for protein expression and mitochondrial respiration . There was no difference in age ( 7.1±3.4 versus 7.1±3.4 months ) , weight ( 7.7±1.8 versus 7.5±1.9 kg ) , or bypass or aortic cross‐clamp times between the groups ( control versus RIPC , mean±SD ) . No differences were seen between the groups for an increase in the ratio of phosphorylated to total protein for protein kinase B , p38 mitogen activated protein kinase , signal transducer and activator of transcription 3 , glycogen synthase kinase 3β , heat shock protein 27 , Connexin43 , or markers associated with promotion of necrosis ( serum cardiac troponin I ) , apoptosis ( Bax , Bcl‐2 ) , and autophagy ( Parkin , Beclin‐1 , LC3B ) . A high proportion of total proteins were in phosphorylated form in control and RIPC myocardium . In leukocytes , mitochondrial respiration and assessed protein levels did not differ between groups . Conclusions In patients with cyanotic heart disease , a high proportion of proteins are in phosphorylated form . RIPC does not further enhance phosphorylated protein signaling in myocardium or circulating leukocytes in children undergoing ToF repair . Clinical Trial Registration URL : ( http://www.anzctr.org.au/trial_view.aspx?id=335613 . Unique identifier : Australian New Zeal and Clinical Trials Registry number ACTRN12610000496011 Background — Radiofrequency ablation of atrial fibrillation has been associated with some risk of thromboembolic events . Previous studies showed that preventive short episodes of forearm ischemia ( remote ischemic preconditioning [ IPC ] ) reduce exercise-induced platelet reactivity . In this study , we assessed whether remote IPC has any effect on platelet activation induced by radiofrequency ablation of atrial fibrillation . Methods and Results — We r and omized 19 patients ( age , 54.7±11 years ; 17 male ) undergoing radiofrequency catheter ablation of paroxysmal atrial fibrillation to receive remote IPC or sham intermittent forearm ischemia ( control subjects ) before the procedure . Blood venous sample s were collected before and after remote IPC/sham ischemia , at the end of the ablation procedure , and 24 hours later . Platelet activation and reactivity were assessed by flow cytometry by measuring monocyte-platelet aggregate formation , platelet CD41 in the monocyte-platelet aggregate gate , and platelet CD41 and CD62 in the platelet gate in the absence and presence of ADP stimulation . At baseline , there were no differences between groups in platelet variables . Radiofrequency ablation induced platelet activation in both groups , which persisted after 24 hours . However , compared with control subjects , remote IPC patients showed a lower increase in all platelet variables , including monocyte-platelet aggregate formation ( P<0.0001 ) , CD41 in the monocyte-platelet aggregate gate ( P=0.002 ) , and CD41 ( P<0.0001 ) and CD62 ( P=0.002 ) in the platelet gate . Compared with control subjects , remote IPC was also associated with a significantly lower ADP-induced increase in all platelet markers . Conclusions — Our data show that remote IPC before radiofrequency catheter ablation for paroxysmal atrial fibrillation significantly reduces the increased platelet activation and reactivity associated with the procedure Background : Remote ischaemic preconditioning ( RIPC ) induced by brief ischaemia and reperfusion of the arm reduces myocardial injury in coronary artery bypass ( CABG ) surgery patients receiving predominantly cross-clamp fibrillation for myocardial protection . However , cold-blood cardioplegia is the more commonly used method world wide . Objective : To assess whether RIPC is cardioprotective in CABG patients receiving cold-blood cardioplegia . Design : Single-centre , single-blinded , r and omised controlled trial . Setting : Tertiary referral hospital in London . Patients : Adults patients ( 18–80 years ) undergoing elective CABG surgery with or without concomitant aortic valve surgery with cold-blood cardioplegia . Patients with diabetes , renal failure ( serum creatinine > 130 mmol/l ) , hepatic or pulmonary disease , unstable angina or myocardial infa rct ion within the past 4 weeks were excluded . Interventions : Patients were r and omised to receive either RIPC ( n = 23 ) or control ( n = 22 ) after anaesthesia . RIPC comprised three 5 min cycles of right forearm ischaemia , induced by inflating a blood pressure cuff on the upper arm to 200 mm Hg , with an intervening 5 min reperfusion . The control group had a deflated cuff placed on the upper arm for 30 min . Main outcome measures : Serum troponin T was measured preoperatively and at 6 , 12 , 24 , 48 and 72 h after surgery and the area under the curve ( AUC at 72 h ) calculated . Results : RIPC reduced absolute serum troponin T release by 42.4 % ( mean ( SD ) AUC at 72 h : 31.53 ( 24.04 ) μg/l.72 h in controls vs 18.16 ( 6.67 ) μg/l.72 h in RIPC ; 95 % CI 2.4 to 24.3 ; p = 0.019 ) . Conclusions : Remote ischaemic preconditioning induced by brief ischaemia and reperfusion of the arm reduces myocardial injury in CABG surgery patients undergoing cold-blood cardioplegia , making this non-invasive cardioprotective technique widely applicable clinical ly . Trial registration number : NCT00397163 OBJECTIVE To determine the pathological mechanism and prevent heart-renal syndrome after heart valve replacement surgery . METHODS A total of 46 patients were admitted for selective valve replacement , and divide into 3 groups r and omly : a control group ( Con , n=16 ) , a remote ischemic perconditioning ( RIPerC ) group ( n=15 ) and a remote ischemic postconditioning ( RIPostC ) group ( n=15 ) . The serum creatinine ( SCr ) , blood urea nitrogen ( BUN ) , serum heme oxygennase-1 ( HO-1 ) , serum iron and urinary neutrophil gelatinase associated lipocalin ( NGAL ) level in the 3 groups were compared preoperatively and 6 , 12 , 24 , 48 h after aortic cross-release . RESULTS Compared with the preoperative level , the SCr , BUN , urinary NGAL , serum iron ( 6 and 12 h ) and serum HO-1 values were significantly increased after the heart valve replacement surgery in the control patients , RIPreC and RIPostC groups ( P<0.05 ) . Compared with the control group , the serum HO-1 was significantly increased at 6 , 12 , 24 , 48 h after the heart valve replacement surgery in both the RIPerC and RIPostC groups ( P<0.05 ) ; the SCr , BUN , urinary NGAL and serum iron values were decreased at 6 , 12 , 24 , 48 h after the heart valve replacement surgery in both the RIPerC and RIPostC groups ( P>0.05 ) . CONCLUSION Abnormal change in urinary NGAL , serum iron and HO-1 can be used as early warning indicators of acute kidney injury when cardio-renal syndrome occurrs among patients under heart valve replacement surgery . Remote ischemic conditioning plays a preventive role in the occurrence of cardio-renal syndrome and renal protection BACKGROUND Cardiac preconditioning is thought to be involved in the observed decreased coronary artery reocclusion rate in patients with angina preceding myocardial infa rct ion . We prospect ively examined whether preconditioning by sevoflurane would decrease late cardiac events in patients undergoing coronary artery bypass graft ( CABG ) surgery . METHODS Seventy-two patients scheduled for elective CABG surgery were r and omized to preconditioning by sevoflurane ( 10 min at 4 vol% ) or placebo . For all patients , follow-up of adverse cardiac events was obtained 6 and 12 months after surgery . Transcript levels for platelet-endothelial cell adhesion molecule-1 ( PECAM-1/CD31 ) , catalase and heat shock protein 70 ( Hsp70 ) were determined in atrial biopsies after sevoflurane preconditioning . RESULTS Pharmacological preconditioning by sevoflurane reduced the incidence of late cardiac events during the first year after CABG surgery ( sevoflurane 3 % vs 17 % in the placebo group , log-rank test , P=0.038 ) . One patient in the sevoflurane group and three patients in the placebo group experienced new episodes of congestive heart failure and three additional patients had coronary artery reocclusion . Perioperative peak concentrations for myocardial injury markers were higher in patients with subsequent late cardiac events [ NTproBNP , 9031 ( 4125 ) vs 3049 ( 1906 ) ng litre(-1 ) , P<0.001 ; cTnT , 1.31 ( 0.88 ) vs 0.46 ( 0.29 ) microg litre(-1 ) , P<0.001 ] . Transcript levels were reduced for PECAM-1 and increased for catalase but unchanged for Hsp70 in atrial biopsies after sevoflurane preconditioning . CONCLUSIONS This prospect i ve r and omized clinical study provides evidence of a protective role for pharmacological preconditioning by sevoflurane in late cardiac events in CABG patients , which may be related to favourable transcriptional changes in pro- and antiprotective proteins Reperfusion is m and atory after ischemia but also triggers ischemia-reperfusion ( I/R ) injury . Ischemic preconditioning ( IPC ) can limit endothelial I/R injury . Nonetheless , translation of IPC to the clinical arena is often disappointing . Since application of IPC typically relates to older patients , efficacy of IPC may be attenuated with aging . Our objective was to examine the impact of advanced age on the ability of IPC to protect against endothelial dysfunction due to I/R injury . We included 15 healthy young ( 20 - 25 yr ) and 15 older ( 68 - 77 yr ) men . We examined brachial artery endothelial function using flow-mediated dilation ( FMD ) before and after arm I/R ( induced by inflation of an upper-arm blood pressure cuff for 20 min and 15 min of reperfusion ) . In a r and omized order , I/R was preceded by IPC or a control intervention consisting of three cycles of 5 min upper-arm cuff inflation to 220 or 20 mmHg , respectively . As a result , in young men , FMD decreased significantly after I/R ( 6.4 ± 2.7 to 4.4 ± 2.5 % ) . This decrease was not present when I/R was preceded by IPC ( 5.9 ± 2.3 to 5.6 ± 2.5 % ) . IPC-induced protection appeared to be significantly reduced in the elderly patients ( P = 0.04 ) . Although FMD decreased after I/R in older men ( 3.5 ± 1.7 to 2.5 ± 1.0 % ) , IPC could not prevent this ( 3.7 ± 2.1 to 2.2 ± 1.1 % ) . In conclusion , this study is the first to observe in humans in vivo that older age is associated with an abolished effect of IPC to protect against endothelial dysfunction after I/R in the brachial artery . This provides a possible explanation for the problematic translation of strategies that reduce I/R injury from pre clinical work to the clinical arena Background Preconditioning by volatile anesthetics is a promising therapeutic strategy to render myocardial tissue resistant to perioperative ischemia . It was hypothesized that sevoflurane preconditioning would decrease postoperative release of brain natriuretic peptide , a biochemical marker for myocardial dysfunction . In addition , several variables associated with the protective effects of preconditioning were evaluated . Methods Seventy-two patients scheduled for coronary artery bypass graft surgery under cardioplegic arrest were r and omly assigned to preconditioning during the first 10 min of complete cardiopulmonary bypass with either placebo ( oxygen – air mixture only ) or sevoflurane 4 vol% ( 2 minimum alveolar concentration ) . No other volatile anesthetics were administered at any time during the study . Treatment was strictly blinded to anesthesiologists , perfusionists , and surgeons . Biochemical markers of myocardial dysfunction and injury ( brain natriuretic peptide , creatine kinase – MB activity , and cardiac troponin T ) , and renal dysfunction ( cystatin C ) were determined . Results of Holter electrocardiography were recorded perioperatively . Translocation of protein kinase C was assessed by immunohistochemical analysis of atrial sample s. Results Sevoflurane preconditioning significantly decreased postoperative release of brain natriuretic peptide , a sensitive biochemical marker of myocardial contractile dysfunction . Pronounced protein kinase C & dgr ; and & egr ; translocation was observed in sevoflurane-preconditioned myocardium . In addition , postoperative plasma cystatin C concentrations increased significantly less in sevoflurane-preconditioned patients . No differences between groups were found for perioperative ST-segment changes , arrhythmias , or creatine kinase – MB and cardiac troponin T release . Conclusions Sevoflurane preconditioning preserves myocardial and renal function as assessed by biochemical markers in patients undergoing coronary artery bypass graft surgery under cardioplegic arrest . This study demonstrated for the first time translocation of protein kinase C isoforms & dgr ; and & egr ; in human myocardium in response to sevoflurane AIMS The aim of this study was to evaluate whether remote ischaemic preconditioning ( RIPC ) combined with remote ischaemic postconditioning ( RIPostC ) improves the clinical outcomes of patients undergoing cardiac surgery . METHODS AND RESULTS From June 2009 to November 2010 , 1280 patients who underwent elective cardiac surgery were r and omized into the RIPC with RIPostC group or the control group in the morning of the surgery . In the RIPC with RIPostC group , four cycles of 5-min ischaemia and 5-min reperfusion were administered twice to the upper limb-before cardiopulmonary bypass ( CPB ) or coronary anastomoses for RIPC and after CPB or coronary anastomoses for RIPostC. The primary endpoint was the composite of major adverse outcomes , including death , myocardial infa rct ion , arrhythmia , stroke , coma , renal failure or dysfunction , respiratory failure , cardiogenic shock , gastrointestinal complication , and multiorgan failure . Remote ischaemic preconditioning with RIPostC did not reduce the composite outcome compared with the control group ( 38.0 vs. 38.1 % , respectively ; P = 0.998 ) and there was no difference in each major adverse outcome . The intensive care unit and hospital stays were not different between the two groups . However , in the off-pump coronary artery bypass surgery subgroup , multivariate logistic regression analysis revealed that RIPC with RIPostC was related to increased composite outcome ( odds ratio : 1.54 ; 95 % confidence interval : 1.02 - 2.30 ; P = 0.038 ) . CONCLUSION Remote ischaemic preconditioning with RIPostC by transient upper limb ischaemia did not improve clinical outcome in patients who underwent cardiac surgery Abstract Objectives . The objective was to investigate the potential protective effects of two conditioning methods , on myocardial ischemic and reperfusion injury in relation to cardiac surgery . Design . Totally 68 patients were r and omly assigned to either a control group ( n = 23 ) , a remote ischemic preconditioning ( RIPC ) group ( n = 23 ) or a glucagon-like peptide-1 ( GLP-1 ) analogue group ( n = 22 ) . The RIPC protocol consisted of three cycles of upper limb ischemia . The GLP-1 analogue protocol consisted of intravenous infusion with exenatide . The primary endpoint was postoperative cardiac enzyme release . The other secondary endpoints were metabolic parameters related to myocardial ischemia , measured using microdialysis technique , as well as other operative- and postoperative data . Results . Postoperative cardiac enzyme release indicated a possible beneficial effect of the interventions , but the difference did not reach statistical significance . RIPC showed a trend toward lower levels ( p = 0.07 ) . We managed to establish a functional myocardial microdialysis model , but we were unable to demonstrate clear protective effects . Conclusions . We were in this prospect i ve r and omized proof-of-concept trial , unable to show distinct protective effects of the studied conditioning methods . However , this trial can hopefully contribute to generate a productive discussion concerning limitations and future use of cardiac conditioning as well as microdialysis technique Hemodialysis (HD)-induced myocardial ischemia is associated with an elevated cardiac troponin T , and is common in asymptomatic patients undergoing conventional HD . Remote ischemic preconditioning ( RIPC ) has a protective effect against myocardial ischemia – reperfusion injury . We hypothesized that RIPC also has a protective effect on HD-induced myocardial injury . Chronic HD patients were r and omized to the control group or the RIPC group . RIPC was induced by transient occlusion of blood flow to the arm with a blood-pressure cuff for 5 min , followed by 5 min of deflation . Three cycles of inflation and deflation were undertaken before every HD session for 1 month ( total 12 times ) . The primary outcome was the change in cardiac troponin T ( cTnT ) level at day 28 from baseline . Demographic and baseline laboratory values were not different between the control ( n = 17 ) and the RIPC groups ( n = 17 ) . cTnT levels tended to decrease from day 2 in the RIPC group through to 28 days , in contrast to no change in the control group . There were significant differences in the change of cTnT level at day 28 from baseline [ Control , median ; −0.002 ng/ml ( interquartile range −0.008 to 0.018 ) versus RIPC , median ; −0.015 ng/ml ( interquartile range −0.055 to 0.004 ) , P = 0.012 ] . RIPC reduced cTnT release in chronic conventional HD patients , suggesting that this simple , cheap , safe , and well-tolerated procedure has a protective effect against HD-induced ischemia Background : Remote ischemic preconditioning ( RIPC ) may confer the protection in critical organs . The authors hypothesized that limb RIPC would reduce lung injury in patients undergoing pulmonary resection . Methods : In a r and omized , prospect i ve , parallel , controlled trial , 216 patients undergoing elective thoracic pulmonary resection under one-lung ventilation with propofol – remifentanil anesthesia were r and omized 1:1 to receive either limb RIPC or conventional lung resection ( control ) . Three cycles of 5-min ischemia/5-min reperfusion induced by a blood pressure cuff served as RIPC stimulus . The primary outcome was PaO2/FIO2 . Secondary outcomes included other pulmonary variables , the incidence of in-hospital complications , markers of oxidative stress , and inflammatory response . Results : Limb RIPC significantly increased PaO2/FIO2 compared with control at 30 and 60 min after one-lung ventilation , 30 min after re-expansion , and 6 h after operation ( 238 ± 52 vs. 192 ± 67 , P = 0.03 ; 223 ± 66 vs. 184 ± 64 , P = 0.01 ; 385 ± 61 vs. 320 ± 79 , P = 0.003 ; 388 ± 52 vs. 317 ± 46 , P = 0.001 , respectively ) . In comparison with control , it also significantly reduced serum levels of interleukin-6 and tumor necrosis factor-&agr ; at 6 , 12 , 24 , and 48 h after operation and malondialdehyde levels at 60 min after one-lung ventilation and 30 min after re-expansion ( all P < 0.01 ) . The incidence of acute lung injury and the length of postoperative hospital stay were markedly reduced by limb RIPC compared with control ( all P < 0.05 ) . Conclusion : Limb RIPC attenuates acute lung injury via improving intraoperative pulmonary oxygenation in patients without severe pulmonary disease after lung resection under propofol – remifentanil anesthesia BACKGROUND Ischemic preconditioning ( IPC ) and anesthetic preconditioning ( APC ) have been reported to attenuate ischemia-reperfusion ( IR ) injury after liver resection under continuous inflow occlusion . This study evaluates whether these strategies enhance hepatic protection of remnant liver against IR after liver resection with intermittent clamping ( INT ) . METHODS A total of 106 patients without underlying liver disease and su bmi tted to liver resection using INT were r and omized into 3 groups : IPC ( 10 minutes of inflow occlusion followed by 10 minutes of reperfusion before liver transection ) , APC ( sevoflurane administration for 20 minutes before liver transection ) , and INT ( no preconditioning ) . Patients were also stratified according to the extent of the hepatectomy . Cytoprotection was evaluated by comparing hepatocyte and endothelial dysfunction markers , apoptosis , histologic lesions , and postoperative outcome . RESULTS No differences were observed in preoperative chemotherapy and steatosis , total warm ischemia time , operative time , or blood loss . Kinetics of transaminases ( aspartate aminotransferase , P = .137 ; alanine aminotransferase , P = .616 ) , bilirubin ( P = .980 ) , and hyaluronic acid increase ( P = .514 ) revealed no differences . Significant apoptosis was present in 40 % of patients , mild-to-moderate leukocyte infiltration and steatosis in 45 % and 55 % , respectively , and mild sinusoidal congestion in 65 % , with a similar distribution in the 3 groups . When patients were stratified by major versus minor resections , no differences were observed in any of the variables studied . Postoperative clinical outcomes were also similar . CONCLUSION These results suggest that these protocol s of IPC and APC used in this study do not provide better cytoprotection from IR when INT is used BACKGROUND The aim of this study was to evaluate the lung-protective effect of combined remote ischemic preconditioning ( RIPCpre ) and postconditioning ( RIPCpost ) in patients undergoing complex valvular heart surgery . METHODS In this r and omized , placebo-controlled , double-blind trial , 54 patients were assigned to an RIPCpre plus RIPCpost group or a control group ( 1:1 ) . Patients in the RIPCpre plus RIPCpost group received three 10-min cycles of right-side lower-limb ischemia of 250 mm Hg at both 10 min after anesthetic induction and weaning from cardiopulmonary bypass . The primary end point was to compare postoperative Pao(2)/Fio(2 ) . Secondary end points were to compare pulmonary variables , incidence of acute lung injury , and inflammatory cytokines . RESULTS In both groups , Pao(2)/Fio(2 ) at 24 h postoperation was significantly decreased compared with each corresponding baseline value . However , intergroup comparisons of pulmonary variables , including Pao(2)/Fio(2 ) and incidence of acute lung injury , revealed no significant differences . Serum levels of IL-6 , IL-8 , IL-10 , and tumor necrosis factor-α were all significantly increased in both groups compared with each corresponding baseline value , without any significant intergroup differences . There were also no significant differences in transpulmonary gradient of IL-6 , IL-10 , and tumor necrosis factor-α between the groups . CONCLUSIONS RIPCpre plus RIPCpost as tested in this r and omized controlled trial did not provide significant pulmonary benefit following complex valvular cardiac surgery Acute kidney injury , a common complication of cardiac surgery with cardiopulmonary bypass , is associated with increased morbidity and mortality . Ischemic preconditioning at a remote site mitigates ischemia-reperfusion injury and may prevent acute kidney injury after cardiac surgery , thus providing clinical benefit . To further study this , we enrolled 120 adult patients undergoing elective cardiac surgery for whom cardiopulmonary bypass was anticipated in a r and omized , single-blind , and controlled pilot trial . Patients were stratified for the type of surgery and equally assigned to a control group or to receive remote ischemic preconditioning by an automated thigh tourniquet consisting of three 5-min intervals of lower extremity ischemia separated by 5-min intervals of reperfusion . The primary end point was acute kidney injury defined as an elevation of serum creatinine of ≥0.3 mg/dl or ≥50 % within 48 h after surgery . Fifty-nine patients in each group were analyzed on an intention-to-treat basis . Acute kidney injury occurred in 12 remote ischemic preconditioned and 28 control patients , reflecting an absolute risk reduction of 0.27 and a significantly reduced relative risk due to preconditioning of 0.43 . Hence , remote ischemic preconditioning prevents acute kidney injury in patients undergoing cardiopulmonary bypass-assisted cardiac surgery Remote ischemic preconditioning ( RIPC ) with transient upper limb ischemia reduces myocardial injury in patients undergoing on-pump coronary artery bypass grafting ( CABG ) with cross-clamp fibrillation or blood cardioplegia for myocardial protection . Whether or not such protection is still operative when st and ard crystalloid cardioplegic arrest is used is uncertain . Fifty-three consecutive , non-diabetic patients with triple-vessel disease and 64 ± 12 years of age ( mean ± SD ) , who underwent elective CABG surgery with crystalloid ( Bretschneider ) cardioplegic arrest , were allocated in a prospect i ve , r and omized , single-blinded protocol to receive either a RIPC protocol ( 3 cycles of 5 min transient left upper arm ischemia induced by inflating a blood pressure cuff to 200 mmHg with 5 min of reperfusion ) or control , respectively , after induction of anesthesia . Cardiac troponin I ( cTnI ) concentration was measured preoperatively and over 72 h postoperatively , and the area under the curve ( AUC ) was calculated . Peak postoperative cTnI concentration was significantly reduced from 13.7 ± 7.7 ng/mL in controls to 8.9 ± 4.4 ng/mL in RIPC ( P = 0.008 ) . Mean cTnI concentration was significantly lower at 6 , 12 , 24 , and 48 h after surgery ( ANOVA ; P < 0.0001 ) in the RIPC patients ( N = 27 ) than in controls ( N = 26 ) , result ing in a 44.5 % reduction of cTnI ( AUC at 72 h ) . RIPC by repetitive inflation of a cuff around the left upper arm before surgery enhances myocardial protection in patients undergoing CABG surgery with ante grade cold crystalloid cardioplegia Background : Remote ischemic preconditioning ( RIPC ) may confer the cytoprotection in critical organs . The authors hypothesized that limb RIPC would reduce intestinal and pulmonary injury in patients undergoing open infrarenal abdominal aortic aneurysm repair . Methods : In this single-center , prospect i ve , double-blinded , r and omized , parallel-controlled trial , 62 patients undergoing elective open infrarenal abdominal aortic aneurysm repair were r and omly assigned in a 1:1 ratio by computerized block r and omization to receive limb RIPC or conventional abdominal aortic aneurysm repair ( control ) . Three cycles of 5-min ischemia/5-min reperfusion induced by a blood pressure cuff placed on the left upper arm served as RIPC stimulus . The primary endpoint was arterial – alveolar oxygen tension ratio . The secondary endpoints mainly included the intestinal injury markers ( serum intestinal fatty acid – binding protein , endotoxin levels , and diamine oxidase activity ) , the markers of oxidative stress and systemic inflammatory response , and the scores of the severity of intestinal and pulmonary injury . Results : In limb RIPC group , a/A ratio was significantly higher than that in control group at 8 , 12 , and 24 h after cross-clamp release ( 66 ± 4 vs. 45 ± 4 , P = 0.003 ; 60 ± 6 vs. 37 ± 4 , P = 0.002 ; and 60 ± 5 vs. 47 ± 6 , P = 0.039 , respectively ) . All biomarkers reflecting intestinal injury increased over time , and there was significant differences between limb RIPC and control group ( P < 0.001 ) . The severity of intestinal and pulmonary injury was decreased by limb RIPC ( P = 0.014 and P = 0.001 , respectively ) . Conclusions : Limb RIPC attenuates intestinal and pulmonary injury in patients undergoing elective open infrarenal abdominal aortic aneurysm repair without any potential risk The objective of this study was to test the hypothesis that ischemia reperfusion damage in kidney transplantation is associated with lipid peroxidation and that inhibition of lipid peroxidation by antioxidants improves the function of the transplanted kidney . Lipid peroxidation was assessed by measuring the plasma malonaldehyde content ( as thiobarbituric acid reaction product ) with high-performance liquid chromatography . Kidney function was assessed by plasma creatinine and creatinine clearance . Thirty patients of an ongoing series were r and omly selected into two groups , with 14 controls and 16 patients in the antioxidant therapy group . Therapy consisted of two ampoules of Omnibionta ( which contains vitamins C , E , A and B complex ) diluted in 500 ml physiological sodium chloride , which was infused intravenously prior to reperfusion onset . No significant differences existed for the age of the patients in the control ( 43.00 + /- 9.86 years ) and the therapy group ( 41.56 + /- 14.14 years ) nor in the kidney preservation time , which was 24.12 + /- 8.73 and 18.43 + /- 9.97 hours in the control and therapy group , respectively . The controls showed a transient increase of plasma lipid peroxides as measured by malonaldehyde with a peak one hour after onset of reperfusion . Compared to the baseline value of 0.74 + /- 0.26 ( mean + /- SD ) the one hour malonaldehyde value increased to 1.46 + /- 0.22 nmol/ml ( P < 0.001 ) . In the therapy group the plasma malonaldehyde level did not increase , but slightly decreased by about 20 % compared to the baseline value . The difference of plasma malonaldehyde between the two groups one hour after reperfusion onset was highly significant ( P > 0.0001 ) . ( ABSTRACT TRUNCATED AT 250 WORDS We aim ed to determine whether remote ischemic preconditioning ( IP ) reduces renal damage following elective open infrarenal abdominal aortic aneurysm ( AAA ) repair . Sequential common iliac clamping was used to induce remote IP in r and omized patients . Urinary retinol binding protein ( RBP ) and albumin-creatinine ratio ( ACR ) were measured following induction and 3 , 24 , and 48 hours postoperatively . In controls ( n = 22 ) , median urinary RBP increased from 112 µg/mL ( interquartile range [ IQR ] 96 - 173 µg/mL ) preoperatively to 5919 µg/mL ( IQR 283 - 17 788 µg/mL ) at 3 hours . Preoperative urinary RBP in preconditioned patients was 96 µg/mL ( IQR 50 to 229 µg/mL ) preoperatively , rising to 1243 µg/mL ( IQR 540 to 15400 µg/mL ) at 3 hours . Although control patients ’ median urinary RBP level was 5 times greater at 3 hours , there were no statistically significant differences in renal outcome indices . This trial could not confirm that remote IP reduces renal injury following elective open aneurysm surgery Background Total knee arthroplasty ( TKA ) can be associated with considerable postoperative pain . Ischemic preconditioning of tissue before inducing procedure-related underperfusion may reduce the postoperative inflammatory response , which further may reduce associated pain . Questions / purpose sIn this prospect i ve , r and omized study , we aim ed at evaluating the impact of ischemic preconditioning on postoperative pain at rest and during exercise ; use of pain medication ; levels of systemic prothrombotic and local inflammatory markers ; and length of stay and achievement of physical therapy milestones . Methods Sixty patients undergoing unilateral TKA under tourniquet were enrolled with half ( N = 30 ) being r and omized to an episode of limb preconditioning before induction of ischemia for surgery ( tourniquet inflation ) . Pain scores , analgesic consumption , markers of inflammation ( interleukin-6 [ IL-6 ] , tumor necrosis factor [TNF]-α in periarticular drainage ) , and periarticular circumference were measured at baseline and during 2 days postoperatively . Changes in prothrombotic markers were evaluated . Results Patients in the preconditioning group had significantly less pain postoperatively at rest ( mean difference = −0.71 , 95 % confidence interval [ CI ] = −1.40 to −0.02 , p = 0.043 ) and with exercise ( mean difference = −1.38 , 95 % CI = −2.32 to −0.44 , p = 0.004 ) , but showed no differences in analgesic consumption . No differences were seen between the study and the control group in terms of muscle oxygenation and intraarticular levels of IL-6 and TNF-α as well as levels of prothrombotic markers . No differences were found between groups in regard to hospitalization length and time to various physical therapy milestones . Conclusions Ischemic preconditioning reduces postoperative pain after TKA , but the treatment effect size we observed with the preconditioning routine used was modest . Clinical Relevance Given the ease of this intervention , ischemic preconditioning may be considered as part of a multimodal analgesic strategy . However , more study into the impact of different preconditioning strategies , elucidation of mechanisms , safety profiles , and cost-effectiveness of this maneuver is needed BACKGROUND Myocardial injury is associated with an adverse outcome after off-pump coronary artery bypass graft surgery ( OPCAB ) . The authors conducted a r and omized controlled trial to evaluate whether remote ischemic preconditioning ( RIPC ) with remote ischemic postconditioning ( RIPostC ) reduces myocardial injury in patients undergoing OPCAB . METHODS AND RESULTS Seventy patients scheduled for OPCAB were r and omly assigned to an RIPC+RIPostC group ( n=35 ) or a control group ( n=35 ) . In the RIPC+RIPostC group , 4 cycles of 5-min ischemia and 5-min reperfusion were done on a lower limb before anastomoses ( RIPC ) and after anastomoses ( RIPostC ) . RIPC+RIPostC significantly reduced postoperative serum troponin I levels ( P=0.001 ) . The area under the curve for postoperative troponin I was 48.7 % lower in the RIPC+RIPostC group ( median [ interquartile range ] , 21.3 h·ng⁻¹·ml⁻¹ , 16.5 - 53.1 h·ng⁻¹·ml⁻¹ vs. 41.5 h·ng⁻¹·ml⁻¹ , 24.6 - 90.2 h·ng⁻¹·ml⁻¹ , P=0.020 ) . There was no significant difference in creatinine levels and PaO₂/F(i)O₂ ratios between the 2 groups . CONCLUSIONS RIPC+RIPostC by lower limb ischemia decreased postoperative myocardial enzyme elevation by almost half postoperatively in patients undergoing OPCAB The efficacy of remote ischemic preconditioning ( RIPC ) in high-risk cardiac surgery is uncertain . In this study , 96 adults undergoing high-risk cardiac surgery were r and omised to RIPC ( 3 cycles of 5 min of upper-limb ischemia induced by inflating a blood pressure cuff to 200 mmHg with 5 min of reperfusion ) or control . Main endpoints were plasma high-sensitivity troponin T ( hsTNT ) levels at 6 and 12 h , worst post-operative acute kidney injury ( AKI ) based on RIFLE criteria , and noradrenaline duration . hsTNT levels were log-normally distributed and higher with RIPC than control at 6-h post cross-clamp removal [ 810 ng/ml ( IQR 527–1,724 ) vs. 634 ng/ml ( 429–1,012 ) ; ratio of means 1.41 ( 99.17 % CI 0.92–2.17 ) ; P=0.04 ] and 12 h [ 742 ng/ml ( IQR 427–1,700 ) vs. 514 ng/ml ( IQR 356–833 ) ; ratio of means 1.56 ( 99.17 % CI 0.97–2.53 ) ; P=0.01 ] . After adjustment for baseline confounders , the ratio of means of hsTNT at 6 h was 1.23 ( 99.17 % CI 0.88–1.72 ; P=0.10 ) and at 12 h was 1.30 ( 99.17 % CI 0.92–1.84 ; P=0.05 ) . In the RIPC group , 35/48 ( 72.9 % ) had no AKI , 5/48 ( 10.4 % ) had AKI risk , and 8/48 ( 16.7 % ) had either renal injury or failure compared to the control group where 34/48 ( 70.8 % ) had no AKI , 7/48 ( 14.6 % ) had AKI risk , and 7/48 ( 14.6 % ) had renal injury or failure ( Chi-squared 0.41 ; two degrees of freedom ; P = 0.82 ) . RIPC increased post-operative duration of noradrenaline support [ 21 h ( IQR 7–45 ) vs. 9 h ( IQR 3–19 ) ; ratio of means 1.70 ( 99.17 % CI 0.86–3.34 ) ; P=0.04 ] . RIPC does not reduce hsTNT , AKI , or ICU-support requirements in high-risk cardiac surgery AIMS Transient ischaemia of non-vital tissue has been shown to enhance the tolerance of remote organs to cope with a subsequent prolonged ischaemic event in a number of clinical conditions , a phenomenon known as remote ischaemic preconditioning ( RIPC ) . However , there remains uncertainty about the efficacy of RIPC in patients undergoing cardiac surgery . The purpose of this report is to describe the design and methods used in the " Remote Ischaemic Preconditioning for Heart Surgery (RIPHeart)- Study " . METHODS We are conducting a prospect i ve , r and omized , double-blind , multicentre , controlled trial including 2070 adult cardiac surgical patients . All types of surgery in which cardiopulmonary bypass is used will be included . Patients will be r and omized either to the RIPC group receiving four 5 min cycles of transient upper limb ischaemia/reperfusion or to the control group receiving four cycles of blood pressure cuff inflation/deflation at a dummy arm . The primary endpoint is a composite outcome ( all-cause mortality , non-fatal myocardial infa rct ion , any new stroke , and /or acute renal failure ) until hospital discharge . CONCLUSION The RIPHeart- Study is a multicentre trial to determine whether RIPC may improve clinical outcome in cardiac surgical patients BACKGROUND Remote ischaemic preconditioning ( RIPC ) can reduce ischaemic-reperfusion injury in distant organs . The myocardial and pulmonary protective effect of RIPC in infants with pulmonary hypertension remains unclear . We conducted a r and omized controlled trial to evaluate the effect of RIPC in infants receiving ventricular septal defect ( VSD ) repair . METHODS We studied 55 infants with pulmonary hypertension undergoing VSD repair ( RIPC group , n=27 ; control group , n=28 ) . RIPC consisted of four 5 min cycles of lower limb ischaemia and reperfusion . Serum troponin I ( TnI ) concentrations were measured after induction of anaesthesia and at 1 , 6 , 12 , and 24 h after surgery . Other clinical data such as inotropic score , lung compliance , alveolar-arterial oxygen gradient , oxygen index , mechanical ventilation time , and length of intensive care unit stay were also recorded at each interval . RESULTS No differences in patient or surgical characteristics were observed between the two groups . There were no significant differences in postoperative TnI levels according to time ( P=0.35 ) or the total amount of TnI release , expressed as the area under the curve over the 24 h after surgery [ RIPC vs control : 207.6 ( 134.0 ) vs 274.6 ( 263.7 ) h ng ml(-1 ) , P=0.24 ] . All other clinical data were also comparable . CONCLUSIONS RIPC does not reduce the postoperative TnI release after VSD repair in infants with pulmonary hypertension . Additionally , it is difficult to find significant clinical benefits of RIPC in this population . The effect of RIPC varies according to clinical situation and patient condition . CLINICAL TRIAL REGISTRATION Clinical Trials.gov , NCT01313832 AIMS Remote ischaemic conditioning as an adjunct to primary percutaneous coronary intervention in patients with ST-elevation myocardial infa rct ion increases myocardial salvage . We investigated the effect of remote ischaemic conditioning on long-term clinical outcome . METHODS AND RESULTS From February 2007 to November 2008 , 333 patients with a suspected first acute ST-elevation myocardial infa rct ion were r and omized to receive primary percutaneous coronary intervention with ( n = 166 ) or without ( n = 167 ) remote ischaemic conditioning ( intermittent arm ischaemia through four cycles of 5-min inflation followed by 5-min deflation of a blood-pressure cuff ) . Patient follow-up extended from the r and omization date until an outcome , emigration or January 2012 ( median follow-up = 3.8 years ) . The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE)-a composite of all-cause mortality , myocardial infa rct ion , readmission for heart failure , and ischaemic stroke/transient ischaemic attack . The individual components of the primary endpoint comprised the secondary endpoints . Outcomes were obtained from Danish nationwide medical registries and vali date d by medical record review and contact to patients ' general practitioner . In the per- protocol analysis of 251 patient fulfilling trial criteria , MACCE occurred for 17 ( 13.5 % ) patients in the intervention group compared with 32 ( 25.6 % ) patients in the control group , yielding a hazard ratio ( HR ) of 0.49 ( 95 % confidence interval : 0.27 - 0.89 , P = 0.018 ) . The HR for all-cause mortality was 0.32 ( 95 % confidence interval : 0.12 - 0.88 , P = 0.027 ) . Although lower precision , the HRs were also directionally lower for all other secondary endpoints . CONCLUSION Remote ischaemic conditioning before primary percutaneous coronary intervention seemed to improve long-term clinical outcomes in patients with ST-elevation myocardial infa rct ion Background : Renal ischemia-reperfusion ( I/R ) injury is a major cause of acute renal failure ( ARF ) . The transcription factor nuclear factor-κB ( NF-κB ) has been implicated as a key mediator of reperfusion injury . Activation of NF-κB is dependent upon the phosphorylation of its inhibitor , IκB , by the specific inhibitory κB kinase ( IKK ) subunit , IKKβ . We hypothesized that ischemic preconditioning ( IPC ) reduces acute renal damage following I/R injury by inhibiting activation of IKKβ . As neutrophil gelatinase-associated lipocalin ( NGAL ) , an early predictive biomarker of acute kidney injury , is regulated by NF-κB , we approached the relationship between NGAL and IKKβ . Method : Thirty male Sprague-Dawley rats were r and omly divided into 3 groups after right kidney nephrectomy . Group A rats were sham-operated controls . Group B rats were 45-min ischemic in the left renal artery while Group C rats were pre-treated with 3 cycles of 2-min ischemia and 5-min reperfusion . All the rats were sacrificed at 24 h after reperfusion . We harvested kidneys and serum to do further analysis , including histological and functional parameters , expressions of NGAL and IKKβ in renal tissues . Results : Compared with rats subjected to I/R injury , pre-treated rats had a significant decrease in serum creatinine level ( Scr ) and tubulointerstitial injury scores ( Scr , 86.79 ± 12.98 vs. 205.89 ± 19.16 μmol/l , p < 0.01 ; tubulointerstitial injury scores , 1.3 ± 0.48 vs. 3.8 ± 0.79 , p < 0.01 ) . In addition , expressions of IKKβ ( 0.95 ± 0.21 vs. 1.74 ± 0.17 , p < 0.05 ) and NGAL ( 1.71 ± 0.032 vs. 2.66 ± 0.078 , p < 0.05 ) at renal tubule in pre-treated rats were attenuated significantly compared with rats subjected to ischemia-reperfusion injury . Moreover , our study showed that IKKβ and NGAL were in positive correlation ( R = 0.965 > R0.01(30 ) = 0.448 , p < 0.01 ) . Conclusions : The evidence suggests that IKKβ may play a role in renal I/R injury and give rise to the generation of NGAL . It appears that IPC may attenuate renal injury and the expression of NGAL following acute I/R injury . IKKβ may offer a clinical ly accessible target for preventing renal injury following OBJECTIVE The objective of this study was to evaluate whether remote ischemic preconditioning can protect kidney function in children undergoing operation for complex congenital heart disease . METHODS Children ( n = 113 ) aged 0 to 15 years admitted for complex congenital heart disease were r and omly allocated according to age to remote ischemic preconditioning and control groups . After exclusion of 8 patients , we conducted the analysis on 105 patients ( remote ischemic preconditioning group , n = 54 ; control group , n = 51 ) . Before surgery , remote ischemic preconditioning was performed as 4 cycles of 5 minutes of ischemia by inflating a cuff around a leg to 40 mm Hg above the systolic pressure . End points were development of acute kidney injury , initiation of dialysis , plasma creatinine , estimated glomerular filtration rate , plasma cystatin C , plasma and urinary neutrophil gelatinase-associated lipocalin , and urinary output . Secondary end points included postoperative blood pressure , inotropic score , and mortality , as well as morbidity reflected by reoperation and stays in the intensive care unit and hospital . RESULTS Overall , 57 of the children ( 54 % ) had acute kidney injury develop , with 27 ( 50 % ) in the remote ischemic preconditioning group and 30 ( 59 % ) in the control group ( P > .2 ) . Remote ischemic preconditioning was not associated with improvement in either any of the renal biomarkers or any of the secondary end points . CONCLUSIONS We found no evidence that remote ischemic preconditioning provided protection of kidney function in children undergoing operation for complex congenital heart disease Up to 1/3 of percutaneous coronary interventions ( PCIs ) are complicated by troponin release . Remote ischemic preconditioning ( IPC ) confers effective cardioprotection ; however , a 30-minute remote IPC protocol may be difficult to implement during ad hoc PCI . This study was performed to assess the ability of a brief remote IPC protocol to attenuate cardiac troponin I ( cTnI ) release after ad hoc PCI . Ninety-four patients undergoing ad hoc PCI for stable coronary artery disease , with undetectable preprocedural cTnI , were recruited and r and omized to receive remote IPC ( induced by one 5-minute inflation of a blood pressure cuff to 200 mm Hg around the upper arm ) or control after the decision for PCI was made . The primary outcome was the difference between cTnI levels 24 hours after PCI and cTnI levels before coronary angiography ( ΔcTnI ) . ΔcTnI in the remote IPC group was significantly lower compared with the control group ( 0.04 ng/ml [ interquartile range 0.01 to 0.14 ] vs 0.19 ng/ml [ interquartile range 0.18 to 0.59 ] , p < 0.001 ) . The incidence of PCI-related myocardial infa rct ion ( MI ) was greater in the control group ( 42.6 % vs 19.1 % , p = 0.014 ) . In multivariate analysis , remote IPC was independently associated with ΔcTnI and PCI-related MI . In conclusion , our results suggest that even 1 cycle of remote IPC immediately before ad hoc PCI attenuates periprocedural cTnI release and reduces the incidence of type 4a MI BACKGROUND Remote ischaemic preconditioning has been associated with reduced risk of myocardial injury after coronary artery bypass graft ( CABG ) surgery . We investigated the safety and efficacy of this procedure . METHODS Eligible patients were those scheduled to undergo elective isolated first-time CABG surgery under cold crystalloid cardioplegia and cardiopulmonary bypass at the West-German Heart Centre , Essen , Germany , between April , 2008 , and October , 2012 . Patients were prospect ively r and omised to receive remote ischaemic preconditioning ( three cycles of 5 min ischaemia and 5 min reperfusion in the left upper arm after induction of anaesthesia ) or no ischaemic preconditioning ( control ) . The primary endpoint was myocardial injury , as reflected by the geometric mean area under the curve ( AUC ) for perioperative concentrations of cardiac troponin I ( cTnI ) in serum in the first 72 h after CABG . Mortality was the main safety endpoint . Analysis was done in intention-to-treat and per- protocol population s. This trial is registered with Clinical Trials.gov , number NCT01406678 . FINDINGS 329 patients were enrolled . Baseline characteristics and perioperative data did not differ between groups . cTnI AUC was 266 ng/mL over 72 h ( 95 % CI 237 - 298 ) in the remote ischaemic preconditioning group and 321 ng/mL ( 287 - 360 ) in the control group . In the intention-to-treat population , the ratio of remote ischaemic preconditioning to control for cTnI AUC was 0·83 ( 95 % CI 0·70 - 0·97 , p=0·022 ) . cTnI release remained lower in the per- protocol analysis ( 0·79 , 0·66 - 0·94 , p=0·001 ) . All-cause mortality was assessed over 1·54 ( SD 1·22 ) years and was lower with remote ischaemic preconditioning than without ( ratio 0·27 , 95 % CI 0·08 - 0·98 , p=0·046 ) . INTERPRETATION Remote ischaemic preconditioning provided perioperative myocardial protection and improved the prognosis of patients undergoing elective CABG surgery . FUNDING German Research Foundation Opinion statementRenal artery stenosis ( RAS ) can accelerate or generate progressive hypertension and renal dysfunction . The goals for treating patients with RAS are to reduce cardiovascu-lar morbidity and mortality attributable to elevated arterial pressure and to preserve renal function beyond critical stenosis . Recent , r and omized trials with current anti-hypertensive agents indicate that many patients with RAS can be managed for years without renal artery revascularization . As it does elsewhere , atherosclerotic disease can progress to more severe occlusion in the renal arteries . Rapid advances in endo-vascular techniques , including stenting , make restoration of renal blood flow possible in more patients than before . Therapeutic goals are achieved by 1 ) avoidance of tobacco , 2 ) reducing arterial pressure with antihypertensive drug therapy , particularly those agents capable of blocking the renin-angiotensin system , and 3 ) renal revascu-larization , using balloon angioplasty and stent placement , surgical bypass , or endart-erectomy . The major clinical challenges are to identify progressive occlusive disease and to determine appropriate timing for vascular intervention Background Reperfusion is m and atory after ischaemia , but it also triggers ischaemia – reperfusion (IR)-injury . It is currently unknown whether heart failure alters the magnitude of IR-injury . Ischaemic preconditioning can limit IR-injury . Since ischaemic preconditioning is typically applied in subjects at risk for cardiovascular complications , it is of clinical importance to underst and its efficacy in heart failure patients . Objective To examine the magnitude of endothelial IR-injury , and the ability of ischaemic preconditioning to protect against endothelial IR-injury in heart failure . Methods We included 15 subjects with heart failure ( 67 ± 10 years , New York Heart Association class II/III ) and 15 healthy , age- and sex-matched controls ( 65 ± 9 years ) . We examined brachial artery endothelial function using flow-mediated dilation before and after arm IR ( induced by 5-min ischaemic h and grip exercise + 15 min reperfusion ) . IR was preceded by ischaemic preconditioning ( consisting in three cycles of 5-min upper arm cuff inflation to 220 mmHg ) or no inflation . Results A significant interaction-effect was found for the change in flow-mediated dilation after IR between groups ( two-way ANOVA interaction-effect : p = 0.01 ) . Whilst post-hoc analysis revealed a significantly decline in flow-mediated dilation in both groups ( p < 0.05 ) , the decline in flow-mediated dilation in heart failure patients ( 6.2 ± 3.6 % to 3.3 ± 1.8 % ) was significantly larger than that observed in controls ( 4.9 ± 2.1 to 4.1 ± 2.0 ) . Neither in heart failure patients nor controls was the decrease in flow-mediated dilation after IR altered by ischaemic preconditioning ( three-way ANOVA interaction : p = 0.87 ) . Conclusion We found that patients with heart failure are associated with exaggerated endothelial IR-injury compared with age- and sex-matched , healthy controls , which may contribute to the poor clinical prognosis in heart failure . Furthermore , we found no protective effect of ischaemic preconditioning ( 3 × 5-min forearm ischaemia ) against endothelial IR-injury in heart failure patients Background —Remote ischemic preconditioning may result in reduction in infa rct size during percutaneous coronary intervention ( PCI ) . It is unclear whether remote ischemic postconditioning ( RIPost ) will reduce the incidence of myocardial injury after PCI , and whether ischemic conditioning of a larger remote organ ( thigh versus arm ) would provide further myocardial protection . Methods and Results —We r and omized 360 patients presenting with stable or unstable angina ( 28 % of patients ) and negative Troponin T at baseline to 3 groups : 2 groups received RIPost ( induced by ischemia to upper or lower limb ) , and a third was the control group . RIPost was applied during PCI immediately after stent deployment , by three 5-minute cycles of blood pressure cuff inflation to > 200 mm Hg in the arm or thigh ( 20 mm Hg in the control ) with 5-minute breaks between each cycle . The primary end-point was the proportion of patients with Troponin T levels > 3 × ULN postprocedure ( at 6 or 18–24 hours ) , where ULN st and s for upper limit of normal . A total of 120 patients were r and omized to each group . There were no differences in baseline characteristics between the 3 groups . The primary outcome occurred in 30 % , 35 % , and 35 % of the arm , thigh , and control groups , respectively ( P=0.64 ) . There were no differences in creatine kinase or high sensitivity C-reactive protein levels after PCI or in the incidence of acute kidney injury between the groups . Conclusions —RIPost during PCI did not reduce the incidence of periprocedural myocardial injury . Similar effect was obtained when remote ischemia was induced to the upper or lower limb . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00970827 PURPOSE OF THE STUDY To evaluate the effects of remote ischemic preconditioning ( RIPC ) on the perioperative period in elective aortic valve replacement ( AVR ) along different anaesthesia techniques . MATERIAL S AND METHODS 48 patients aged 50 to 75 years ( 64 ( 56;69 ) ) which were scheduled for AVR due to aortic valve stenosis were included into the prospect i ve , r and omized study . Four groups were formed after r and omization : 1 ) RIPC applied during propofol anesthesia ( RIPCprop , n = 12 ) , 2 ) RIPC applied during sevoflurane anesthesia ( RIPCsevo , n = 12 ) , 3 ) propofol anesthesia without RIPC ( CONTROLprop , n = 12 ) , 4 ) sevoflurane anesthesia without RIPC ( CONTROLsevo , n = 12 ) . Groups were similar in baseline data of patients . RIPC protocol : three five-minutes episodes of simultaneous both lower limbs ischemia with five-minutes reperfusion intervals . Troponin I ( cTrI ) , interleukin-6 ( IL-6 ) , Interleukin-8 ( IL-8 ) and C-reactive protein ( CRP ) levels were assessed prior to induction of anesthesia , at 30 min , 6 , 12 , 24 and 48 hours after the cessation of CPB . Significant differences were assessed by the nonparametric Mann-Whitney and Fisher 's exact tests . Data are presented as : median ( 25th percentile , 75th percentile ) . RESULTS . Significant differences in cTnI were found between RIPCsevo and CONTROLsevo groups at 6 , 12 and 24 hours : 1.68 ( 1.28 , 2.09 ) ng/ml vs 3.66 ( 2.07 , 4.49 ) ng/ml , respectively at 6 hours ( p = 0.04 ) ; 1.89 ( 1.59 , 2.36 ) ng/ml vs 3.66 ( 2.91 , 5.64 ) ng/ml , respectively at 12 hours ( p = 0.001 ) ; 1.68 ( 1.55 ; 2.23 ) ng/ml vs 3.32 ( 2.10 ; 5.46 ) ng/ml , respectively at 24 hours ( p = 0.01 ) . There were no differences found in cTnI between RIPCprop and CONTROLprop groups during the whole study . There were no significant differences found in the levels of IL-6 and CRP between RIPC and control groups during the whole study Unexpectedly significant excess concentrations of IL-8 at 24 h were found when RIPC applied during sevoflurane anesthesia : 12.3 ( 10.6 , 14.4 ) pg/mL in RIPCsevo group vs 6.2 ( 4.8 , 11.1 ) pg/ml in CONTROLsevo group ( p = 0.02 ) . There was no paroxysmal atrial fibrillation ( AF ) after RIPC , and 5 cases were registered in the control groups ( p = 0.02 ) . No other significant differences in the clinical course of the postoperative period were found . CONCLUSIONS Cardioprotective effect of RIPC and its effect on systemic inflammatory response should be assessed in the selected anesthesia groups . RIPC on the background of sevoflurane anesthesia reduces myocardial injury during AVR . RIPC does not reduce the severity of the systemic inflammatory response after AVR . RIPC reduces the risk of AF after AVR BACKGROUND Whether remote ischaemic preconditioning , an intervention in which brief ischaemia of one tissue or organ protects remote organs from a sustained episode of ischaemia , is beneficial for patients undergoing coronary artery bypass graft surgery is unknown . We did a single-blinded r and omised controlled study to establish whether remote ischaemic preconditioning reduces myocardial injury in these patients . METHODS 57 adult patients undergoing elective coronary artery bypass graft surgery were r and omly assigned to either a remote ischaemic preconditioning group ( n=27 ) or to a control group ( n=30 ) after induction of anaesthesia . Remote ischaemic preconditioning consisted of three 5-min cycles of right upper limb ischaemia , induced by an automated cuff-inflator placed on the upper arm and inflated to 200 mm Hg , with an intervening 5 min of reperfusion during which the cuff was deflated . Serum troponin-T concentration was measured before surgery and at 6 , 12 , 24 , 48 , and 72 h after surgery . Analysis was by intention to treat . This trial is registered with Clinical Trials.gov , number NCT00397163 . FINDINGS Remote ischaemic preconditioning significantly reduced overall serum troponin-T release at 6 , 12 , 24 , and 48 h after surgery . The total area under the curve was reduced by 43 % , from 36.12 microg/L ( SD 26.08 ) in the control group to 20.58 microg/L ( 9.58 ) in the remote ischaemic preconditioning group ( mean difference 15.55 [ SD 5.32 ] ; 95 % CI 4.88 - 26.21 ; p=0.005 ) . INTERPRETATION We have shown that adult patients undergoing elective coronary artery bypass graft surgery at a single tertiary centre could benefit from remote ischaemic preconditioning , using transient upper limb ischaemia OBJECTIVE Cardiopulmonary bypass is associated with ischemia-reperfusion injury to multiple organs . We aim ed to evaluate whether remote ischemic preconditioning performed the day before surgery for congenital heart disease with cardiopulmonary bypass attenuates the postoperative inflammatory response and myocardial dysfunction . METHODS This was a prospect i ve , r and omized , single-blind , controlled trial . Children allocated to remote ischemic preconditioning underwent 4 periods of 5 minutes of lower limb ischemia by a blood pressure cuff intercalated with 5 minutes of reperfusion . Blood sample s were collected 4 , 12 , 24 , and 48 hours after cardiopulmonary bypass to evaluate nuclear factor kappa B activation in leukocytes by quantification of mRNA of I kappa B alpha by real-time quantitative polymerase chain reaction and for interleukin-8 and 10 plasma concentration measurements by enzyme-linked immunosorbent assay . Myocardial dysfunction was assessed by N-terminal pro-B-type natriuretic peptide and cardiac troponin I plasma concentrations , measured by chemiluminescence , and clinical parameters of low cardiac output syndrome . RESULTS Twelve children were allocated to remote ischemic preconditioning , and 10 children were allocated to the control group . Demographic data and Risk Adjustment for Congenital Heart Surgery 1 classification were comparable in both groups . Remote ischemic preconditioning group had lower postoperative values of N-terminal pro-B-type natriuretic peptide , but cardiac troponin I levels were not significantly different between groups . Interleukin-8 and 10 concentrations and I kappa B alpha gene expression were similar in both groups . Postoperative morbidity was similar in both groups ; there were no postoperative deaths in either group . CONCLUSIONS Late remote ischemic preconditioning did not provide clinical ly relevant cardioprotection to children undergoing cardiopulmonary bypass OBJECTIVE Remote ischemic preconditioning protects the myocardium from ischemia/reperfusion injury . We recently identified protection by remote ischemic preconditioning to be associated with the activation of signal transducer and activator of transcription 5 in left ventricular biopsy specimens of patients undergoing coronary artery bypass grafting during isoflurane anesthesia . Because remote ischemic preconditioning did not protect the heart during propofol anesthesia , we hypothesized that propofol anesthesia interferes with signal transducer and activator of transcription 5 activation . METHODS In a r and omized , single-blind , placebo-controlled , prospect i ve study , we analyzed an array of established cardioprotective proteins during propofol anesthesia with or without remote ischemic preconditioning in 24 nondiabetic patients with 3-vessel coronary artery disease . RESULTS Remote ischemic preconditioning ( n = 12 ) compared with no remote ischemic preconditioning ( n = 12 ) failed to decrease the area under the troponin I time curve ( 273 ± 184 ng/mL × 72 hours vs 365 ± 301 ng/mL × 72 hours ; P = .374 ) . Although phosphorylation of several protein kinases was increased from baseline to reperfusion , signal transducer and activator of transcription 5 phosphorylation was not increased and was not different between the remote ischemic preconditioning and no remote ischemic preconditioning groups . CONCLUSIONS Remote ischemic preconditioning during propofol anesthesia did not evoke either signal transducer and activator of transcription 5 activation or cardioprotection , implying interaction of propofol with cardioprotective signaling upstream of signal transducer and activator of transcription 5 IMPORTANCE No interventions have yet been identified to reduce the risk of acute kidney injury in the setting of cardiac surgery . OBJECTIVE To determine whether remote ischemic preconditioning reduces the rate and severity of acute kidney injury in patients undergoing cardiac surgery . DESIGN , SETTING , AND PARTICIPANTS In this multicenter trial , we enrolled 240 patients at high risk for acute kidney injury , as identified by a Clevel and Clinic Foundation score of 6 or higher , between August 2013 and June 2014 at 4 hospitals in Germany . We r and omized them to receive remote ischemic preconditioning or sham remote ischemic preconditioning ( control ) . All patients completed follow-up 30 days after surgery and were analyzed according to the intention-to-treat principle . INTERVENTIONS Patients received either remote ischemic preconditioning ( 3 cycles of 5-minute ischemia and 5-minute reperfusion in one upper arm after induction of anesthesia ) or sham remote ischemic preconditioning ( control ) , both via blood pressure cuff inflation . MAIN OUTCOMES AND MEASURES The primary end point was the rate of acute kidney injury defined by Kidney Disease : Improving Global Outcomes criteria within the first 72 hours after cardiac surgery . Secondary end points included use of renal replacement therapy , duration of intensive care unit stay , occurrence of myocardial infa rct ion and stroke , in-hospital and 30-day mortality , and change in acute kidney injury biomarkers . RESULTS Acute kidney injury was significantly reduced with remote ischemic preconditioning ( 45 of 120 patients [ 37.5 % ] ) compared with control ( 63 of 120 patients [ 52.5 % ] ; absolute risk reduction , 15 % ; 95 % CI , 2.56%-27.44 % ; P = .02 ) . Fewer patients receiving remote ischemic preconditioning received renal replacement therapy ( 7 [ 5.8 % ] vs 19 [ 15.8 % ] ; absolute risk reduction , 10 % ; 95 % CI , 2.25%-17.75 % ; P = .01 ) , and remote ischemic preconditioning reduced intensive care unit stay ( 3 days [ interquartile range , 2 - 5 ] ) vs 4 days ( interquartile range , 2 - 7 ) ( P = .04 ) . There was no significant effect of remote ischemic preconditioning on myocardial infa rct ion , stroke , or mortality . Remote ischemic preconditioning significantly attenuated the release of urinary insulinlike growth factor-binding protein 7 and tissue inhibitor of metalloproteinases 2 after surgery ( remote ischemic preconditioning , 0.36 vs control , 0.97 ng/mL2/1000 ; difference , 0.61 ; 95 % CI , 0.27 - 0.86 ; P < .001 ) . No adverse events were reported with remote ischemic preconditioning . CONCLUSIONS AND RELEVANCE Among high-risk patients undergoing cardiac surgery , remote ischemic preconditioning compared with no ischemic preconditioning significantly reduced the rate of acute kidney injury and use of renal replacement therapy . The observed reduction in the rate of acute kidney injury and the need for renal replacement warrants further investigation . TRIAL REGISTRATION German Clinical Trials Register Identifier : DRKS00005333 Remote ischaemic preconditioning ( RIPC ) gained attention as a possibility to reduce myocardial injury after a subsequent sustained episode of myocardial ischaemia . This prospect i ve r and omized study was carried out to assess whether RIPC reduces myocardial injury in coronary artery bypass grafting patients . Eighty patients were assigned to remote preconditioning or control treatment . Ischaemic preconditioning was induced by three 5-min cycles of upper limb ischaemia and reperfusion after anaesthesia induction . Haemodynamic and markers of myocardial damage were analysed preoperatively and over 48 h postoperatively . The cardiac index was higher immediately after remote preconditioning in the main group . There were no differences in other haemodynamic , troponin I and creatine kinase-MB concentrations at any time point between groups . Thus , short-term remote preconditioning improves haemodynamics and does not reduce myocardial injury after coronary artery bypass surgery . Further study of high-risk patients may be needed to fully evaluate the clinical effect of RIPC OBJECTIVE Acute kidney injury after cardiac surgery with cardiopulmonary bypass is closely related to systemic inflammatory reactions and oxidative stresses . Remote ischemic preconditioning is a systemic protective strategy whereby brief limb ischemia confers systemic protection against prolonged ischemia and inflammatory reactions in distant organs . This study investigated whether remote ischemic preconditioning provides systemic protective effect on kidneys that are not directly exposed to ischemia-reperfusion injury during complex valvular heart surgery . METHODS Seventy-six adult patients undergoing complex valvular heart surgery were r and omly assigned to either remote ischemic preconditioning group ( n = 38 ) or control group ( n = 38 ) . Remote ischemic preconditioning consisted of 3 10-minute cycles of lower limb ischemia and reperfusion with an automated cuff inflator . Primary end points were comparisons of biomarkers of renal injury including serum creatinine , cystatin C and neutrophil gelatinase-associated lipocalin , and incidence of acute kidney injury . Secondary end points were comparisons of myocardial enzyme release and pulmonary parameters . RESULTS There were no significant differences in serum levels of biomarkers of renal injury between groups throughout the study period . The incidence of acute kidney injury did not differ between groups . Creatine kinase isoenzyme MB at 24 hours after surgery was lower , and intensive care unit stay was shorter in the remote ischemic preconditioning group than in the control group . CONCLUSIONS In patients undergoing complex valvular heart surgery , remote ischemic preconditioning did not reduce degree of renal injury or incidence of acute kidney injury whereas it did reduce myocardial injury and intensive care unit stay Background — Contrast medium – induced acute kidney injury is associated with substantial morbidity and mortality . The underlying mechanism has been attributed in part to ischemic kidney injury . The aim of this r and omized , double-blind , sham-controlled trial was to assess the impact of remote ischemic preconditioning on contrast medium – induced acute kidney injury . Methods and Results — Patients with impaired renal function ( serum creatinine > 1.4 mg/dL or estimated glomerular filtration rate < 60 mL · min−1 · 1.73 m−2 ) undergoing elective coronary angiography were r and omized in a 1:1 ratio to st and ard care with ( n=50 ) or without ischemic preconditioning ( n=50 ; intermittent arm ischemia through 4 cycles of 5-minute inflation and 5-minute deflation of a blood pressure cuff ) . Overall , both study groups were at high risk of developing contrast medium – induced acute kidney injury according to the Mehran risk score . The primary end point was the incidence of contrast medium – induced kidney injury , defined as an increase in serum creatinine ≥25 % or ≥0.5 mg/dL above baseline at 48 hours after contrast medium exposure . Contrast medium – induced acute kidney injury occurred in 26 patients ( 26 % ) , 20 ( 40 % ) in the control group and 6 ( 12 % ) in the remote ischemic preconditioning group ( odds ratio , 0.21 ; 95 % confidence interval , 0.07–0.57 ; P=0.002 ) . No major adverse events were related to remote ischemic preconditioning . Conclusions — Remote ischemic preconditioning before contrast medium use prevents contrast medium – induced acute kidney injury in high-risk patients . Our findings merit a larger trial to establish the effect of remote ischemic preconditioning on clinical outcomes . Clinical Trial Registration — URL : http://www.germanctr.de . Unique identifier : U1111 - 1118 - 8098 BACKGROUND Remote ischemic preconditioning by transient limb ischemia reduces myocardial ischemia-reperfusion injury in patients undergoing percutaneous coronary intervention . The aim of the study we report here was to assess the effect of remote ischemic preconditioning on endothelial function in patients with acute myocardial infa rct ion who underwent primary percutaneous coronary intervention . METHODS Forty-eight patients with acute myocardial infa rct ion were enrolled . All participants were r and omly divided into 2 groups . In Group I ( n = 23 ) , remote ischemic preconditioning was performed before primary percutaneous coronary intervention ( intermittent arm ischemia-reperfusion through 4 cycles of 5-minute inflation and 5-minute deflation of a blood-pressure cuff to 200 mm Hg ) . In Group II ( n = 25 ) , st and ard percutaneous coronary intervention without preconditioning was performed . We assessed endothelial function using the flow-mediated dilation test on baseline , then within 1 - 3 hours after percutaneous coronary intervention , and again on days 2 and 7 after percutaneous coronary intervention . RESULTS The brachial artery flow-mediated dilation results were significantly higher on the first day after primary percutaneous coronary intervention in the preconditioning group ( Group I ) than in the control group ( Group II ) ( 12.1 % vs 0.0 % , P = .03 , and 11.1 % vs 6.3 % , P = .016 , respectively ) , and this difference remained on the seventh day ( 12.3 % vs 7.4 % , P = .0005 , respectively ) . CONCLUSION We demonstrated for the first time that remote ischemic preconditioning before primary percutaneous coronary intervention significantly improves endothelial function in patients with acute myocardial infa rct ion , and this effect remains constant for at least a week . We suppose that the improvement of endothelial function may be one of the possible explanations of the effect of remote ischemic preconditioning Purpose : To report a r and omized clinical trial design ed to determine if remote ischemic preconditioning ( IP ) has the ability to reduce renal and cardiac damage following endovascular aneurysm repair ( EVAR ) . Methods : Forty patients ( all men ; mean age 76±7 years ) with abdominal aortic aneurysms averaging 6.3±0.8 cm in diameter were enrolled in the trial from November 2006 to January 2008 . Eighteen patients ( mean age 74 years , range 72–81 ) were r and omized to preconditioning and completed the full remote IP protocol ; there were no withdrawals . Twenty-two patients ( mean age 76 years , range 66–80 ) were assigned to the control group . Remote IP was induced using sequential lower limb ischemia . Serum and urinary markers of renal and cardiac injury were compared between the groups . Results : Urinary retinol binding protein ( RBP ) levels increased 10-fold from a median of 235 µmol/L to 2356 µmol/L at 24 hours ( p=0.0001 ) . There was a lower increase in the preconditioned group , from 167 µmol/L to 413 µmol/L at 24 hours ( p=0.04 ) . The median urinary albumin : creatinine ratio was significantly lower in the preconditioned group at 24 hours ( 5 versus 8.8 , p=0.06 ) . There were no differences in the rates of renal impairment or major adverse cardiac events . Conclusion : Remote preconditioning reduces urinary biomarkers of renal injury in patients undergoing elective EVAR . This small pilot trial was unable to detect an effect on clinical endpoints ; further trials are warranted |
13,682 | 32,216,835 | Discussion Immunomodulation seems to be a promising strategy in solid tumors .
PD-1 and PD-L1 are key physiologic suppressors of the cytotoxic immune reaction . | Background Breast cancer is one of the most common malignancies in women worldwide , and one of the leading causes of cancer-related death .
Programmed cell death 1 ( PD-1 ) and its lig and ( PD-L1 ) are key physiologic suppressors of the cytotoxic immune reaction .
Some authors advocate that PD-L1 expression may help in breast cancer prognosis .
Breast cancer is the most common malignancies in women worldwide , and one of the leading causes of cancer death . | Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items BACKGROUND Blockade of programmed death 1 ( PD-1 ) , an inhibitory receptor expressed by T cells , can overcome immune resistance . We assessed the antitumor activity and safety of BMS-936558 , an antibody that specifically blocks PD-1 . METHODS We enrolled patients with advanced melanoma , non-small-cell lung cancer , castration-resistant prostate cancer , or renal-cell or colorectal cancer to receive anti-PD-1 antibody at a dose of 0.1 to 10.0 mg per kilogram of body weight every 2 weeks . Response was assessed after each 8-week treatment cycle . Patients received up to 12 cycles until disease progression or a complete response occurred . RESULTS A total of 296 patients received treatment through February 24 , 2012 . Grade 3 or 4 drug-related adverse events occurred in 14 % of patients ; there were three deaths from pulmonary toxicity . No maximum tolerated dose was defined . Adverse events consistent with immune-related causes were observed . Among 236 patients in whom response could be evaluated , objective responses ( complete or partial responses ) were observed in those with non-small-cell lung cancer , melanoma , or renal-cell cancer . Cumulative response rates ( all doses ) were 18 % among patients with non-small-cell lung cancer ( 14 of 76 patients ) , 28 % among patients with melanoma ( 26 of 94 patients ) , and 27 % among patients with renal-cell cancer ( 9 of 33 patients ) . Responses were durable ; 20 of 31 responses lasted 1 year or more in patients with 1 year or more of follow-up . To assess the role of intratumoral PD-1 lig and ( PD-L1 ) expression in the modulation of the PD-1-PD-L1 pathway , immunohistochemical analysis was performed on pretreatment tumor specimens obtained from 42 patients . Of 17 patients with PD-L1-negative tumors , none had an objective response ; 9 of 25 patients ( 36 % ) with PD-L1-positive tumors had an objective response ( P=0.006 ) . CONCLUSIONS Anti-PD-1 antibody produced objective responses in approximately one in four to one in five patients with non-small-cell lung cancer , melanoma , or renal-cell cancer ; the adverse-event profile does not appear to preclude its use . Preliminary data suggest a relationship between PD-L1 expression on tumor cells and objective response . ( Funded by Bristol-Myers Squibb and others ; Clinical Trials.gov number , NCT00730639 . ) BACKGROUND T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival . To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker , we have conducted the largest study of T cells in breast cancer to date . PATIENTS AND METHODS Four studies totalling 12 439 patients were used for this work . Cytotoxic ( CD8 + ) and regulatory ( forkhead box protein 3 , FOXP3 + ) T cells were quantified using immunohistochemistry ( IHC ) . IHC for CD8 was conducted using available material from all four studies ( 8978 sample s ) and for FOXP3 from three studies ( 5239 sample s)-multiple imputation was used to resolve missing data from the remaining patients . Cox regression was used to test for associations with breast cancer-specific survival . RESULTS In ER-negative tumours [ triple-negative breast cancer and human epidermal growth factor receptor 2 ( human epidermal growth factor receptor 2 ( HER2 ) positive ) ] , presence of CD8 + T cells within the tumour was associated with a 28 % [ 95 % confidence interval ( CI ) 16 % to 38 % ] reduction in the hazard of breast cancer-specific mortality , and CD8 + T cells within the stroma with a 21 % ( 95 % CI 7 % to 33 % ) reduction in hazard . In ER-positive HER2-positive tumours , CD8 + T cells within the tumour were associated with a 27 % ( 95 % CI 4 % to 44 % ) reduction in hazard . In ER-negative disease , there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8 + tumours [ hazard ratio ( HR ) = 0.54 ; 95 % CI 0.37 - 0.79 ] versus CD8-negative tumours ( HR = 0.87 ; 95 % CI 0.55 - 1.38 ) . The difference in effect between these subgroups was significant when limited to cases with complete data ( P heterogeneity = 0.04 ) and approached significance in imputed data ( P heterogeneity = 0.1 ) . CONCLUSIONS The presence of CD8 + T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [ supplementary Figure S1 , available at Annals of Oncology online ] and the ER-positive HER2-positive subtypes . Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes . NEAT Clinical Trials.gov : NCT00003577 Breast carcinomas are often infiltrated by inflammatory cells , particularly macrophages and T lymphocytes , but the significance of these cells remains unclear . One possible role of these inflammatory cells is that they represent a cell-mediated immune response against the carcinoma . CD8(+ ) lymphocytes are a known crucial component of cell-mediated immunity . The purpose of this study was to explore the prognostic value of tumor-infiltrating CD8(+ ) cytotoxic lymphocytes in breast cancer . Tumor-infiltrating CD8(+ ) lymphocytes were assessed by immunohistochemical staining of tissue microarray cores from 1,334 unselected breast tumors from patients with long-term follow-up . The number of CD8(+ ) T cells was counted in tumor nests ( intratumoral ) , in stroma adjacent to tumor cells , and in stroma distant to tumor cells , and their relationship with clinical outcome was determined . The total number of CD8(+ ) cells was positively correlated with tumor grade ( r(s ) = 0.20 ; P < .001 ) and inversely correlated with patient 's age at diagnosis , estrogen receptor-alpha ( ER-α ) , and progesterone receptor ( PgR ) expression ( Mann-Whitney U test , P < .001 ) . The total patient cohort was r and omly divided into two separate training and validation sets before performing univariate survival analysis . Total number and distant stromal CD8(+ ) lymphocytes were associated with better patient survival ( P = .041 and P < .001 , respectively ) in the training set . In multivariate analysis , total CD8(+ ) T-cell count was an independent prognostic factor in both training and validation sets . These results suggest that tumor-infiltrating CD8(+ ) T lymphocytes have antitumor activity as judged by their favorable effect on patients ' survival and could potentially be exploited in the treatment of breast cancer Background Testicular cancer is primarily treated with the surgical removal of the affected testis . About 50 % of testicular cancer patients present with a stage I seminoma . If no chemo- or radiotherapy as adjuvant treatment is initiated after orchiectomy , 15–20 % of these patients will develop metastases . Although adjuvant treatment is effective in reducing the relapse risk , there is rising concern about overtreatment of these patients . Prognostic factors at primary diagnosis might have the potential to identify patients at higher risk of tumor relapse , allowing to guide individual therapy and to avoid overtreatment . Therefore , we aim to synthesize the available evidence on tumor or patient characteristics as possible prognostic factors for cancer recurrence in patients with clinical stage I seminoma . Methods / design We will conduct a broad systematic review to analyze what prognostic factors predict cancer recurrence in patients with a first time diagnosis of clinical stage I seminoma , who received no adjuvant chemo- or radiotherapy after orchiectomy . The literature search will comprise MEDLINE , Web of Science , the Cochrane Central Register of Controlled Trials ( CENTRAL ) , and the conference proceedings of the American Society of Clinical Oncology ( ASCO ) , American Urologic Association ( AUA ) , and European Urologic Association ( EAU ) Annual Meetings . Prospect i ve and retrospective longitudinal studies reporting on prognostic factors for cancer recurrence will be considered . We will consider the wealth of any c and i date clinical or pathological prognostic factor reported in the literature . Our outcome of interest will be tumor recurrence at a minimum of 2 years follow-up . Study screening , data extraction , and quality assessment will be done by two review ers independently . Hazard ratios will be used to measure the relationship between the potential prognostic factor and tumor recurrence . Meta-analyses will be conducted with sufficiently homogeneous studies and separately with respect to study design , by using the r and om-effects generic inverse variance model . Discussion Limitations and strengths will be discussed in our review , and the results will be put into context with other studies in this field . Our results will help to guide evidence -based decision-making on patients with clinical stage I seminoma , allowing a better adjustment of therapies with regard to the individual patient ’s risk . Our findings will furthermore help to formulate recommendations for future research . Systematic review registration PROSPERO BACKGROUND We have previously shown the prognostic importance of tumor-infiltrating lymphocytes ( TILs ) in newly diagnosed triple-negative breast cancer ( TNBC ) using tumor sample s from a large clinical trial cohort . In this study , we aim ed to vali date these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease ( HER2 + ) . PATIENTS AND METHODS A prospect ive-retrospective study was conducted using sample s from the FinHER adjuvant , phase III trial that enrolled 1010 early-stage BC patients , 778 of whom were HER2-nonamplified . Those with HER2 + disease ( n = 232 ) were r and omized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy . Two pathologists independently quantified stromal TILs in 935 ( 92.6 % ) available slides . The primary end point of distant disease-free survival ( DDFS ) and interactions with trastuzumab were studied in Cox regression models . RESULTS Confirming our previous findings , in TNBC ( n = 134 ) each 10 % increase in TILs was significantly associated with decreased distant recurrence in TNBC ; for DDFS the hazard ratio adjusted for clinicopathological factors : 0.77 ; 95 % confidence interval ( CI ) 0.61 - 0.98 , P = 0.02 . In HER2 + BC ( n = 209 ) , each 10 % increase in lymphocytic infiltration was significantly associated with decreased distant recurrence in patients r and omized to the trastuzumab arm ( DDFS P interaction = 0.025 ) . CONCLUSIONS Higher levels of TILs present at diagnosis were significantly associated with decreased distant recurrence rates in primary TNBC . These results confirm our previous data and further support that TILs should be considered as a robust prognostic factor in this BC subtype . We also report for the first time an association between higher levels of TILs and increased trastuzumab benefit in HER2 + disease . Further research into why some TN and HER2 + BCs can or can not generate a host antitumor immune response and how trastuzumab can favorably alter the immune microenvironment is warranted Analysis of prospect i ve follow-up data usually includes a Cox regression model . When a hazard rate ratio , obtained as the exponential of an estimated regression coefficient from the Cox model , is greater than 1.0 , it consistently exceeds relative risk , and is exceeded by the odds ratio . The divergence of these distinct epidemiologic measures increases with the product of three factors : ( 1 ) the length of follow-up , ( 2 ) the average rate of the end point occurence over the follow-up period , and ( 3 ) the magnitude of risk , either above or below 1 . Cornfield 's rare disease assumption is basically the product of the first two of these factors . However , risks in excess of 2.5 have a powerful effect on the divergence of these measures , and this point has received less emphasis . Conversely , and as seen frequently in applications , relative risk , hazard rate ratio , and odds ratio numerically approximate one another with shorter follow-up , rarer end points , and risks closer to 1 . Although the hazard rate ratio is not always distinguished from relative risk , it is commonly close to , and is always between , relative risk and the odds ratio . Consistent and accurate terminology would have us use hazard rate ratio with Cox regression and odds ratio with logistic regression . The term " relative risk " seems to be a default choice , regardless of the model being used . However , when relative risk is the object of the model chosen , as in a Poisson regression approximation of two binomial proportions or an equivalent weighted least squares , then for us , relative risk is the accurate terminology PURPOSE St and ardized definitions of breast cancer clinical trial end points must be adopted to permit the consistent interpretation and analysis of breast cancer clinical trials and to facilitate cross-trial comparisons and meta-analyses . St and ardizing terms will allow for uniformity in data collection across studies , which will optimize clinical trial utility and efficiency . A given end point term ( eg , overall survival ) used in a breast cancer trial should always encompass the same set of events ( eg , death attributable to breast cancer , death attributable to cause other than breast cancer , death from unknown cause ) , and , in turn , each event within that end point should be commonly defined across end points and studies . METHODS A panel of experts in breast cancer clinical trials representing medical oncology , biostatistics , and correlative science convened to formulate st and ard definitions and address the confusion that nonst and ard definitions of widely used end point terms for a breast cancer clinical trial can generate . We propose st and ard definitions for efficacy end points and events in early-stage adjuvant breast cancer clinical trials . In some cases , it is expected that the st and ard end points may not address a specific trial question , so that modified or customized end points would need to be prospect ively defined and consistently used . CONCLUSION The use of the proposed common end point definitions will facilitate interpretation of trial outcomes . This approach may be adopted to develop st and ard outcome definitions for use in trials involving other cancer sites PURPOSE Previous pre clinical and clinical data suggest that the immune system influences prognosis and response to chemotherapy ( CT ) ; however , clinical relevance has yet to be established in breast cancer ( BC ) . We hypothesized that increased lymphocytic infiltration would be associated with good prognosis and benefit from immunogenic CT-in this case , anthracycline-only CT-in selected BC subtypes . PATIENTS AND METHODS We investigated the relationship between quantity and location of lymphocytic infiltrate at diagnosis with clinical outcome in 2009 node-positive BC sample s from the BIG 02 - 98 adjuvant phase III trial comparing anthracycline-only CT ( doxorubicin followed by cyclophosphamide , methotrexate , and fluorouracil [ CMF ] or doxorubicin plus cyclophosphamide followed by CMF ) versus CT combining doxorubicin and docetaxel ( doxorubicin plus docetaxel followed by CMF or doxorubicin followed by docetaxel followed by CMF ) . Readings were independently performed by two pathologists . Disease-free survival ( DFS ) , overall survival ( OS ) , and interaction with type of CT associations were studied . Median follow-up was 8 years . RESULTS There was no significant prognostic association in the global nor estrogen receptor ( ER ) -positive/human epidermal growth factor receptor 2 ( HER2 ) -negative population . However , each 10 % increase in intratumoral and stromal lymphocytic infiltrations was associated with 17 % and 15 % reduced risk of relapse ( adjusted P = .1 and P = .025 ) , respectively , and 27 % and 17 % reduced risk of death in ER-negative/HER2-negative BC regardless of CT type ( adjusted P = .035 and P = .023 ) , respectively . In HER2-positive BC , there was a significant interaction between increasing stromal lymphocytic infiltration ( 10 % increments ) and benefit with anthracycline-only CT ( DFS , interaction P = .042 ; OS , P = .018 ) . CONCLUSION In node-positive , ER-negative/HER2-negative BC , increasing lymphocytic infiltration was associated with excellent prognosis . Further validation of the clinical utility of tumor-infiltrating lymphocytes in this context is warranted . Our data also support the evaluation of immunotherapeutic approaches in selected BC subtypes |
13,683 | 27,919,918 | Conclusions Foot orthoses were found to be effective for preventing overall injuries and stress fractures but not soft-tissue injuries , while shock-absorbing insoles were not found to be effective for preventing any injury . | Objective To investigate the evidence relating to the effectiveness of foot orthoses and shock-absorbing insoles for the prevention of musculoskeletal injury . | This r and omised feasibility study aim ed to examine the clinical and biomechanical effects of functional foot orthoses ( FFOs ) in the treatment of midfoot osteoarthritis ( OA ) and the feasibility of conducting a full r and omised controlled trial . Participants with painful , radiographically confirmed midfoot OA were recruited and r and omised to receive either FFOs or a sham control orthosis . Feasibility measures included recruitment and attrition rates , practicality of blinding and adherence rates . Clinical outcome measures were : change from baseline to 12 weeks for severity of pain ( numerical rating scale ) , foot function ( Manchester Foot Pain and Disability Index ) and patient global impression of change scale . To investigate the biomechanical effect of foot orthoses , in-shoe foot kinematics and plantar pressures were evaluated at 12 weeks . Of the 119 participants screened , 37 were r and omised and 33 completed the study ( FFO = 18 , sham = 15 ) . Compliance with foot orthoses and blinding of the intervention was achieved in three quarters of the group . Both groups reported improvements in pain , function and global impression of change ; the FFO group reporting greater improvements compared to the sham group . The biomechanical outcomes indicated the FFO group inverted the hindfoot and increased midfoot maximum plantar force compared to the sham group . The present findings suggest FFOs worn over 12 weeks may provide detectable clinical and biomechanical benefits compared to sham orthoses . This feasibility study provides useful clinical , biomechanical and statistical information for the design and implementation of a definitive r and omised controlled trial to evaluate the effectiveness of FFOs in treating painful midfoot OA Background Musculoskeletal injuries during initial military training are a significant medical problem facing military organisations globally . In order to develop an injury management programme , this study aims to quantify the incidence and rehabilitation times for injury specific diagnoses . Methods This was a prospect i ve follow-up study of musculoskeletal injuries in 6608 British Army recruits during a 26-week initial military training programme over a 2-year period . Incidence and rehabilitation times for injury specific diagnoses were recorded and analysed . Results During the study period the overall incidence of musculoskeletal injuries was 48.6 % , and the most common diagnosis was iliotibial b and syndrome ( 6.2 % ) . A significant proportion of the injuries occurred during the first 11 weeks of the programme . The longest rehabilitation times were for stress fractures of the femur , calcaneus and tibia ( 116 ± 17 days , 92 ± 12 days , and 85 ± 11 days , respectively ) . The combination of high incidence and lengthy rehabilitation indicates that medial tibial stress syndrome had the greatest impact on training , accounting for almost 20 % of all days spent in rehabilitation . Conclusion When setting prevention priorities consideration should be given to both the incidence of specific injury diagnoses and their associated time to recovery BACKGROUND Shock-absorbing and biomechanic shoe orthoses are frequently used in the prevention and treatment of back and lower extremity problems . One review concludes that the former is clinical ly effective in relation to prevention , whereas the latter has been tested in only 1 r and omized clinical trial , concluding that stress fractures could be prevented . OBJECTIVES To investigate if biomechanic shoe orthoses can prevent problems in the back and lower extremities and if reducing the number of days off-duty because of back or lower extremity problems is possible . DESIGN Prospect i ve , r and omized , controlled intervention trial . STUDY SUBJECTS One female and 145 male military conscripts ( aged 18 to 24 years ) , representing 25 % of all new conscripts in a Danish regiment . METHOD Health data were collected by question naires at initiation of the study and 3 months later . Custom-made biomechanic shoe orthoses to be worn in military boots were provided to all in the study group during the 3-month intervention period . No intervention was provided for the control group . Differences between the 2 groups were tested with the chi-square test , and statistical significance was accepted at P < .05 . Risk ratio ( RR ) , risk difference ( ARR ) , numbers needed to prevent ( NNP ) , and cost per successfully prevented case were calculated . OUTCOME VARIABLES Outcome variables included self-reported back and /or lower extremity problems ; specific problems in the back or knees or shin splints , Achilles tendonitis , sprained ankle , or other problems in the lower extremity ; number of subjects with at least 1 day off-duty because of back or lower extremity problems and total number of days off-duty within the first 3 months of military service because of back or lower extremity problems . RESULTS Results were significantly better in an actual-use analysis in the intervention group for total number of subjects with back or lower extremity problems ( RR 0.7 , ARR 19 % , NNP 5 , cost 98 US dollars ) ; number of subjects with shin splints ( RR 0.2 , ARR 19 % , NNP 5 , cost 101 US dollars ) ; number of off-duty days because of back or lower extremity problems ( RR 0.6 , ARR < 1 % , NNP 200 , cost 3750 US dollars ) . In an intention-to-treat analysis , a significant difference was found for only number of subjects with shin splints ( RR 0.3 , ARR 18 % , NNP 6 cost 105 US dollars ) , whereas a worst-case analysis revealed no significant differences between the study groups . CONCLUSIONS This study shows that it may be possible to prevent certain musculoskeletal problems in the back or lower extremities among military conscripts by using custom-made biomechanic shoe orthoses . However , because care-seeking for lower extremity problems is rare , using this method of prevention in military conscripts would be too costly . We also noted that the choice of statistical approach determined the outcome Orthotic insoles are suggested to prevent low back pain . This r and omized controlled study assessed if customised orthotic insoles prevent low back pain . Healthy military conscripts ( n = 228 ; mean age 19 years , range 18–29 ) were r and omly assigned to use either customised orthotic insoles ( treatment group , n = 73 ) or nothing ( control group , n = 147 ) . The main outcome measure was low back pain requiring a physician visit and result ing in minimum 1 day suspension from military duty . Twenty-four ( 33 % ) treated subjects and 42 ( 27 % ) control subjects were suspended from duty due to low back pain ( p = 0.37 ; risk difference 4.3 % ; 95 % CI : −8.7 to 17.3 % ) . Mean suspension duration was 2 days ( range 1–7 ) in both groups . Four ( 5 % ) treated subjects and eight ( 5 % ) control subjects were released from duty due to persistent low back pain ( p = 0.92 ; risk difference 0 % ; 95 % CI : −6 to 6 % ) . Use of orthotic insoles is therefore not recommended to prevent physical stress-related low back pain Study Design . R and omized controlled trial . Objectives . To determine if the use of custom shoe orthoses can lessen the incidence of weight bearing-induced back pain . Summary of Background Data . The scientific basis for the use of orthoses to prevent back pain is based principally on studies that show that shoe orthoses can attenuate the shock wave generated at heel strike . The repetitive impulsive loading that occurs because of this shock wave can cause wear of the mechanical structures of the back . Previous r and omized studies showed mixed results in preventing back pain , were not blinded , and used orthoses for only short periods of time . Methods . A total of 404 eligible new infantry recruits without a history of prior back pain were r and omly assigned to received either custom soft , semirigid biomechanical , or simple shoe inserts without supportive or shock absorbing qualities . Recruits were review ed biweekly by an orthopaedist for back signs and symptoms during the course of 14 weeks of basic training Results . The overall incidence of back pain was 14 % . By intention-to treat and per- protocol analyses , there was no statistically significant difference between the incidence of either subjective or objective back pain among the 3 treatment groups . Significantly more recruits who received soft custom orthoses finished training in their assigned orthoses ( 67.5 % ) than those who received semirigid biomechanical orthoses ( 45.5 % ) or simple shoe inserts ( 48.6 % ) , P = 0.001 . Conclusions . The results of this study do not support the use of orthoses , either custom soft or semirigid biomechanical , as prophylactic treatment for weight bearing-induced back pain . Custom soft orthoses had a higher utilization rate than the semirigid biomechanical or simple shoe inserts . The pretraining physical fitness and sports participation of recruits were not related to the incidence of weight bearing-induced back pain Background Foot orthoses are frequently used for the prevention of lower limb overuse injuries but evidence for their effectiveness is limited . The primary aim of this study is to determine if prefabricated foot orthoses reduce the incidence of lower limb overuse injuries in naval recruits undertaking 11 weeks of basic training . Methods This study is a participant and assessor blinded , parallel-group , r and omised controlled trial . The trial will recruit participants undertaking 11 weeks of basic training at the Royal Australian Navy Recruit School , Cerberus , Victoria , Australia . Participants will be r and omised to a control group ( flat insole ) or an intervention group ( prefabricated foot orthosis ) . Over the 11 weeks of basic training , participants will document the presence and location of pain in weekly self-report diaries . The end-point for each participant will be the completion of 11 weeks of basic training . The primary outcome measure will be the combined incidence of four lower limb injuries ( medial tibial stress syndrome , patellofemoral pain , Achilles tendinopathy , and plantar fasciitis/plantar heel pain ) which are common among defence members . Secondary outcome measures include : ( i ) overall incidence of lower limb pain , ( ii ) severity of lower limb pain , ( iii ) time to injury , ( iv ) time to drop-out due to injury , ( v ) adverse events , ( vi ) number of lost training days , ( vii ) shoe comfort , and ( viii ) general health status . Data will be analysed using the intention-to-treat principle . Discussion This r and omised controlled trial will evaluate the effectiveness of prefabricated foot orthoses for the prevention of common lower limb overuse injuries in naval recruits . Trial registration Australian New Zeal and Clinical Trials Registry : ACTRN12615000024549 Background The effectiveness of foot orthoses has been evaluated in many clinical trials with sham foot orthoses used as the control intervention in at least 10 clinical trials . However , the mechanical effects and credibility of sham orthoses has been rarely quantified . This study aim ed to : ( i ) compare the effects on plantar pressures of three sham foot orthoses to a customised foot orthosis , and ( ii ) establish the perceived credibility and the expected benefit of each orthotic condition . Methods Thirty adults aged between 18 and 51 participated in this study . At 0 and 4 weeks , plantar pressure data were collected for the heel , midfoot and forefoot using the pedar ® -X in-shoe system for the following five r and omly assigned conditions : ( i ) shoe alone , ( ii ) customised foot orthosis , ( iii ) contoured polyethylene sham foot orthosis , ( iv ) contoured EVA sham foot orthosis , and ( v ) flat EVA sham foot orthosis . At the initial data collection session , each participant completed a Credibility/Expectancy Question naire ( CEQ ) to determine the credibility and expected benefit of each orthotic condition . Results Compared to the shoe alone at week 0 , the contoured polyethylene sham orthosis was the only condition to not significantly effect peak pressure at any region of the foot . In contrast , the contoured EVA sham orthosis , the flat EVA sham orthosis and the customised orthosis significantly reduced peak pressure at the heel . At the medial midfoot , all sham orthoses provided the same effect as the shoe alone , which corresponded to effects that were significantly different to the customised orthosis . There were no differences in peak pressure between conditions at the other mask regions , the lateral midfoot and forefoot . When the conditions were compared at week 4 , the differences between the conditions were generally similar to the findings observed at week 0 . With respect to credibility and expected benefit , all orthotic conditions were considered the same with the exception of the contoured polyethylene sham orthosis , which was perceived as being less credible and less likely to provide benefits . Conclusion The findings of this study indicate that all of the sham orthoses tested provided the same effect on plantar pressures at the midfoot and forefoot as a shoe alone . However , the contoured EVA sham orthosis and the flat EVA sham orthosis significantly reduced peak pressure under the heel , which was similar to the customised orthosis . In contrast , the contoured polyethylene sham orthosis had no significant effect on plantar pressure and was comparable to the shoe alone at all regions of the foot . Hence , lower plantar pressures were found under the heel with some sham orthoses , but not with others . Importantly , participants perceived the polyethylene sham orthosis – the sham that had no effect on plantar pressure – to be the least credible orthosis and the least likely to provide benefits . This may be critical for the design of future clinical trials as it may introduce confounding effects that produce inaccurate results . These findings provide some evidence for the mechanical effects , treatment credibility and expected benefit of sham foot orthoses , which should be considered when they are used as a control intervention in a clinical trial Soccer referees participating in large soccer tournaments may develop overuse injuries . In this study the effect of shock absorbing heel inserts in the incidence of soreness was investigated . Forty-eight referees were r and omly selected to wear shock absorbing heel inserts ( SAH ) in the 5 day-tournament , while 43 referees were the control group . A daily question naire inquiring about complaints from the locomotive system was completed for each referee and in case of any soreness they were examined by doctors to document and classify the anatomical site . Calf , thigh , back , achilles tendon and knee were the most common localizations of overuse symptoms . The incidence of soreness in achilles tendon , calf and back were significantly reduced by the use of ( SAH ) inserts Lower limb overuse injuries are common among people who are exposed to physical stress . Orthotic shoe insoles are widely used to prevent lower limb overuse injuries . Here , we conducted a r and omized-controlled study to examine whether the use of orthotic insoles prevents lower limb overuse injuries . Participants ( n=228 ) were r and omly assigned to use ( n=73 ) or not to use ( n=147 ) orthotic insoles . The insoles were molded to the shape of the foot to provide support during physical activity . The main outcome measure in the present study was the physician-diagnosed lower limb overuse injury . Thirty-four ( 46.6 % ) subjects in the insole group were diagnosed with a lower limb overuse injury compared with 56 ( 38.1 % ) in the control group ( P=0.29 ) during the 6-month study period . When body mass index and the results of a 12-min running test and muscle strength were adjusted in a Cox 's regression model , the hazard ratio for lower limb overuse injury in the insole group was 1.3 ( 95 % confidence intervals : 0.8 - 2.1 ) compared with the control group . Use of orthotic insoles was not associated with a decrease in lower limb overuse injuries . Our findings suggest that routine use of orthotic insoles does not prevent physical-stress-related lower limb injuries in healthy young male adults BACKGROUND AND PURPOSE Assessment of the quality of r and omized controlled trials ( RCTs ) is common practice in systematic review s. However , the reliability of data obtained with most quality assessment scales has not been established . This report describes 2 studies design ed to investigate the reliability of data obtained with the Physiotherapy Evidence Data base ( PEDro ) scale developed to rate the quality of RCTs evaluating physical therapist interventions . METHOD In the first study , 11 raters independently rated 25 RCTs r and omly selected from the PEDro data base . In the second study , 2 raters rated 120 RCTs r and omly selected from the PEDro data base , and disagreements were resolved by a third rater ; this generated a set of individual rater and consensus ratings . The process was repeated by independent raters to create a second set of individual and consensus ratings . Reliability of ratings of PEDro scale items was calculated using multirater kappas , and reliability of the total ( summed ) score was calculated using intraclass correlation coefficients ( ICC [ 1,1 ] ) . RESULTS The kappa value for each of the 11 items ranged from.36 to.80 for individual assessors and from.50 to.79 for consensus ratings generated by groups of 2 or 3 raters . The ICC for the total score was.56 ( 95 % confidence interval=.47-.65 ) for ratings by individuals , and the ICC for consensus ratings was.68 ( 95 % confidence interval=.57-.76 ) . DISCUSSION AND CONCLUSION The reliability of ratings of PEDro scale items varied from " fair " to " substantial , " and the reliability of the total PEDro score was " fair " to " good . In a prospect i ve study of stress fractures the hypothesis that a shock-absorbing orthotic device worn within military boots could lessen the incidence of stress fractures was tested . The incidence of metatarsal , tibial , and femoral stress fractures was lower in the orthotic group , but only the latter difference was statistically significant . The time of onset and the location of stress fractures between orthotic and nonorthotic users did not differ . These findings suggest that the incidence of femoral stress fractures , which are the most dangerous type of stress fracture because of their high risk of developing into displaced fractures , can be reduced by an orthotic device Sedentary individuals , particularly new military recruits , who start a physical training program have a substantial risk of developing an overuse injury of the lower limb . In this study we investigated the effect of neoprene insoles on the incidence of overuse injuries during 9 weeks of basic military training . The experimental group consisted of 237 r and omly selected new recruits , while 1151 recruits were the control group . Insoles were given to the experimental group and compliance was monitored . A panel of doctors documented and classi fied all injuries occurring during the 9 week period . A total of 54 ( 22.8 % ) and 237 ( 31.9 % ) injuries were reported in the experimental and control groups , re spectively . In both groups , the majority of injuries were overuse ( experimental group , 90.7 % ; control group , 86.4 % ) . The mean weekly incidence of total overuse injuries and tibial stress syndrome was significantly lower ( P < 0.05 ) in the experimental group . The mean incidence of stress fractures was lower in the experimental group but not significantly so ( 0.05 < P < 0.1 ) . This study shows that the incidence of total overuse injuries and tibial stress syndrome during 9 weeks of basic military training can be reduced by wearing insoles In a prospect i ve study of stress fractures the hypothesis that training with custom made biomechanical shoe orthoses could lessen the incidence of stress fractures in infantry recruits was tested . Recruits were assigned r and omly to groups and given soft biomechanical orthoses or semirigid biomechanical orthoses and compared with a control group that did not train in biomechanical orthoses . All recruits wore infantry boots with soles design ed like those of basketball shoes . Recruits were examined biweekly during 14 weeks of basic training . The incidence of stress fractures was 15.7 % for the recruits with the semirigid biomechanical orthoses , 10.7 % for the recruits with the soft biomechanical orthoses , and 27 % for the control group . The soft biomechanical orthoses were tolerated better by the recruits than were the semirigid devices . Among trainees at high risk for stress fractures , prophylactic use of custom made biomechanical orthoses may be warranted The utility of shock-absorbing boot and sneaker inserts for reducing the occurrence of lower limb pain among male US Army basic trainees was evaluated . Every other training unit was given inserts . The inserts were issued prior to the start of training when combat boots and sneakers were fitted . According to post-training question naires and the participants ' medical records , the inserts did not have any preventive effect on occurrence of lower limb problems during training . Five hundred seventeen trainees were issued inserts , 397 were followed but not issued inserts , and 218 were not issued but purchased them on their own . Thirty-eight percent of those issued inserts had lower limb pain problems compared with 29 % of those not issued inserts and 38 % of those who bought their own . There was no statistical difference between these rates of occurrence . Prior to training , there were minor differences between the groups ' scores on physical fitness test scores and run times . These differences disappeared during training so that there were no differences among the groups on either training or clinical variables during or after basic training OBJECTIVES Despite several consensus statements , different injury definitions are used in the literature . This study aim ed to identify the impact of different injury definitions on the nature and incidence of complaints captured during a short-term running program for novice runners . DESIGN Prospect i ve cohort study . METHODS 1696 participants completed weekly diaries on running exposure and musculoskeletal complaints during a 6-week running program . These data were used to compare six different injury definitions ( presence of running-related pain , training-reduction , time-loss of one day or one week ) . Injuries were registered under these different definitions . Consequently incidence and the nature of complaints were compared between definitions . RESULTS The different injury definitions result ed in incidences that varied between 7.5 % and 58.0 % , or 18.7 and 239.6 injuries per 1000h of running . The median duration of injury complaints was 4 - 7 days for injuries registered under a ' day definition ' , while complaints registered under a ' week definition ' lasted 20 - 22 days . For running-related pain injuries the median of the maximum amount of pain was 3.0 . In training-reduction and time-loss injuries these median values were scored between 5.0 and 7.0 . No significant differences in anatomical locations between injuries that were registered under a ' day definition ' or a ' week definition ' were found . Injuries registered under a time-loss definition were located relatively more often at the knee , while complaints at the pelvis/sacrum/buttock were captured more often under a running-related pain definition . CONCLUSIONS Injury definitions largely impact injury incidence . Location of injury is also affected by choice of injury definition . This stressed the need for st and ardized injury registration methods OBJECTIVES To assess the benefits , if any , of the use of shock absorbing insoles in reducing lower limb injury among Air Force recruits , and to assess the differences , if any , in the efficacy of two commonly available shock absorbing insoles . DESIGN R and omized controlled trial . SETTING RAF Halton , UK . Site of all basic training for RAF personnel . PARTICIPANTS 1205 recruits participating in basic training between 17 September 2003 and 7 April 2004 . INTERVENTIONS Participants were r and omized to receive either st and ard issue Saran non-shock absorbing insoles , or shock absorbing Sorbothane or Poron insoles , on a 1:1:1 basis . MAIN OUTCOME MEASURES The primary outcome measure was withdrawal from training for lower limb injury . The two primary comparisons were shock absorbing insole versus non-shock absorbing insole , and Sorbothane versus Poron ( comparison of different shock absorbing insoles ) . Secondary outcomes were medical withdrawals for reasons other than those qualifying for the primary outcome measure . RESULTS When comparing the non-shock absorbing insole to the shock absorbing insoles 72/401 participants ( 18.0 % ) allocated to Saran insoles were removed from training because of a qualifying lower limb injury , compared with 149/804 ( 18.5 % ) allocated to the shock absorbing insole ( Sorbothane or Poron ) , odds ratio 1.04 ( 95 % CI 0.75 to 1.44 ; P=0.87 ) . When comparing the two shock absorbing insole 73/421 participants ( 17.3 % ) r and omized to Sorbothane were removed from training because of a qualifying lower limb injury , compared with 76/383 for Poron ( 19.8 % ) , odds ratio 0.85 ( 95 % CI 0.58 to 1.23 ; P=0.37 ) . CONCLUSIONS Similar rates of lower limb injuries were observed for all insoles ( shock absorbing and non-shock absorbing ) in the trial . The trial provides no support for a change in policy to the use of shock absorbing insoles for military recruits A user trial was undertaken to determine whether a shock-absorbing insole is suitable for military use . Two thicknesses of insole ( 3 mm and 6 mm ) were studied and were issued to 38 Royal Marine recruits to wear in their military boots for weeks 12 to 30 of training . Biomechanical measurements showed that both thicknesses of insole significantly ( p < 0.05 ) attenuated the peak pressures generated at heel strike and during forefoot loading when new ( relative to a no-insole condition ) and that this was well maintained after wear . This was supported by mechanical tests conducted on the insoles . It was concluded that the insoles are sufficiently durable for military use . The main user complaint was that water retention reduced the comfort of the insoles ; however , insulation tests conducted with a foot manikin indicated that switching from the current-issue Saran insoles to the trial insoles would not increase the risk of recruits sustaining nonfreezing cold injuries to their feet In a prospect i ve study , quantitative measures of the structure of the longitudinal arch of the foot were established and related to the incidence of stress fractures in the bones of the lower limbs of military recruits . In addition , the role of a semirigid orthotic device ( Langer military stress orthotic ) in preventing stress fractures was evaluated as a function of the structure of the longitudinal arch . Femoral and tibial stress fractures were found to be more prevalent in the presence of feet with high arches , whereas the incidence of metatarsal fractures was higher in feet with low arches . The use of an orthotic device reduced the incidence of femoral stress fractures only in the presence of feet with high arches and the incidence of metatarsal fractures only among feet with low arches . The findings suggest that the normal foot with a low arch acts as a better shock absorber than the normal foot with a high arch , and that an orthotic device may improve the shock absorbing capacity of the arch OBJECTIVE To investigate the influence of a custom foot orthotic intervention on the lower extremity dynamics in healthy runners . DESIGN Three-dimensional kinematics and kinetics were collected on 15 female runners ( > 15 miles per week ) while each performed the over-ground running trials in either a shoe only or a shoe+custom foot orthotic condition . Kinematic and kinetic variables were analyzed using Paired Sample t-tests . BACKGROUND Custom foot orthotics are frequently prescribed treatment modality for the management of overuse running injuries . Although it is generally accepted that a custom foot orthotic intervention produces positive clinical outcomes , it remains unclear what influence this therapeutic modality has on the dynamics of the lower extremity . METHODS Each subject performed five acceptable over-ground running trials ( 3.6 m s(-1 ) + /-5 % ) with and without the custom foot orthotic intervention in a running shoe . Selected maximum ankle and knee joint angles and moments were measured during the stance phase . RESULTS While wearing the custom foot orthotic , subjects exhibited significantly decreased maximum values in rearfoot eversion angle , rearfoot eversion velocity and internal ankle inversion moment . CONCLUSIONS In this sample of healthy female runners , the custom foot orthotic intervention led to significant decreases in maximum values for ankle dynamics in the frontal plane and in the sagittal plane of the knee joint . Relevance It remains unclear how a custom foot orthotic intervention influences lower extremity dynamics to produce positive clinical outcomes . Furthering our underst and ing of the dynamic influence will not only inform improved prescription and manufacturing practice s but may provide insight into the mechanisms that cause overuse injuries A prospect i ve controlled trial was carried out to determine the usefulness of a viscoelastic polymer insole in prevention of stress fractures and stress reactions of the lower extremities . The subjects were 3,025 US Marine recruits who were followed for 12 weeks of training at Parris Isl and , South Carolina . Polymer and st and ard mesh insoles were systematic ally distributed in boots that were issued to members of odd and even numbered platoons . The most important finding was that an elastic polymer insole with good shock absorbency properties did not prevent stress reactions of bone during a 12-week period of vigorous physical training . To control for the confounding effects of running in running shoes , which occurred for about one and one-half hours per week for the first five weeks , we also examined the association of age of shoes and cost of shoes with injury incidence . A slight trend of increasing stress injuries by increasing age of shoes was observed . However , this trend did not account for the similarity of rates in the two insole groups . In addition , we observed a strong trend of decreasing stress injury rate by history of increasing physical activity , as well as a higher stress injury rate in White compared to Black recruits . The results of the trial were not altered after controlling for these factors . This prospect i ve study confirms previous clinical reports of the association of stress fractures with physical activity history . The clinical application of a shock absorbing insole as a preventive for lower extremity stress reactions is not supported in these uniformly trained recruits . The findings are relevant to civilian population Background : Foot orthoses are widely prescribed both to treat existing pathological conditions and to prevent overuse injuries , but little is known about the effect of their material composition and fabrication technique on patient comfort and the incidence of overuse injuries . Material s and Methods : The acceptance rates and comfort scores of soft custom , soft prefabricated , semirigid biomechanical , and semirigid prefabricated orthoses and their effect on the incidence of stress fractures , ankle sprains , and foot problems were studied in a prospect i ve , r and omized , single-blinded clinical trial among 874 infantry recruits during basic training . Results : A statistically significantly lower number of recruits given soft prefabricated orthoses ( 53 % ) finished basic training in their assigned devices than in the soft custom group ( 72 % ) , in the semirigid biomechanical group ( 75 % ) , and in the semirigid prefabricated group ( 82 % ) ( p = .003 ) . For recruits who finished training in their assigned orthoses , the soft custom ( 3.54 ) and soft prefabricated ( 3.43 ) orthoses had significantly higher comfort scores than the semirigid biomechanical ( 3.23 ) and prefabricated ( 3.17 ) orthoses , ( p = .0001 ) . There was no statistically significant difference in the incidence of stress fractures , ankle sprains , or foot problems between recruits using the different types of orthoses . Conclusions : These findings suggest that if a foot orthosis is being dispensed as prophylaxis for overuse injuries in an active , healthy population , there is little justification for prescribing semirigid biomechanical orthoses . Their cost is high compared to other types of orthoses , without an advantage in comfort or a reduction in stress fractures , ankle sprains , and foot problems Background : Overuse lower limb injury is common in incidence and morbidity . Many risk factors , gait related and biomechanical , have been identified , although little conclusive evidence has been found in terms of injury prevention to date . Hypothesis : Orthoses , as produced by proprietary software interpretation of plantar pressures , are able to reduce injury rates in an “ at risk ” military population . Study Design : R and omized controlled trial ; Level of evidence , 1 . Methods : Four hundred military officer trainees were assessed by means of pressure plate recording of their contact foot pressures during walking . Participants were risk assessed and r and omized to receive or not receive customized orthoses using the D3D system . Both cohorts were followed up for injury through their basic training at the 7-week point . Results : The orthotic intervention group sustained 21 injuries in total ( 1 injury per 4666 hours of training ) , whereas the control group sustained 61 injuries in total ( 1 injury per 1600 hours of training ) ( P < .0001 ) , thereby demonstrating an absolute risk reduction of 0.49 from use of the orthoses ( P < .0001 , chi square ; confidence interval , 1.7 , 2.4 ) . Conclusion : In this military trainee population , orthoses were effective in the prevention of overuse lower limb injury . This is the first study to identify a positive preventive role of orthoses |
13,684 | 24,388,450 | Three ACL intervention programs successfully reduced noncontact ACL injury incidence rates in female adolescent athletes . | PURPOSE The purpose of this study was to identify neuromuscular training intervention programs that significantly reduced the incidence of noncontact anterior cruciate ligament ( ACL ) injury rates in female adolescent athletes . | Background Female athletes have a higher risk of anterior cruciate ligament injury than their male counterparts who play at similar levels in sports involving pivoting and l and ing . Hypothesis The competitive female basketball players who participated in a sports injury prevention training program would show better muscle strength and flexibility and improved biomechanical properties associated with anterior cruciate ligament injury than during the pretraining period and than posttraining parameters in a control group . Study Design Controlled laboratory study . Methods A total of 22 high school female basketball players were recruited and r and omly divided into 2 groups ( the experimental group and the control group , 11 participants each ) . The experimental group was instructed in the 6 parts of the sports injury prevention training program and performed it during the first 20 minutes of team practice for the next 8 weeks , while the control group performed their regular training program . Both groups were tested with a rebound-jump task before and after the 8-week period . A total of 21 reflective markers were placed in preassigned positions . In this controlled laboratory study , a 2-way analysis of variance ( 2 × 2 ) experimental design was used for the statistical analysis ( P < .05 ) using the experimental group and a testing session as within and between factors , respectively . Post hoc tests with Sidak correction were used when significant factor effects and /or interactions were observed . Results A comparison of the experimental group 's pretraining and posttraining results identified training effects on all strength parameters ( P = .004 to .043 ) and on knee flexion , which reflects increased flexibility ( P = .022 ) . The experimental group showed higher knee flexion angles ( P = .024 ) , greater interknee distances ( P = .004 ) , lower hamstring-quadriceps ratios ( P = .023 ) , and lower maximum knee extension torques ( P = .043 ) after training . In the control group , no statistical differences were observed between pretraining and posttraining findings ( P = .084 to .873 ) . At pretraining , no significant differences were observed between the 2 groups for any parameter ( P = .067 to .784 ) . However , a comparison of the 2 groups after training revealed that the experimental group had significantly higher knee flexion angles ( P = .023 ) , greater knee distances ( P = .005 ) , lower hamstring-quadriceps ratios ( P = .021 ) , lower maximum knee extension torques ( P = .124 ) , and higher maximum knee abduction torques ( P = .043 ) than the control group . Conclusion The sports injury prevention training program improved the strength and flexibility of the competitive female basketball players tested and biomechanical properties associated with anterior cruciate ligament injury as compared with pretraining parameters and with posttraining parameters in the control group . Clinical Relevance This injury prevention program could potentially modify the flexibility , strength , and biomechanical properties associated with ACL injury and lower the athlete 's risk for injury Objective To evaluate the effectiveness of neuromuscular training in reducing the rate of acute knee injury in adolescent female football players . Design Stratified cluster r and omised controlled trial with clubs as the unit of r and omisation . Setting 230 Swedish football clubs ( 121 in the intervention group , 109 in the control group ) were followed for one season ( 2009 , seven months ) . Participants 4564 players aged 12 - 17 years ( 2479 in the intervention group , 2085 in the control group ) completed the study . Intervention 15 minute neuromuscular warm-up programme ( targeting core stability , balance , and proper knee alignment ) to be carried out twice a week throughout the season . Main outcome measures The primary outcome was rate of anterior cruciate ligament injury ; secondary outcomes were rates of severe knee injury ( > 4 weeks ’ absence ) and any acute knee injury . Results Seven players ( 0.28 % ) in the intervention group , and 14 ( 0.67 % ) in the control group had an anterior cruciate ligament injury . By Cox regression analysis according to intention to treat , a 64 % reduction in the rate of anterior cruciate ligament injury was seen in the intervention group ( rate ratio 0.36 , 95 % confidence interval 0.15 to 0.85 ) . The absolute rate difference was −0.07 ( 95 % confidence interval −0.13 to 0.001 ) per 1000 playing hours in favour of the intervention group . No significant rate reductions were seen for secondary outcomes . Conclusions A neuromuscular warm-up programme significantly reduced the rate of anterior cruciate ligament injury in adolescent female football players . However , the absolute rate difference did not reach statistical significance , possibly owing to the small number of events . Trial registration Clinical trials NCT00894595 Previous research suggests high impact forces generated during l and ings contribute to noncontact anterior cruciate ligament ( ACL ) injuries . In women , neuromuscular differences appear to modify the ability to dissipate l and ing forces when compared to men . This study examined peak vertical impact forces ( Fp ) and rate of force development ( RFD ) following a 9-week , low-intensity ( simple jump-l and ing-jump tasks ) and volume ( number of foot contacts per workout ) plyometric-based knee ligament injury prevention ( KLIP ) program . Female subjects were r and omly assigned into control ( n = 14 ) and treatment ( n = 14 ) groups . Treatment subjects attended KLIP sessions twice a week for 9 weeks , and control subjects received no intervention . Ground reaction forces ( Fp and RFD ) generated during a step-l and protocol were assessed at study onset and termination . Significant reductions in Fp ( p = 0.0004 ) and RFD ( p = 0.0205 ) were observed in the treatment group . Our results indicate that 9 weeks of KLIP training altered l and ing strategies in women to lower Fp and RFD . These changes are considered conducive to a reduced risk of knee injury while l and ing Background Anterior cruciate ligament ( ACL ) injury prevention programs show promising results with changing movement ; however , little information exists regarding whether a program design ed for an individual 's movements may be effective or how baseline movements may affect outcomes . Hypothesis A program design ed to change specific movements would be more effective than a “ one-size-fits-all ” program . Greatest improvement would be observed among individuals with the most baseline error . Subjects of different ages and sexes respond similarly . Study Design R and omized controlled trial ; Level of evidence , 1 . Methods One hundred seventy-three youth soccer players from 27 teams were r and omly assigned to a generalized or stratified program . Subjects were videotaped during jump-l and ing trials before and after the program and were assessed using the L and ing Error Scoring System ( LESS ) , which is a valid clinical movement analysis tool . A high LESS score indicates more errors . Generalized players performed the same exercises , while the stratified players performed exercises to correct their initial movement errors . Change scores were compared between groups of varying baseline errors , ages , sexes , and programs . Results Subjects with the highest baseline LESS score improved the most ( 95 % CI , −3.4 to −2.0 ) . High school subjects ( 95 % CI , −1.7 to −0.98 ) improved their technique more than pre – high school subjects ( 95 % CI , −1.0 to −0.4 ) . There was no difference between the programs or sexes . Conclusions Players with the greatest amount of movement errors experienced the most improvement . A program 's effectiveness may be enhanced if this population is targeted To prospect ively evaluate the effect of neuromuscular training on the incidence of knee injury in female athletes , we monitored two groups of female athletes , one trained before sports participation and the other not trained , and a group of untrained male athletes throughout the high school soccer , volleyball , and basketball seasons . Weekly reports included the number of practice and competition exposures and mechanism of injury . There were 14 serious knee injuries in the 1263 athletes tracked through the study . Ten of 463 untrained female athletes sustained serious knee injuries ( 8 noncontact ) , 2 of 366 trained female athletes sustained serious knee injuries ( 0 noncontact ) , and 2 of 434 male athletes sustained serious knee injuries ( 1 noncontact ) . The knee injury incidence per 1000 athlete-exposures was 0.43 in untrained female athletes , 0.12 in trained female athletes , and 0.09 in male athletes ( P 0.02 , chi-square analysis ) . Untrained female athletes had a 3.6 times higher incidence of knee injury than trained female athletes ( P 0.05 ) and 4.8 times higher than male athletes ( P 0.03 ) . The incidence of knee injury in trained female athletes was not significantly different from that in untrained male athletes ( P 0.86 ) . The difference in the incidence of noncontact injuries between the female groups was also significant ( P 0.01 ) . This prospect i ve study demonstrated a decreased incidence of knee injury in female athletes after a specific plyometric training program Abstract Objective To investigate the effect of a structured warm-up programme design ed to reduce the incidence of knee and ankle injuries in young people participating in sports . Design Cluster r and omised controlled trial with clubs as the unit of r and omisation . Setting 120 team h and ball clubs from central and eastern Norway ( 61 clubs in the intervention group , 59 in the control group ) followed for one league season ( eight months ) . Participants 1837 players aged 15 - 17 years ; 958 players ( 808 female and 150 male ) in the intervention group ; 879 players ( 778 female and 101 male ) in the control group . Intervention A structured warm-up programme to improve running , cutting , and l and ing technique as well as neuromuscular control , balance , and strength . Main outcome measure The rate of acute injuries to the knee or ankle . Results During the season , 129 acute knee or ankle injuries occurred , 81 injuries in the control group ( 0.9 ( SE 0.09 ) injuries per 1000 player hours ; 0.3 ( SE 0.17 ) in training v 5.3 ( SE 0.06 ) during matches ) and 48 injuries in the intervention group ( 0.5 ( SE 0.11 ) injuries per 1000 player hours ; 0.2 ( SE 0.18 ) in training v 2.5 ( SE 0.06 ) during matches ) . Fewer injured players were in the intervention group than in the control group ( 46 ( 4.8 % ) v ( 76 ( 8.6 % ) ; relative risk intervention group v control group 0.53 , 95 % confidence interval 0.35 to 0.81 ) . Conclusion A structured programme of warm-up exercises can prevent knee and ankle injuries in young people playing sports . Preventive training should therefore be introduced as an integral part of youth sports programmes Objective Introduction of a neuromuscular training program will increase muscle strength , balance , and proprioception in elite female h and ball players . Design Prospect i ve intervention study . Participants Thirty-five female team h and ball players from 2 teams in the elite division participated . Their mean age was 23 ( ±2.5 ) years , and their mean weight was 69.2 ( ±7.3 ) kg . They had played h and ball for 14.9 ( ±3.2 ) years , 4.7 ( ±2.8 ) years at the top level . The total number of training hours per week was 10 to 11 . InterventionBased on earlier studies and knowledge about common risk situations in team h and ball , an anterior cruciate ligament ( ACL ) injury prevention program with 3 different sets of exercises was developed , each set with a 5-step progression from simple to more challenging exercises . The teams were instructed to use the program a minimum of 3 times a week during a training period of 5 to 7 weeks , and then once a week during the season . The duration of each training session was approximately 15 minutes . Main outcome measures Balance ( KAT 2000 ) , proprioception ( threshold to detection of passive motion ) , muscle strength ( Cybex 6000 ) , and 3 functional knee tests . The players were tested pretraining ( test 1 ) and 8 weeks ( test 2 ) and 12 months ( test 3 ) after the training started . Results There was a significant improvement in dynamic balance between test 1 and test 2 , with a balance index ( BI ) of 924 ( ±225 ) and 778 ( ±174 ) , respectively ( P = 0.01 ) . The effect on dynamic balance was maintained 1 year after training ( BI , 730 ± 156 ) . For static balance , no statistically significant changes were found . For the other variables measured , there were no statistical differences during the study period . Conclusion The ACL injury prevention training program improved dynamic balance in an elite team h and ball players A set of exercises -- the " 11"--have been selected to prevent football injuries . The purpose of this cluster-r and omized controlled trial was to investigate the effect of the " 11 " on injury risk in female youth football . Teams were r and omized to an intervention ( n=59 teams , 1091 players ) or a control group ( n=54 teams , 1001 players ) . The intervention group was taught the " 11 , " exercises for core stability , lower extremity strength , neuromuscular control and agility , to be used as a 15-min warm-up program for football training over an 8-month season . A total of 396 players ( 20 % ) sustained 483 injuries . No difference was observed in the overall injury rate between the intervention ( 3.6 injuries/1000 h , confidence interval ( CI ) 3.2 - 4.1 ) and control group ( 3.7 , CI 3.2 - 4.1 ; RR=1.0 , CI 0.8 - 1.2 ; P=0.94 ) nor in the incidence for any type of injury . During the first 4 months of the season , the training program was used during 60 % of the football training sessions , but only 14 out of 58 intervention teams completed more than 20 prevention training sessions . In conclusion , we observed no effect of the injury prevention program on the injury rate , most likely because the compliance with the program was low Recent publications have reported differences in the incidence , rate , risk , and type of sports injury among men and women . We undertook a prospect i ve study to determine the incidence of injury among high school basketball players and to examine the differences in injury type , incidence , rate , and risk between male and female athletes . During a single basketball season , an injury survey of girls ' varsity teams at 100 class 4A and 5A high schools in Texas was conducted . These data were previously reported . We surveyed the same 100 high schools during a subsequent season to gather injury data from the boys ' varsity teams . The athletic trainer collected data on each reportable injury and reported the data weekly to the University Interscholastic League . A reportable injury was defined as one that occurred during a practice or a game , result ed in missed practice or game time , required physician consultation , or involved the head or the face . The boys ' and girls ' data were compared and statistically analyzed . The rate of injury was 0.56 among the boys and 0.49 among the girls . The risk of injury per hour of exposure was not significantly different between the two groups . In both groups , the most common injuries were sprains , and the most commonly injured area was the ankle , followed by the knee . Female athletes had a significantly higher rate of knee injuries including a 3.79 times greater risk of anterior cruciate ligament injuries . For both sexes , the risk of injury during a game was significantly higher than during practice OBJECTIVE To determine the effectiveness of coach-led neuromuscular warm-up on reducing lower extremity ( LE ) injuries in female athletes in a mixed-ethnicity , predominantly low-income , urban population . DESIGN Cluster r and omized controlled trial . SETTING Chicago public high schools . PARTICIPANTS Of 258 coaches invited to participate , 95 ( 36.8 % ) enrolled ( 1558 athletes ) . Ninety coaches and 1492 athletes completed the study . INTERVENTIONS We r and omized schools to intervention and control groups . We trained intervention coaches to implement a 20-minute neuromuscular warm-up . Control coaches used their usual warm-up . MAIN OUTCOME MEASURES Coach compliance was tracked by self-report and direct observation . Coaches reported weekly athlete exposures ( AEs ) and LE injuries causing a missed practice or game . Research assistants interviewed injured athletes . Injury rates were compared between the control and intervention groups using χ(2 ) and Fisher exact tests . Significance was set at P < .05 . Poisson regression analysis adjusted for clustering and covariates in an athlete subset reporting personal information ( n = 855 ; 57.3 % ) . RESULTS There were 28 023 intervention AEs and 22 925 control AEs . Intervention coaches used prescribed warm-up in 1425 of 1773 practice s ( 80.4 % ) . Intervention athletes had lower rates per 1000 AEs of gradual-onset LE injuries ( 0.43 vs 1.22 , P < .01 ) , acute-onset noncontact LE injuries ( 0.71 vs 1.61 , P < .01 ) , noncontact ankle sprains ( 0.25 vs 0.74 , P = .01 ) , and LE injuries treated surgically ( 0 vs 0.17 , P = .04 ) . Regression analysis showed significant incidence rate ratios for acute-onset noncontact LE injuries ( 0.33 ; 95 % CI , 0.17 - 0.61 ) , noncontact ankle sprains ( 0.38 ; 95 % CI , 0.15 - 0.98 ) , noncontact knee sprains ( 0.30 ; 95 % CI , 0.10 - 0.86 ) , and noncontact anterior cruciate ligament injuries ( 0.20 ; 95 % CI , 0.04 - 0.95 ) . CONCLUSION Coach-led neuromuscular warm-up reduces noncontact LE injuries in female high school soccer and basketball athletes from a mixed-ethnicity , predominantly low-income , urban population . TRIAL REGISTRATION CLINICAL TRIALS.ORG IDENTIFIER : NCT01092286 The purpose of this study was to examine lower extremity kinematics following implementation of the Sportsmetrics Warm-Up for Injury Prevention and Performance ( WIPP ) training program . The hypothesis was that there would be no difference in l and ing mechanics between 2 groups of female youth soccer players ( 9–11 years of age ) , with 1 group ( Treatment ) completing the 8-week– duration ( 2 days per week ) WIPP program and the other serving as a Control group . We recruited 21 female youth soccer players . Treatment ( n = 12 ) and Control ( n = 9 ) groups were established . Using the Sportsmetrics Software for Analysis of Jumping Mechanics , we analyzed lower extremity movement during l and ing after subjects jumped off a 30.5-cm box and immediately went into a vertical jump . No significant changes in knee separation values were observed in the Treatment group after 8 weeks of WIPP training . The results indicate that 8 weeks of WIPP training did not significantly alter l and ing strategies OBJECTIVE To determine the numbers needed to treat ( NNT ) and relative risk reduction ( RRR ) associated with neuromuscular training programs aim ed at preventing noncontact anterior cruciate ligament ( ACL ) injuries in female athletes . DATA SOURCES We search ed PubMed , MEDLINE , SPORT Discus , CINAHL , and Web of Science from 1966 through 2005 using the terms knee , injury , anterior cruciate ligament , ACL , prevention , plyometric , and neuromuscular training . STUDY SELECTION Selected articles were from peer- review ed journals written in English that described original research studies comparing neuromuscular training programs with control programs to determine the number of noncontact ACL injuries per event exposure or hours of playing time . Five studies met the inclusion criteria and were independently rated by 3 review ers using the Physiotherapy Evidence Data base ( PEDro ) scale . Consensus PEDro scores ranged from 4 to 7 out of 10 . DATA EXTRACTION We used numbers of subjects , ACL injuries , and injury exposure rates to calculate NNT and RRR for each study . The NNT calculations from all studies were based on the number of players across 1 competitive season and were described as NNT benefit or NNT harm . DATA SYNTHESIS All 5 studies demonstrated a prophylactic effect due to the neuromuscular training programs . The pooled NNT estimates showed that 89 individuals ( 95 % confidence interval : 66 to 136 ) would need to participate in the prophylactic training program to prevent 1 ACL injury over the course of 1 competitive season . Pooled RRR was 70 % ( 95 % confidence interval : 54 % to 80 % ) among individuals who participated in the intervention program . One high- quality r and omized control trial and 4 medium- quality prospect i ve cohort studies showed mostly consistent findings . Thus , a Strength of Recommendation Taxonomy level of evidence of 1 with a grade B recommendation supports the use of neuromuscular training programs in the prevention of noncontact ACL injuries in female athletes Background Neuromuscular and proprioceptive training programs can decrease noncontact anterior cruciate ligament injuries ; however , they may be difficult to implement within an entire team or the community at large . Hypothesis A simple on-field alternative warm-up program can reduce noncontact ACL injuries . Study Design R and omized controlled trial ( clustered ) ; Level of evidence , 1 . Methods Participating National Collegiate Athletic Association Division I women 's soccer teams were assigned r and omly to intervention or control groups . Intervention teams were asked to perform the program 3 times per week during the fall 2002 season . All teams reported athletes ’ participation in games and practice s and any knee injuries . Injury rates were calculated based on athlete exposures , expressed as rate per 1000 athlete exposures . A z statistic was used for rate ratio comparisons . Results Sixty-one teams with 1435 athletes completed the study ( 852 control athletes ; 583 intervention ) . The overall anterior cruciate ligament injury rate among intervention athletes was 1.7 times less than in control athletes ( 0.199 vs 0.340 ; P = .198 ; 41 % decrease ) . Noncontact anterior cruciate ligament injury rate among intervention athletes was 3.3 times less than in control athletes ( 0.057 vs 0.189 ; P = .066 ; 70 % decrease ) . No anterior cruciate ligament injuries occurred among intervention athletes during practice versus 6 among control athletes ( P = .014 ) . Game-related noncontact anterior cruciate ligament injury rates in intervention athletes were reduced by more than half ( 0.233 vs 0.564 ; P = .218 ) . Intervention athletes with a history of anterior cruciate ligament injury were significantly less likely to suffer another anterior cruciate ligament injury compared with control athletes with a similar history ( P = .046 for noncontact injuries ) . Conclusion This program , which focuses on neuromuscular control , appears to reduce the risk of anterior cruciate ligament injuries in collegiate female soccer players , especially those with a history of anterior cruciate ligament injury Abstract Noyes , FR , Barber-Westin , SD , Smith , STT , and Campbell , T. A training program to improve neuromuscular and performance indices in female high school soccer players . J Strength Cond Res 27(2 ) : 340–351 , 2013—The purpose of this study was to determine if a sports-specific anterior cruciate ligament injury prevention training program could improve neuromuscular and performance indices in female high school soccer players . We combined components from a published knee ligament intervention program for jump and strength training with other exercises and drills to improve speed , agility , overall strength , and aerobic fitness . We hypothesized that this program would significantly improve neuromuscular and athletic performance indices in high school female soccer players . The supervised 6-week program was done 3 d·wk−1 for 90–120 minutes per session on the soccer fields and weight room facilities in area high schools . In phase 1 , 62 athletes underwent a video drop-jump test , t-test , 2 vertical jump tests , and a 37-m sprint test before and upon completion of the training program . In phase 2 , 62 other athletes underwent a multistage fitness test before and after training . There were significant improvements in the mean absolute knee separation distance ( p < 0.0001 ) , mean absolute ankle separation distance ( p < 0.0001 ) , and mean normalized knee separation distance ( p < 0.0001 ) on the drop-jump , indicating a more neutral lower limb alignment on l and ing . Significant improvements were found in the t-test ( p < 0.0001 ) , estimated maximal aerobic power ( p < 0.0001 ) , 37-m sprint test ( p = 0.02 ) , and in the 2-step approach vertical jump test ( p = 0.04 ) . This is the first study we are aware of that demonstrated the effectiveness of a knee ligament injury prevention training program in improving athletic performance indices in high school female soccer players . Future studies will determine if these findings improve athlete compliance and team participation in knee ligament injury intervention training BACKGROUND Studies have suggested that exercise programs can reduce the incidence of noncontact injuries of the anterior cruciate ligament in female athletes . We conducted a two-year prospect i ve study to assess the effects of a knee ligament injury prevention exercise program on the incidence of noncontact anterior cruciate ligament injuries in high-school female athletes . METHODS A prospect i ve cohort design was used to study high-school female athletes ( playing soccer , basketball , and volleyball ) from fifteen schools ( 112 teams ) for two consecutive seasons . The schools were divided into treatment and control groups . The treatment group participated in a plyometric-based exercise program twice a week throughout the season . Practice and game exposures and compliance with the exercise program were recorded on a weekly basis . Suspected noncontact anterior cruciate ligament injuries were confirmed on the basis of the history as well as at the time of surgery and /or with magnetic resonance imaging . RESULTS A total of 1439 athletes ( 862 in the control group and 577 in the treatment group ) were monitored . There were six confirmed noncontact anterior cruciate ligament injuries : three in the treatment group , and three in the control group . The incidence of noncontact anterior cruciate ligament injuries per 1000 exposures was 0.167 in the treatment group and 0.078 in the control group , yielding an odds ratio of 2.05 , which was not significant ( p > 0.05 ) . CONCLUSIONS Our results suggest that a twenty-minute plyometric-based exercise program that focuses on the mechanics of l and ing from a jump and deceleration when running performed twice a week throughout the season will not reduce the rate of noncontact anterior cruciate ligament injuries in high-school female athletes Background Among female athletes it has not been established whether a neuromuscular and proprioceptive sports-specific training program will consistently reduce the incidence of anterior cruciate ligament injuries . Purpose To determine whether a neuromuscular and proprioceptive performance program was effective in decreasing the incidence of anterior cruciate ligament injury within a select population of competitive female youth soccer players . Study Design Cohort study ; Level of evidence , 2 . Methods In 2000 , 1041 female subjects from 52 teams received a sports-specific training intervention in a prospect i ve non-r and omized trial . The control group consisted of the remaining 1905 female soccer players from 95 teams participating in the same league who were age and skill matched . In the 2001 season , 844 female athletes from 45 teams were enrolled in the study , with 1913 female athletes ( from 112 teams ) serving as the age- and skill-matched controls . All subjects were female soccer players between the ages of 14 and 18 and participated in either their traditional warm-up or a sports-specific training intervention before athletic activity over a 2-year period . The intervention consisted of education , stretching , strengthening , plyometrics , and sports-specific agility drills design ed to replace the traditional warm-up . Results During the 2000 season , there was an 88 % decrease in anterior cruciate ligament injury in the enrolled subjects compared to the control group . In year 2 , during the 2001 season , there was a 74 % reduction in anterior cruciate ligament tears in the intervention group compared to the age- and skill-matched controls . Conclusion Using a neuromuscular training program may have a direct benefit in decreasing the number of anterior cruciate ligament injuries in female soccer players |
13,685 | 19,805,771 | The potential clinical benefit of new risk factors for refining global risk assessment is thought to be greatest for persons who are classified as intermediate-risk when stratified by using conventional risk factors ( 15 ) .
Most studies provided an overall estimate of the risk associated with high CRP levels , after adjustment for other risk factors , but did not provide specific evidence about the intermediate-risk group . | In the United States , cardiovascular disease accounts for nearly 40 % of all deaths each year ( 1 ) .
The factors that make up the Framingham risk score ( age , sex , blood pressure , serum total cholesterol or low-density lipoprotein cholesterol level , high-density lipoprotein cholesterol level , cigarette smoking , and diabetes ) account for most of the excess risk for incident coronary heart disease ( CHD ) ( 2 , 3 ) .
However , these factors do not explain all of the excess risk ( 4 , 5 ) , and approximately 40 % of CHD deaths occur in persons with cholesterol levels that are lower than the population average ( 6 ) .
Several lines of evidence ( 7 , 8) have implicated chronic inflammation in CHD , and inflammatory markers have received much attention as new or emerging risk factors that could account for some of the unexplained variability in CHD risk .
C-reactive protein ( CRP ) is a sensitive , nonspecific systemic marker of inflammation ( 9 ) .
Although it is unknown whether CRP is involved in CHD pathogenesis ( 10 , 11 ) , elevated serum CRP levels are associated with traditional cardiovascular risk factors and obesity ( 12 , 13 ) .
This would permit more aggressive risk reduction therapy in persons reclassified as high-risk and may consequently reduce incident CHD events ( 16 ) .
Several previous meta-analyses ( 1719 ) have assessed the possible independent predictive ability of CRP level for incident CHD risk .
We conducted a systematic review and meta-analyses of epidemiologic studies to help the U.S. Preventive Services Task Force ( USPSTF ) determine whether CRP level should be incorporated into guidelines for coronary and cardiovascular risk assessment in primary care .
Our review addresses the question of whether elevated CRP levels are independently predictive of incident CHD events , specifically among intermediate-risk persons .
Data Synthesis and Analysis The ideal approach to assessing the clinical effect of exp and ing the Framingham risk score has been debated extensively .
Most previous research on the effect of a new risk factor has focused on the c-statistic , a measure of discrimination .
The c-statistic , however , may be a poor indicator of the effect of using CRP level to further stratify persons classified as intermediate-risk by the Framingham risk score . | Abstract — Plasma levels of C-reactive protein ( CRP , a marker of the reactant plasma protein component of the inflammatory response ) and of fibrin D-dimer ( a marker of cross-linked fibrin turnover ) have each been associated in recent studies with the risk of future ischemic heart disease ( IHD ) . Previous experimental studies have shown that fibrin degradation products , including D-dimer , have effects on inflammatory processes and acute-phase protein responses . In the Speedwell Prospect i ve Study , we therefore measured CRP and D-dimer levels in stored plasma sample s from 1690 men aged 49 to 67 years who were followed-up for incident IHD for an average of 75±4 months ( mean±SD ) and studied their associations with each other , with baseline and incident IHD , and with IHD risk factors . CRP and D-dimer levels were each associated with age , plasma fibrinogen , smoking habit , and baseline evidence of IHD . CRP was associated with D-dimer ( r = 0.21 , P < 0.00001 ) . On univariate analyses , both CRP and D-dimer were associated with incident IHD . The incidence of IHD increased with CRP independently of the level of D-dimer ( P = 0.0002 ) and also increased with D-dimer independently of the level of CRP ( P = 0.048 ) . In multivariate analyses , inclusion of D-dimer and conventional risk factors reduced the strength of the association between CRP and incident IHD ; likewise , inclusion of CRP and conventional risk factors reduced the strength of the association between D-dimer and incident IHD . We conclude that although these respective markers of inflammation and fibrin turnover show modest association with each other in middle-aged men , they may have additive associations with risk of incident IHD . Further larger studies are required to test this hypothesis BACKGROUND Epidemiologic studies have shown that C-reactive protein ( CRP ) is a risk factor for coronary heart disease . Whether routine measurement of CRP has a role in the prediction of future coronary disease in everyday clinical practice has not yet been investigated . METHODS Within the Rotterdam Study , a population -based cohort study of 7983 men and women 55 years and older , we conducted a nested case-control study to investigate the value of CRP in coronary disease prediction . Data are based on 157 participants who experienced a myocardial infa rct ion during follow-up and 500 r and omly selected controls . High-sensitivity CRP and traditional cardiovascular risk factors were measured at baseline . RESULTS The age- and sex-adjusted relative risk of myocardial infa rct ion for subjects in the highest quartile of the population distribution of CRP compared with the lowest quartile was 2.0 ( 95 % confidence interval , 1.1 - 3.4 ) . After additional adjustment for traditional cardiovascular risk factors , the increase in risk largely disappeared ( odds ratio , 1.2 ; 95 % confidence interval , 0.6 - 2.2 ) . Adding CRP to a coronary disease risk function based on risk factors that are routinely assessed in clinical practice or to the Framingham risk function did not improve the area under the receiver operating characteristic curve of these risk functions . Sensitivity and specificity of both risk functions , computed after dichotomizing the estimated disease probabilities using prespecified cutoff points , hardly improved when CRP was added . CONCLUSION Measurement of CRP in elderly people has no additional value in coronary disease risk prediction when traditional cardiovascular risk factors are known In 1998 , the American Heart Association convened Prevention Conference V to examine strategies for the identification of high-risk patients who need primary prevention . Among the strategies discussed was the measurement of markers of inflammation.1 The Conference concluded that “ many of these markers ( including inflammatory markers ) are not yet considered applicable for routine risk assessment because of : ( 1 ) lack of measurement st and ardization , ( 2 ) lack of consistency in epidemiological findings from prospect i ve studies with endpoints , and ( 3 ) lack of evidence that the novel marker adds to risk prediction over and above that already achievable through the use of established risk factors . ” The National Cholesterol Education Program Adult Treatment Panel III Guidelines identified these markers as emerging risk factors,1a which could be used as an optional risk factor measurement to adjust estimates of absolute risk obtained using st and ard risk factors . Since these publications , a large number of peer- review ed scientific reports have been published relating inflammatory markers to cardiovascular disease ( CVD ) . Several commercial assays for inflammatory markers have become available . As a consequence of the exp and ing research base and availability of assays , the number of inflammatory marker tests ordered by clinicians for CVD risk prediction has grown rapidly . Despite this , there has been no consensus from professional societies or governmental agencies as to how these assays of markers of inflammation should be used in clinical practice . On March 14 and 15 , 2002 , a workshop titled “ CDC/AHA Workshop on Inflammatory Markers and Cardiovascular Disease : Applications to Clinical and Public Health Practice ” was convened in Atlanta , Ga , to address these issues . The goals of this workshop were to determine which of the currently available tests should be used ; what results should be used to define high risk ; which patients should be tested ; and the indications for which the tests would be most useful . These Objective —This study was undertaken to examine the association of plasma inflammatory markers such as C-reactive protein ( CRP ) , interleukin-6 , and fibrinogen with the incidence of coronary heart disease within the prospect i ve cohort study on myocardial infa rct ion ( PRIME study ) . Methods and Results —Multiple risk factors were recorded at baseline in 9758 men aged 50 to 59 years who were free of coronary heart disease ( CHD ) on entry . Nested case-control comparisons were carried out on 317 participants who suffered myocardial infa rct ion (MI)-coronary death ( n=163 ) or angina ( n=158 ) as an initial CHD event during a follow-up for 5 years . After adjustment for traditional risk factors , incident MI-coronary death , but not angina , was significantly associated with CRP , interleukin-6 , and fibrinogen , but only interleukin-6 remained significantly associated with MI-coronary death when the 3 inflammatory markers were included in the model . The different interleukin-6 levels in Northern Irel and and France partly explained the difference in risk between these countries . Interleukin-6 appeared as a risk marker of MI-coronary death , and it improved the definition of CHD risk beyond LDL cholesterol . Conclusions —This association may reflect the underlying inflammatory reaction located in the atherosclerotic plaque or a genetic susceptibility on the part of CHD subjects to answer a proinflammatory stimulus and subsequent increase in hepatic CRP gene expression C-reactive protein ( CRP ) was proposed as a stronger predictor of cardiovascular events than low-density lipoprotein cholesterol ( LDL-C ) ; however , these associations may differ between myocardial infa rct ion ( MI ) and stroke . We compared statistically the associations of CRP and LDL-C levels with risk of MI versus stroke and examined to what extent consideration of CRP or LDL-C increases the population attributable fractions ( PAFs ) of MI and stroke beyond traditional risk factors among 27,548 subjects from the European Prospect i ve Investigation into Cancer and Nutrition-Potsdam Study in a case-cohort design . Among subjects without prior MI or stroke , 156 developed MI and 132 stroke during 6.0 years of follow-up . In adjusted competing risk analyses CRP was positively related to MI and stroke ( P difference between endpoints = 0.55 ) , whereas LDL-C was related to MI but not stroke ( P difference between endpoints = 0.003 ) . The PAF for smoking , diabetes , and hypertension combined was 0.76 for MI , and 0.58 for stroke . With additional consideration of CRP the PAFs were 0.80 and 0.68 , while with addition of LDL-C the PAFs were 0.88 and 0.55 . We conclude that CRP is equally strongly related to risk of MI and stroke , whereas LDL-C is related to risk of MI but not stroke . Consideration of LDL-C beyond smoking , diabetes and hypertension may increase the PAF of MI slightly more than CRP . In contrast , consideration of CRP but not of LDL-C may increase the PAF of stroke beyond these factors BACKGROUND Since inflammation is believed to have a role in the pathogenesis of cardiovascular events , measurement of markers of inflammation has been proposed as a method to improve the prediction of the risk of these events . METHODS We conducted a prospect i ve , nested case-control study among 28,263 apparently healthy postmenopausal women over a mean follow-up period of three years to assess the risk of cardiovascular events associated with base-line levels of markers of inflammation . The markers included high-sensitivity C-reactive protein ( hs-CRP ) , serum amyloid A , interleukin-6 , and soluble intercellular adhesion molecule type 1 ( sICAM-1 ) . We also studied homocysteine and a variety of lipid and lipoprotein measurements . Cardiovascular events were defined as death from coronary heart disease , nonfatal myocardial infa rct ion or stroke , or the need for coronary-revascularization procedures . RESULTS Of the 12 markers measured , hs-CRP was the strongest univariate predictor of the risk of cardiovascular events ; the relative risk of events for women in the highest as compared with the lowest quartile for this marker was 4.4 ( 95 percent confidence interval , 2.2 to 8.9 ) . Other markers significantly associated with the risk of cardiovascular events were serum amyloid A ( relative risk for the highest as compared with the lowest quartile , 3.0 ) , sICAM-1 ( 2.6 ) , interleukin-6 ( 2.2 ) , homocysteine ( 2.0 ) , total cholesterol ( 2.4 ) , LDL cholesterol ( 2.4 ) , apolipoprotein B-100 ( 3.4 ) , HDL cholesterol ( 0.3 ) , and the ratio of total cholesterol to HDL cholesterol ( 3.4 ) . Prediction models that incorporated markers of inflammation in addition to lipids were significantly better at predicting risk than models based on lipid levels alone ( P<0.001 ) . The levels of hs-CRP and serum amyloid A were significant predictors of risk even in the subgroup of women with LDL cholesterol levels below 130 mg per deciliter ( 3.4 mmol per liter ) , the target for primary prevention established by the National Cholesterol Education Program . In multivariate analyses , the only plasma markers that independently predicted risk were hs-CRP ( relative risk for the highest as compared with the lowest quartile , 1.5 ; 95 percent confidence interval , 1.1 to 2.1 ) and the ratio of total cholesterol to HDL cholesterol ( relative risk , 1.4 ; 95 percent confidence interval , 1.1 to 1.9 ) . CONCLUSIONS The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying persons at risk for cardiovascular events BACKGROUND Statins lower the levels of low-density lipoprotein ( LDL ) cholesterol and C-reactive protein ( CRP ) . Whether this latter property affects clinical outcomes is unknown . METHODS We evaluated relationships between the LDL cholesterol and CRP levels achieved after treatment with 80 mg of atorvastatin or 40 mg of pravastatin per day and the risk of recurrent myocardial infa rct ion or death from coronary causes among 3745 patients with acute coronary syndromes . RESULTS Patients in whom statin therapy result ed in LDL cholesterol levels of less than 70 mg per deciliter ( 1.8 mmol per liter ) had lower event rates than those with higher levels ( 2.7 vs. 4.0 events per 100 person-years , P=0.008 ) . However , a virtually identical difference was observed between those who had CRP levels of less than 2 mg per liter after statin therapy and those who had higher levels ( 2.8 vs. 3.9 events per 100 person-years , P=0.006 ) , an effect present at all levels of LDL cholesterol achieved . For patients with post-treatment LDL cholesterol levels of more than 70 mg per deciliter , the rates of recurrent events were 4.6 per 100 person-years among those with CRP levels of more than 2 mg per liter and 3.2 events per 100 person-years among those with CRP levels of less than 2 mg per liter ; the respective rates among those with LDL cholesterol levels of less than 70 mg per deciliter were 3.1 and 2.4 events per 100 person-years ( P<0.001 ) . Although atorvastatin was more likely than pravastatin to result in low levels of LDL cholesterol and CRP , meeting these targets was more important in determining the outcomes than was the specific choice of therapy . Patients who had LDL cholesterol levels of less than 70 mg per deciliter and CRP levels of less than 1 mg per liter after statin therapy had the lowest rate of recurrent events ( 1.9 per 100 person-years ) . CONCLUSIONS Patients who have low CRP levels after statin therapy have better clinical outcomes than those with higher CRP levels , regardless of the result ant level of LDL cholesterol . Strategies to lower cardiovascular risk with statins should include monitoring CRP as well as cholesterol BACKGROUND The objective of this study was to examine the association of Joint National Committee ( JNC-V ) blood pressure and National Cholesterol Education Program ( NCEP ) cholesterol categories with coronary heart disease ( CHD ) risk , to incorporate them into coronary prediction algorithms , and to compare the discrimination properties of this approach with other noncategorical prediction functions . METHODS AND RESULTS This work was design ed as a prospect i ve , single-center study in the setting of a community-based cohort . The patients were 2489 men and 2856 women 30 to 74 years old at baseline with 12 years of follow-up . During the 12 years of follow-up , a total of 383 men and 227 women developed CHD , which was significantly associated with categories of blood pressure , total cholesterol , LDL cholesterol , and HDL cholesterol ( all P<.001 ) . Sex-specific prediction equations were formulated to predict CHD risk according to age , diabetes , smoking , JNC-V blood pressure categories , and NCEP total cholesterol and LDL cholesterol categories . The accuracy of this categorical approach was found to be comparable to CHD prediction when the continuous variables themselves were used . After adjustment for other factors , approximately 28 % of CHD events in men and 29 % in women were attributable to blood pressure levels that exceeded high normal ( > or = 130/85 ) . The corresponding multivariable-adjusted attributable risk percent associated with elevated total cholesterol ( > or = 200 mg/dL ) was 27 % in men and 34 % in women . CONCLUSIONS Recommended guidelines of blood pressure , total cholesterol , and LDL cholesterol effectively predict CHD risk in a middle-aged white population sample . A simple coronary disease prediction algorithm was developed using categorical variables , which allows physicians to predict multivariate CHD risk in patients without overt CHD Key Summary Points Risk prediction models are statistical models used to predict the probability of an outcome on the basis of the values of 1 or more risk factors ( markers ) . The accuracy of the model 's predictions is typically summarized with statistics that describe the model 's discrimination and calibration . Risk stratification tables are a more informative way to assess and compare the models . The tables illustrate the distribution of predictions across risk categories . That illustration allows users to assess 3 key measures of the models ' value for guiding medical decisions : the models ' calibration , ability to stratify people into clinical ly relevant risk categories , and accuracy at classifying patients into higher- and lower-risk categories . This information is contained in the margins of the risk stratification table rather than in its cells . The tables should only be used to compare risk prediction models when one of the models contains all of the markers that are contained in the other ( nested models ) ; they should not be used to compare models with different sets of markers ( nonnested models ) . The table predictions require corrections when casecontrol data are used . The recent epidemiologic and clinical literature is filled with studies evaluating statistical models that predict risk for disease or some other adverse event ( 15 ) . Because risk prediction models are intended to help patients and clinicians make decisions , evaluation of these models requires methods that differ from those used to assess models describing disease etiology . This is because the characteristics of the models are less important than their value for guiding decisions . Cook and colleagues ( 1 , 6 ) recently proposed a new approach to evaluate risk prediction models : a risk stratification table . This methodology appropriately focuses on the key purpose of a risk prediction model , which is to classify individuals into clinical ly relevant risk categories , and it has therefore been widely adopted in the literature ( 24 ) . We examine the risk stratification approach in detail in this article , identifying the relevant information that can be abstract ed from a risk stratification table and caution ing against misuses of the method that frequently occur in practice . We use a recently published study of a breast cancer risk prediction model by Tice and colleagues ( 2 ) to illustrate the concepts . Background A risk prediction marker is any measure that is used to predict a person 's risk for an event . It may be a quantitative measure , such as high-density lipoprotein cholesterol level , or a qualitative measure , such as family history of disease . Risk predictors are also risk factors , in the sense that they will necessarily be strongly associated with the risk for disease . But a large , significant association does not assure that the marker has value in predicting risk for many people . A risk prediction model is a statistical model that combines information from several markers . Common types include logistic regression models , Cox proportional hazard models , and classification trees . Each type of model produces a predicted risk for each person by using information in the model . Consider , for example , a model predicting breast cancer risk that includes age as the only predictor . The result ing risk prediction for a woman of a given age is simply the proportion of women her age who develop breast cancer . The woman 's predicted risk will change if more information is included in the model . For instance , if family history information is added , her predicted risk will be the proportion of women her age and with her family history who develop breast cancer . The purpose of a risk prediction model is to accurately stratify individuals into clinical ly relevant risk categories . This risk information can be used to guide clinical or policy decisions , for example , about preventive interventions for persons or disease screening for sub population s identified as high risk , or to select persons for inclusion in clinical trials . The value of a risk prediction model for guiding these kinds of decisions can be judged by the extent to which the risk calculated from the model reflects the fraction of persons in the population with actual events ( its calibration ) ; the proportions in which the population is stratified into clinical ly relevant risk categories ( its stratification capacity ) ; and the extent to which participants with events are assigned to high-risk categories and those without events are assigned to low-risk categories ( its classification accuracy ) . Risk prediction models are commonly evaluated by using the receiver-operating characteristic ( ROC ) curve ( 4 , 7 ) , which is a st and ard tool for evaluating the discriminatory accuracy of diagnostic or screening markers . This curve shows the true-positive rate plotted against the false-positive rate for rules that classify persons by using risk thresholds that vary over allpossible values . Receiver-operating characteristic curves are generally not helpful for evaluating risk prediction models because they do not provide information about the actual risks that the models predict or about the proportion of participants who have high or low risk values . Moreover , when comparing ROC curves for 2 risk prediction models , the models are aligned according to their false-positive rates ( that is , different risk thresholds are applied to the 2 models to achieve the same false-positive rate ) . This is clearly inappropriate . In addition , the area under the ROC curve or c-statistic , a commonly reported summary measure that can be interpreted as the probability that the predicted risk for a participant with an event is higher than that for a participant without an event , has little direct clinical relevance . Clinicians are never asked to compare risks for a pair of patients one who will eventually have the event and one who will not . Neither the ROC curve nor the c-statistic relates to the practical task of predicting risks for clinical decision making . Cook and colleagues ( 1 , 6 ) propose using risk stratification tables to evaluate the incremental value of a new marker , or the benefit of adding a new marker ( for example , C-reactive protein ) , to an established set of risk predictors ( for example , Framingham risk predictors , such as age , diabetes , cholesterol level , smoking , and low-density lipoprotein cholesterol levels ) . In these stratification tables , risks calculated from models with and without the new marker are cross-tabulated . This approach represents a substantial improvement over the use of ROC methodology because it displays the risks calculated by use of the model and the proportions of individuals in the population who are stratified into the risk groups . We will provide an example of this approach and show how information about model calibration , stratification capacity , and classification accuracy can be derived from a risk stratification table and used to assess the added value of a marker for clinical and health care policy decisions . Example Tice and colleagues ( 2 ) published a study that builds and evaluates a model for predicting breast cancer risk by using data from 1095484 women in a prospect i ve cohort and incidence data from the Surveillance , Epidemiology , and End Results data base . Age , race or ethnicity , family history , and history of breast biopsy were used to model risk with a Cox proportional hazard model . The study focused on the benefit of adding breast density information to the model . The hazard ratio for breast density in the multivariate model ( extremely dense vs. almost entirely fat ) was estimated as 4.2 for women younger than age 65 years and 2.2 for women age 65 years or older . This suggests that breast density is strongly associated with disease riskthat is , that breast cancer rates are higher among women with higher breast density . However , it does not describe the value of breast density for helping women make informed clinical decisions , which requires knowledge of the frequency distribution of breast density in the population . To evaluate the added value of breast density , Tice and colleagues defined 5-year breast cancer risk categories as low ( # # lt##1 % ) , low to intermediate ( 1 % to 1.66 % ) , intermediate to high ( 1.67 % to 2.5 % ) , and high ( # # gt##2.5 % ) . The 1.67 % cutoff for intermediate risk was presumably chosen on the basis of recommendations by the American Society of Clinical Oncology ( 8) and the Canadian Task Force on Preventive Health Care ( 9 ) to counsel women with 5-year risks greater than this threshold about considering tamoxifen for breast cancer prevention . Tice and colleagues used a risk stratification table ( Table 1 ) to compare risk prediction models with and without breast density . Table 1 . Five-Year Risks for Breast Cancer as Predicted by Models That Do and Do Not Include Breast Density Calibration Assessing model calibration is an important first step in evaluating any risk prediction model . Good calibration is essential ; it means that the model-predicted probability of an event for a person with specified predictor values is the same as or very close to the proportion of all persons in the population with those same predictor values who experience the event ( 10 ) . With many predictors , and especially with continuous predictors , we can not evaluate calibration at each possible predictor value because there are too few participants with exactly those values . Instead , the st and ard approach is to place persons within categories of predicted risk and to compare the category values with the observed event rates for participants in each category . The calibration of the risk prediction models for breast cancer can be assessed by comparing the proportions of events in the margins of Table 1 with the corresponding row and column labels . For the model without breast density , the proportions of observed events within each risk category are in the far-right Total column and they generally agree BACKGROUND C-reactive protein ( CRP ) predicts risk of myocardial infa rct ion ( MI ) and stroke among apparently healthy men , but in women , virtually no data are available . METHODS AND RESULTS CRP was measured in baseline blood sample s from 122 apparently healthy participants in the Women 's Health Study who subsequently suffered a first cardiovascular event and from 244 age- and smoking-matched control subjects who remained free of cardiovascular disease during a 3-year follow-up period . Women who developed cardiovascular events had higher baseline CRP levels than control subjects ( P=0.0001 ) , such that those with the highest levels at baseline had a 5-fold increase in risk of any vascular event ( RR=4.8 ; 95 % CI , 2.3 to 10.1 ; P=0.0001 ) and a 7-fold increase in risk of MI or stroke ( RR=7.3 ; 95 % CI , 2.7 to 19.9 ; P=0.0001 ) . Risk estimates were independent of other risk factors , and prediction models that included CRP provided a better method to predict risk than models that excluded CRP ( all P values < 0.01 ) . In stratified analyses , CRP was a predictor among subgroups of women with low as well as high risk as defined by other cardiovascular risk factors . CONCLUSIONS In these prospect i ve data among women , CRP is a strong independent risk factor for cardiovascular disease that adds to the predictive value of risk models based on usual factors alone . ( Circulation . 1998;98:731 - 733 . OBJECTIVES We sought to determine the relative strength of high-sensitivity C-reactive protein ( hs-CRP ) and lipid levels as markers for future ischemic stroke compared with coronary heart disease ( CHD ) in women . BACKGROUND Although hs-CRP and lipid levels are established risk determinants for vascular disease , the relative strength of these biomarkers for ischemic stroke compared with CHD is uncertain . METHODS Among 15,632 initially healthy women who were followed for a 10-year period , we compared hs-CRP , total cholesterol ( TC ) , low-density lipoprotein cholesterol ( LDL-C ) , non-high-density lipoprotein cholesterol ( non-HDL-C ) , high-density lipoprotein cholesterol ( HDL-C ) , apolipoproteins A-I and B100 , and lipid ratios as determinants of ischemic stroke compared with CHD . RESULTS After adjustment for age , smoking status , blood pressure , diabetes , and obesity , the hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) for the third versus the first tertile for future ischemic stroke compared with CHD were , respectively , 1.91 ( 95 % CI 1.13 to 3.21 ) and 2.26 ( 95 % CI 1.64 to 3.12 ) for TC , 1.29 ( 95 % CI 0.83 to 2.02 ) and 2.09 ( 95 % CI 1.53 to 2.85 ) for LDL-C , 0.57 ( 95 % CI 0.36 to 0.92 ) and 0.38 ( 95 % CI 0.27 to 0.52 ) for HDL-C , 1.72 ( 95 % CI 1.03 to 2.86 ) and 2.93 ( 95 % CI 2.04 to 4.21 ) for non-HDL-C , and 2.76 ( 95 % CI 1.51 to 5.05 ) and 1.66 ( 95 % CI 1.17 to 2.34 ) for hs-CRP . Of the lipid ratios , that of TC to HDL-C had the largest HR for both future ischemic stroke and CHD ( HR 1.95 [ 95 % CI 1.16 to 3.26 ] and 4.20 [ 95 % CI 2.79 to 6.32 ] , respectively ) . CONCLUSIONS In this large prospect i ve cohort of initially healthy women , lipid levels are significant risk determinants for ischemic stroke , but with a magnitude of effect smaller than that observed for CHD . High-sensitivity CRP associates more closely with ischemic stroke than with CHD . Concomitant evaluation of lipid levels and hs-CRP may improve risk assessment for stroke as well as CHD . ( The Women 's Health Study ; http://www . clinical trials.gov/ct/show/NCT00000479/ ; NCT00000479 ) INTRODUCTION Measurement of C-reactive protein ( CRP ) levels has been proposed as a useful marker to improve the prediction of future coronary artery disease ( CAD ) risk , but this notion has been challenged recently . METHODS AND RESULTS We performed a prospect i ve case-control study among apparently healthy men and women . The odds ratio ( OR ) for future CAD incidence was 2.49 ( 95 % CI=2.02 - 3.08 , p for linearity < 0.0001 ) unadjusted , and 1.66 ( 95 % CI=1.31 - 2.12 , p for linearity < 0.0001 ) , after adjustment for classical cardiovascular risk factors , for top versus bottom quartile of the CRP distribution . Notably , the risk factor adjusted predictive value was substantially stronger for fatal CAD ( OR=2.92 , 95 % CI=1.83 - 4.67 , p for linearity < 0.0001 ) than for non-fatal CAD ( OR=1.25 , 95 % CI=0.93 - 1.66 , p for linearity=0.06 ) . CRP levels were among the strongest predictors of CAD incidence and mortality . CRP levels remained a statistically significant predictor of future CAD , even after adjustment for the Framingham risk score . CONCLUSIONS In this British cohort with risk factor levels representative of a contemporary Western population , CRP concentration was among the strongest predictors of CAD incidence and mortality . We suggest that current guidelines on CRP measurement in clinical practice should be based on contemporary and representative population Background — Current guidelines suggest measuring high-sensitivity C-reactive protein ( hs-CRP ) as an aid to coronary risk assessment in adults without cardiovascular disease ( CVD ) . Whether other inflammatory biomarkers , such as fibrinogen , add further prognostic information is uncertain . Methods and Results — In a prospect i ve study of 27 742 initially healthy middle-aged women , the associations of baseline immunoassay fibrinogen and hs-CRP measurements with incident CVD were examined over a 10-year follow-up period . Compared with women in the bottom biomarker quintile , age-adjusted hazard ratios ( 95 % confidence intervals [ CIs ] ) for incident CVD for quintiles 2 to 5 of fibrinogen were 1.10 ( 0.86 to 1.41 ) , 1.30 ( 1.03 to 1.65 ) , 1.46 ( 1.16 to 1.85 ) , and 2.43 ( 1.95 to 3.02 ) ; for hs-CRP they were 1.48 ( 1.06 to 2.05 ) , 1.70 ( 1.24 to 2.33 ) , 2.20 ( 1.63 to 2.96 ) , and 3.24 ( 2.43 to 4.31 ) . After further adjustment for established risk factors , both biomarkers remained associated ( P for trend ≤0.001 ) with incident CVD ( hazard ratio , 1.35 ; 95 % CI , 1.07 to 1.71 for top fibrinogen quintile ; and hazard ratio , 1.68 ; 95 % CI , 1.22 to 2.29 for top hs-CRP quintile compared with the bottom quintiles ) . Further adjustment for the other biomarker result ed in hazard ratios of 1.23 and 1.56 ( P for trend=0.02 and 0.002 ) , respectively . Although fibrinogen correlated positively with hs-CRP ( rs=0.41 , P<0.001 ) , the highest CVD risk was associated with elevated levels of both fibrinogen and hs-CRP : age-adjusted hazard ratio of 3.45 ( 95 % CI , 2.60 to 4.57 ) for women with fibrinogen > 393 mg/dL and hs-CRP > 3 mg/L compared with < 329 mg/dL and < 1 mg/L , respectively . Conclusions — In this cohort of initially healthy women , baseline levels of fibrinogen measured with a high- quality immunoassay provided additive value to hs-CRP and traditional risk factors in predicting incident CVD BACKGROUND The role of infections and inflammation in the pathophysiology of coronary heart disease is emerging . We studied the independent and joint effects of these 2 components on coronary risk . METHODS AND RESULTS We measured baseline levels of C-reactive protein ( CRP ) and antibodies to adenovirus , enterovirus , cytomegalovirus , and herpes simplex virus as well as to Chlamydia pneumoniae ( Cpn ) and Helicobacter pylori in 241 subjects who suffered either myocardial infa rct ion or coronary death during the 8.5-year trial in the Helsinki Heart Study , a coronary primary prevention trial . The 241 controls in this nested case-control study were subjects who completed the study without coronary events . Antibody levels to herpes simplex type I ( HSV-1 ) and to Cpn were higher in cases than in controls , whereas the distributions of antibodies to other infectious agents were similar . Mean CRP was higher in cases ( 4.4 versus 2.0 mg/L ; P<0.001 ) , and high CRP increased the risks associated with smoking and with high antimicrobial antibody levels . The odds ratios in subjects with high antibody and high CRP levels were 25.4 ( 95 % CI 2.9 - 220.3 ) for HSV-1 and 5.4 ( 95 % CI 2.4 - 12.4 ) for Cpn compared with subjects with low antibody levels and low CRP . High antibody levels to either HSV-1 or to Cpn increased the risk independently of the other , and their joint effect was close to additive . CONCLUSIONS Two chronic infections , HSV-1 and Cpn , increase the risk of coronary heart disease . The effect is emphasized in subjects with ongoing inflammation , denoted by increased CRP levels Background —Accumulating data suggest a link between blood pressure and vascular inflammation . Methods and Results —We examined the relationship between blood pressure , C-reactive protein ( CRP ) , and incident first cardiovascular events among 15 215 women followed prospect ively over a median of 8.1 years . In cross-sectional analyses at baseline , median levels of CRP for women with blood pressure < 120/75 , 120 to 129/75 to 84 , 130 to 139/85 to 89 , 140 to 159/90 to 94 , and ≥160/95 mm Hg were 0.96 , 1.42 , 2.20 , 2.82 , and 3.34 mg/L , respectively ( P for trend < 0.0001 ) . Increasing categories of blood pressure were significant predictors of CRP levels at baseline . In prospect i ve analyses , both elevated CRP levels ( ≥3 mg/L ) and increasing categories of blood pressure were independent determinants of future cardiovascular events , and CRP had incremental prognostic value at all levels of blood pressure . The adjusted hazard ratio for women with blood pressure ≥160/95 mm Hg and CRP levels ≥3 mg/L was 8.31 ( 95 % CI , 4.44 to 15.55 , P < 0.0001 ) compared with those with blood pressure < 120/75 and CRP levels <3 mg/L. After participants had been divided into 4 groups on the basis of CRP levels ( <3 or ≥3 mg/L ) and blood pressure levels ( < 130/85 or ≥130/85 ) , the risk factor – adjusted hazard ratios were as follows : low CRP/low blood pressure , 1.0 ; high CRP/low blood pressure , 1.87 ( P = 0.002 ) ; low CRP/high blood pressure , 2.54 ( P < 0.0001 ) ; and high CRP/high blood pressure , 3.27 ( P < 0.0001 ) . Conclusions —CRP and blood pressure are independent determinants of cardiovascular risk , and their predictive value is additive Background —The Framingham Coronary Heart Disease ( CHD ) prediction score is recommended for global risk assessment in subjects prone to CHD . Recently , C-reactive protein ( CRP ) has emerged as an independent predictor of CHD . We sought to assess the potential of CRP measurements to enhance risk prediction based on the Framingham Risk Score ( FRS ) in a large cohort of middle-aged men from the general population . Methods and Results —We measured CRP and traditional cardiovascular risk factors at baseline in 3435 white men of German nationality , 45 to 74 years of age . All men were drawn from 3 r and om sample s of the general population in the Augsburg area located in Southern Germany in 1984 to 1985 , 1989 to 1990 , and 1994 to 1995 ( response rate , 80 % ) , and the FRS was calculated in all of them . Outcome was defined as nonfatal and fatal coronary events , including sudden cardiac death . During an average follow-up of 6.6 years , a total of 191 coronary events occurred . Cox regression showed a significant contribution of CRP to coronary event risk prediction independent of the FRS ( P = 0.0002 ) . In stratified analysis for 5 categories of FRS , CRP significantly added prognostic information to the FRS in subjects in 2 intermediate risk categories ( P = 0.03 and P = 0.02 ) . Conclusions —Our results suggest that CRP enhances global coronary risk as assessed by the FRS , especially in intermediate risk groups . This might have implication s for future risk assessment BACKGROUND Recent evidence implicates inflammation in the pathogenesis of coronary heart disease ( CHD ) . C-reactive protein , a plasma marker of inflammation , is a marker of CHD risk but has been studied in few prospect i ve investigations of the general population . METHODS AND RESULTS We prospect ively examined the association of CRP with incident CHD among middle-aged adults in the Atherosclerosis Risk In Communities ( ARIC ) study . With the use of a nested case-cohort approach , we measured CRP in stored , baseline blood sample s of 2 groups of subjects in whom CHD developed during follow-up ( 242 incident cases from 1987 to 1993 and 373 from 1990 to 1995 ) and , for comparison , 2 stratified r and om sample s of noncases . In analyses adjusted for demographic variables and traditional CHD risk factors , the relative risk of CHD across quintiles of CRP was 1.0 , 0.8 , 1.6 , 1.9 , and 1.5 for events from 1987 to 1995 ( P for trend = .01 ) . As expected , inclusion of fibrinogen , intracellular adhesion molecule-1 , and white blood cell count ( other potential markers of the inflammatory reaction ) attenuated the association of CRP with CHD incidence . In a supplemental cross-sectional analysis , CRP was not associated with carotid intima-media thickness after adjustment for major risk factors . CONCLUSIONS C-reactive protein is a moderately strong marker of risk of CHD in this cohort of middle-aged adults , consistent with the role of inflammation in the pathogenesis of CHD events . The association was not specific to CRP because other markers of inflammation could largely account for the finding Increased levels of von Willebr and factor ( vWf ) and C-reactive protein ( CRP ) predict cardiovascular mortality in selected population s. It is uncertain whether vWf and CRP predict mortality in a general population and whether vWf and CRP predict mortality through similar pathways . This study investigated the association of vWf and CRP with cardiovascular and all-cause mortality among diabetic and nondiabetic subjects . An age- , sex- , and glucose tolerance-stratified sample ( n=631 ) of a population -based cohort aged 50 to 75 years was followed prospect ively for 5 years . After 5 years of follow-up , 58 subjects had died ( 24 of cardiovascular causes ) . vWf ( > 1.56 IU/mL ) and CRP ( > 2.84 mg/L ) levels in the upper tertile were associated with , respectively , a 3- and 2-fold increase in cardiovascular mortality after adjustment for age , sex , and glucose tolerance status . Analyses in nondiabetic and diabetic subjects separately gave similar results . After further adjustment for hypertension , levels of HDL cholesterol and triglyceride , smoking habits , ischemic heart disease , and peripheral arterial disease , the relative risks ( RRs ) were 3.0 ( 95 % CI 1.2 to 7.9 ) for vWf and 1.4 ( 95 % CI 0.6 to 3.5 ) for CRP . When both vWf and CRP were included in the latter multivariate analysis , the RRs were 3.0 ( 95 % CI 1.1 to 7.9 ) for vWf and 1.3 ( 95 % CI 0.5 to 3.4 ) for CRP . The association between vWf and risk of cardiovascular mortality was independent of blood group ( O versus non-O ) and , moreover , similar among subjects with different blood groups . Repeating the analyses for all-cause mortality gave similar results for CRP . For vWf , the RR was 2.0 ( 95 % CI 1.1 to 3.5 ) after adjustment for all other risk factors . Increased levels of vWf are independently associated with cardiovascular and all-cause mortality in both diabetic and nondiabetic subjects . The association between increased levels of CRP and cardiovascular mortality was partly explained by other risk factors . Mutual adjustment of vWf and CRP did not markedly change the results , favoring the hypothesis that vWf and CRP predict mortality through different pathways CONTEXT A frequently cited concept is that individual major risk factors for coronary heart disease ( CHD ) are absent in many patients ( perhaps > 50 % ) with CHD . However , prior studies have not systematic ally evaluated the extent to which CHD patients have previous exposure to at least 1 risk factor , including diabetes , cigarette smoking , or clinical ly elevated levels of cholesterol or blood pressure . OBJECTIVE To determine the frequency of exposure to major CHD risk factors . DESIGN , SETTING , AND PARTICIPANTS Three prospect i ve cohort studies were included : the Chicago Heart Association Detection Project in Industry , with a population sample of 35 642 employed men and women aged 18 to 59 years ; screenees for the Multiple Risk Factor Intervention Trial , including 347 978 men aged 35 to 57 years ; and a population -based sample of 3295 men and women aged 34 to 59 years from the Framingham Heart Study ( FHS ) . Follow-up lasted 21 to 30 years across the studies . MAIN OUTCOME MEASURES Fatal CHD in all cohorts and nonfatal myocardial infa rct ion ( MI ) in the FHS , compared by exposure to major CHD risk factors , defined as total cholesterol of at least 240 mg/dL ( > or = 6.22 mmol/L ) , systolic blood pressure of at least 140 mm Hg , diastolic blood pressure of at least 90 mm Hg , cigarette smoking , and diabetes . Participants were stratified by sex and age ( 18 - 39 vs 40 - 59 years ) . RESULTS For fatal CHD ( n = 20 995 ) , exposure to at least 1 clinical ly elevated major risk factor ranged from 87 % to 100 % . Among those aged 40 to 59 years at baseline with fatal CHD ( n = 19 263 ) , exposure to at least 1 major risk factor ranged from 87 % to 94 % . For nonfatal MI , prior exposure was documented in 92 % ( 95 % CI , 87%-96 % ) ( n = 167 ) of men aged 40 to 59 years at baseline and in 87 % ( 95 % CI , 80%-94 % ) ( n = 94 ) of women in this age group . CONCLUSIONS Antecedent major CHD risk factor exposures were very common among those who developed CHD , emphasizing the importance of considering all major risk factors in determining CHD risk estimation and in attempting to prevent clinical CHD . These results challenge cl aims that CHD events commonly occur in persons without exposure to at least 1 major CHD risk factor BACKGROUND Inflammatory reactions in coronary plaques play an important role in the pathogenesis of acute atherothrombotic events ; inflammation elsewhere is also associated with both atherogenesis generally and its thrombotic complications . Recent studies indicate that systemic markers of inflammation can identify subjects at high risk of coronary events . METHODS AND RESULTS We used a sensitive immunoradiometric assay to examine the association of serum C-reactive protein ( CRP ) with the incidence of first major coronary heart disease ( CHD ) event in 936 men 45 to 64 years of age . The subjects , who were sample d at r and om from the general population , participated in the first MONICA Augsburg survey ( 1984 to 1985 ) and were followed for 8 years . There was a positive and statistically significant unadjusted relationship , which was linear on the log-hazards scale , between CRP values and the incidence of CHD events ( n=53 ) . The hazard rate ratio ( HRR ) of CHD events associated with a 1-SD increase in log-CRP level was 1.67 ( 95 % CI , 1.29 to 2 . 17 ) . After adjustment for age , the HRR was 1.60 ( 95 % CI , 1.23 to 2 . 08 ) . Adjusting further for smoking behavior , the only variable selected from a variety of potential confounders by a forward stepping process with a 5 % change in the relative risk of CRP as the selection criterion , yielded an HRR of 1.50 ( 95 % CI , 1.14 to 1.97 ) . CONCLUSIONS These results confirm the prognostic relevance of CRP , a sensitive systemic marker of inflammation , to the risk of CHD in a large , r and omly selected cohort of initially healthy middle-aged men . They suggest that low- grade inflammation is involved in pathogenesis of atherosclerosis , especially its thrombo-occlusive complications BACKGROUND Recent trials have demonstrated better outcomes with intensive than with moderate statin treatment . Intensive treatment produced greater reductions in both low-density lipoprotein ( LDL ) cholesterol and C-reactive protein ( CRP ) , suggesting a relationship between these two biomarkers and disease progression . METHODS We performed intravascular ultrasonography in 502 patients with angiographically documented coronary disease . Patients were r and omly assigned to receive moderate treatment ( 40 mg of pravastatin orally per day ) or intensive treatment ( 80 mg of atorvastatin orally per day ) . Ultrasonography was repeated after 18 months to measure the progression of atherosclerosis . Lipoprotein and CRP levels were measured at baseline and follow-up . RESULTS In the group as a whole , the mean LDL cholesterol level was reduced from 150.2 mg per deciliter ( 3.88 mmol per liter ) at baseline to 94.5 mg per deciliter ( 2.44 mmol per liter ) at 18 months ( P<0.001 ) , and the geometric mean CRP level decreased from 2.9 to 2.3 mg per liter ( P<0.001 ) . The correlation between the reduction in LDL cholesterol levels and that in CRP levels was weak but significant in the group as a whole ( r=0.13 , P=0.005 ) , but not in either treatment group alone . In univariate analyses , the percent change in the levels of LDL cholesterol , CRP , apolipoprotein B-100 , and non-high-density lipoprotein cholesterol were related to the rate of progression of atherosclerosis . After adjustment for the reduction in these lipid levels , the decrease in CRP levels was independently and significantly correlated with the rate of progression . Patients with reductions in both LDL cholesterol and CRP that were greater than the median had significantly slower rates of progression than patients with reductions in both biomarkers that were less than the median ( P=0.001 ) . CONCLUSIONS For patients with coronary artery disease , the reduced rate of progression of atherosclerosis associated with intensive statin treatment , as compared with moderate statin treatment , is significantly related to greater reductions in the levels of both atherogenic lipoproteins and CRP Background —The South Bay Heart Watch is a prospect i ve cohort study design ed to appraise the value of coronary calcium and risk factors for predicting outcomes in asymptomatic adults . Two factors that may be related to subsequent cardiovascular events are coronary calcium ( CAC , a manifestation of sub clinical atherosclerosis ) and high-sensitivity C-reactive protein ( CRP , a measure of chronic inflammation ) . Methods and Results —Between December 1990 and December 1992 , 1461 participants without coronary heart disease underwent baseline risk factor screening , computed tomography for CAC , and measurement of CRP . Participants were followed up for 6.4±1.3 years . Cox regression analyses were conducted for the 967 nondiabetics with CRP levels ≤10 mg/L to estimate the risk-factor – adjusted relative risks of CAC and CRP for the occurrence of ( 1 ) nonfatal myocardial infa rct ion ( MI ) or coronary death and ( 2 ) any cardiovascular event ( MI , coronary death , coronary revascularization , or stroke ) . CAC was a predictor of both end points ( P < 0.005 ) , and CRP was a predictor of any cardiovascular event ( P = 0.03 ) . Risk group analysis defined by tertiles for CAC ( < 3.7 , 3.7 to 142.1 , > 142.1 ) and the 75th percentile for CRP ( > 4.05 mg/L ) indicated that there was increasing risk with increasing calcium and CRP . Relative risks for the medium-calcium/low-CRP risk group to high-calcium/high-CRP risk group ranged from 1.8 to 6.1 for MI/coronary death ( P = 0.003 ) and 2.8 to 7.5 for any cardiovascular event ( P < 0.001 ) . Conclusions — Participants without diabetes and those at intermediate risk may benefit from risk stratification based on high-sensitivity CRP levels and CAC , because both factors contribute independently toward the incidence of cardiovascular events Background —Measuring C-reactive protein ( CRP ) has been recommended to identify patients at high risk for coronary heart disease ( CHD ) with low LDL cholesterol ( LDL-C ) . Lipoprotein-associated phospholipase A2 ( Lp-PLA2 ) is a proinflammatory enzyme associated primarily with LDL . Methods and Results —In a prospect i ve , case cohort study in 12 819 apparently healthy middle-aged men and women in the Atherosclerosis Risk in Communities study , the relation between Lp-PLA2 , CRP , traditional risk factors , and risk for CHD events over a period of ≈6 years was examined in a proportional hazards model , stratified by LDL-C. Lp-PLA2 and CRP levels were higher in the 608 cases than the 740 noncases . Both Lp-PLA2 and CRP were associated with incident CHD after adjustment for age , sex , and race with a hazard ratio of 1.78 for the highest tertile of Lp-PLA2 and 2.53 for the highest category of CRP versus the lowest categories . Lp-PLA2 correlated positively with LDL-C ( r = 0.36 ) and negatively with HDL-C ( r = −0.33 ) but not with CRP ( r = −0.05 ) . In a model adjusted for traditional risk factors including LDL-C , the association of Lp-PLA2 with CHD was attenuated and not statistically significant . For individuals with LDL-C below the median ( 130 mg/dL ) , Lp-PLA2 and CRP were both significantly and independently associated with CHD in fully adjusted models . For individuals with LDL-C < 130 mg/dL , those with both Lp-PLA2 and CRP levels in the highest tertile were at the greatest risk for a CHD event . Conclusions —Lp-PLA2 and CRP may be complementary in identifying individuals at high CHD risk who have low Context Inflammatory markers , such as C-reactive protein ( CRP ) , independently predict future coronary artery disease in patients without known disease at baseline . However , an elevated CRP level also predicts all-cause mortality ; therefore , it may not be specific for cardiovascular disease . Contribution This prospect i ve casecontrol study showed that CRP level predicted the development of acute cardiovascular events but not cancer among 28 345 women followed for a mean of 58 months . Clinical Implication s parental history of coronary heart disease . In women , CRP level appears specifically predictive of car-diovascular disease but not cancer . This study adds further evidence that CRP levels may be useful in the clinical prediction of cardiovascular risk , at least in population s. The Editors Recent evidence suggests that atherosclerosis is in part a chronic low- grade inflammatory condition ( 1 ) , and prospect i ve epidemiologic studies have demonstrated that plasma markers of inflammation , such as C-reactive protein ( CRP ) , are strong independent predictors of future coronary events in apparently healthy persons ( 2 - 6 ) . However , as an acute-phase reactant , CRP increases dramatically in various pathologic conditions . Moreover , CRP has been shown to predict all-cause mortality ( 7 , 8) , an observation that raises the possibility that CRP may not be specific for vascular disease . To evaluate this hypothesis , we directly compared the predictive value of CRP for incident cancer and cardiovascular disease , the two most important determinants of all-cause mortality in the western world . Methods We performed a prospect i ve , nested casecontrol analysis within the Women 's Health Study , an ongoing r and omized , double-blind , placebo-controlled trial of aspirin and vitamin E for primary prevention of heart disease and cancer , which involves 39 876 U.S. women 45 years of age and older . Of these study participants , 28 345 ( 71 % ) provided baseline blood sample s , which were stored at 70 C until the time of laboratory analysis . In the Women 's Health Study , all participants are followed prospect ively for incident health events , including cancer and cardiovascular events . The methods used for cohort follow-up , end-point ascertainment , and adjudication for both cancer and cardiovascular events are described in detail elsewhere ( 5 , 9 ) . For this study , we defined case- patients as apparently healthy women who provided an adequate baseline plasma sample and who subsequently developed cancer ( n = 513 ) or an acute cardiovascular event ( myocardial infa rct ion , stroke , or cardiovascular death ) ( n = 130 ) over a mean follow-up period of 58 months . For each woman who had confirmed cancer or cardiovascular event during follow-up , one control of the same age ( 1 year ) and smoking habit ( former smoker , current smoker , or nonsmoker ) was selected from among participants who provided baseline plasma sample s and remained free of reported disease during the same follow-up period . Using these criteria , we evaluated 643 case- patients and an equal number of controls in two separate matched pairs , one for cancer ( n = 513 ) and another for cardiovascular events ( n = 130 ) . The Institutional Review Board of the Brigham and Women 's Hospital approved this study . For each case-patient and control , plasma stored since the baseline examination was thawed and assayed for CRP levels by using a high-sensitivity assay ( Dade Behring , Newark , Delaware ) ( 10 ) . Blood specimens were analyzed in blinded pairs with the position of the patient 's specimen varied at r and om to reduce the possibility of systematic bias and to decrease interassay variability . The day-to-day precision values , at CRP concentrations of 0.15 mg/L and 0.49 mg/L , were 4.9 % and 6.4 % , respectively . Because CRP values are skewed rightward , median plasma concentrations were computed , and the significance of any difference in the distributions between the case- patients and controls was assessed by performing the Wilcoxon rank-sum test . We then used conditional logistic regression models to determine the risk for developing cancer or cardiovascular end points after dividing the study sample into quartiles on the basis of the distribution of the control group . Adjusted estimates of risk were obtained by use of similar models that accounted for the matching variables and that controlled for r and omized treatment assignment ( for vitamin E , aspirin , or both ) , body mass index , diabetes mellitus , history of hyperlipidemia , history of hypertension , and parental history of coronary heart disease . All analyses were performed by using SAS software , release 8.2 ( SAS Institute , Inc. , Cary , North Carolina ) . All P values were two tailed , and CIs were computed at the 95 % level . The funding sources played no role in the design , conduct , or reporting of the study . Results Table 1 shows the baseline characteristics of the study participants . We noted no significant differences at baseline between women who subsequently developed cancer and those who did not . As expected , women who subsequently developed cardiovascular events had an increased baseline prevalence of hyperlipidemia , hypertension , diabetes , and obesity compared with controls who did not develop vascular events during follow-up . Table 1 . Baseline Clinical Characteristics of the Study Participants Overall , median levels of CRP at baseline among women who subsequently developed cancer ( 2.6 mg/L [ interquartile range , 1.1 to 5.9 mg/L ] ) were not significantly different from those of the control group ( 2.5 mg/L [ interquartile range , 0.9 to 5.5 mg/L ] ) ( P > 0.2 ) . Furthermore , we observed no evidence of an association between baseline CRP level and the development of cancer in site-specific analyses evaluating carcinoma of the breast ( n = 223 ) , ovary or uterus ( n = 75 ) , colon ( n = 44 ) , lung ( n = 32 ) , hematopoietic system ( n = 31 ) , thyroid ( n = 14 ) , bladder ( n = 9 ) , brain ( n = 8) , or pancreas ( n = 8) ; melanoma ( n = 31 ) ; or other types of cancer ( n = 38 ) . In contrast , and consistent with previous work in this cohort for the end point of any vascular event ( 5 ) , median CRP levels at baseline among women who subsequently developed cardiovascular disease ( 5.1 mg/L [ interquartile range , 2.6 to 8.5 mg/L ] ) were significantly higher than those of the control group ( P < 0.001 ) . Table 2 presents relative risks for developing either cancer or cardiovascular disease according to increasing quartiles of CRP levels obtained at study entry . As Table 2 shows , there was little evidence that baseline levels of CRP predicted incident cancer in either crude or adjusted analyses . We found similar results after additional correction for alcohol use and age at menarche ( data not shown ) . In contrast , increasing quartiles of baseline CRP level were a strong marker of risk for incident cardiovascular disease in crude and adjusted analyses . For example , the adjusted relative risks from the lowest to the highest quartiles of baseline CRP levels were 1.0 , 2.9 , 3.4 , and 5.6 , respectively ( P for trend < 0.001 ) . Table 2 . Relative Risk for Future Cancer and Cardiovascular Events , according to Baseline Plasma C-Reactive Protein Level Discussion In this prospect i ve study of apparently healthy middle-aged and older women , baseline plasma CRP concentrations were not significantly related to the incidence of future cancer but were a strong independent predictor of future myocardial infa rct ion , stroke , and cardiovascular death . We believe these data have importance for general medical practice for several reasons . First , our data corroborate the findings in several previous reports ( 2 - 6 ) that baseline levels of CRP predict future vascular events among apparently healthy men and women ( 2 - 6 ) and that CRP level adds to the predictive value of total and high-density lipoprotein cholesterol levels ( 5 , 11 ) . As a result of these earlier findings , outpatient screening for CRP has recently become available . However , if CRP is clinical ly nonspecific , as two recent studies evaluating all-cause mortality suggest ( 7 , 8) , then screening for this inflammatory marker might have reduced diagnostic utility . Thus , our finding that CRP appears to be specific for incident vascular disease but not for incident cancer has substantial clinical importance and suggests that data linking CRP level to overall death rates may have been due to the large contribution that vascular disorders make to all-cause mortality , particularly in the western world . Second , the relative risks for future myocardial infa rct ion or stroke observed among women in the top versus bottom quartile of baseline CRP in this analysis are somewhat greater than those previously reported from this cohort for the end point of any vascular eventan end point that included not only myocardial infa rct ion , stroke , and cardiovascular disease mortality , but also coronary revascularization ( 5 ) . Thus , these data also suggest that CRP level may be a stronger marker for events involving atherosclerotic plaque rupture and acute thrombosis than for events primarily involving progression of lesional stenosis . These epidemiologic data are thus consistent with the hypothesis that inflammation is an important determinant of plaque vulnerability ( 12 ) . Finally , we believe that our observation that CRP levels do not strongly predict future cancers is itself of pathophysiologic interest ; this is of particular interest because levels of CRP and other inflammatory biomarkers are known to increase after development of certain malignancies ( 13 , 14 ) . As such , our data also suggest that the systemic inflammatory component of cancer previously reported in cross-sectional studies may be a late development in the genesis of that disease but is not likely to prove useful in determining risk among healthy persons . Several limitations of our study deserve attention . Plasma CRP levels increase acutely in a wide variety of pathologic conditions , including febrile illness , various inflammatory states , and trauma ( 15 ) . In CONTEXT The Framingham Heart Study produced sex-specific coronary heart disease ( CHD ) prediction functions for assessing risk of developing incident CHD in a white middle-class population . Concern exists regarding whether these functions can be generalized to other population s. OBJECTIVE To test the validity and transportability of the Framingham CHD prediction functions per a National Heart , Lung , and Blood Institute workshop organized for this purpose . DESIGN , SETTING , AND SUBJECTS Sex-specific CHD functions were derived from Framingham data for prediction of coronary death and myocardial infa rct ion . These functions were applied to 6 prospect ively studied , ethnically diverse cohorts ( n = 23 424 ) , including whites , blacks , Native Americans , Japanese American men , and Hispanic men : the Atherosclerosis Risk in Communities Study ( 1987 - 1988 ) , Physicians ' Health Study ( 1982 ) , Honolulu Heart Program ( 1980 - 1982 ) , Puerto Rico Heart Health Program ( 1965 - 1968 ) , Strong Heart Study ( 1989 - 1991 ) , and Cardiovascular Health Study ( 1989 - 1990 ) . MAIN OUTCOME MEASURES The performance , or ability to accurately predict CHD risk , of the Framingham functions compared with the performance of risk functions developed specifically from the individual cohorts ' data . Comparisons included evaluation of the e quality of relative risks for st and ard CHD risk factors , discrimination , and calibration . RESULTS For white men and women and for black men and women the Framingham functions performed reasonably well for prediction of CHD events within 5 years of follow-up . Among Japanese American and Hispanic men and Native American women , the Framingham functions systematic ally overestimated the risk of 5-year CHD events . After recalibration , taking into account different prevalences of risk factors and underlying rates of developing CHD , the Framingham functions worked well in these population s. CONCLUSIONS The sex-specific Framingham CHD prediction functions perform well among whites and blacks in different setting s and can be applied to other ethnic groups after recalibration for differing prevalences of risk factors and underlying rates of CHD events BACKGROUND Determination of C-reactive protein ( CRP ) level has been suggested to improve cardiovascular disease ( CVD ) risk assessment . This study examines the utility of CRP levels to assess CVD risk in a community setting . METHODS We performed a prospect i ve observational cohort study on a community population sample . A total of 1949 men and 2497 women without CVD from the Framingham Heart Study underwent CVD risk factor assessment . Initial CVD events during 8 years of follow-up were recorded . RESULTS There were 283 major CVD and 160 major coronary heart disease incident events . Age- , sex- , and multivariable-adjusted analyses generally used CRP level categories of less than 1 , 1 to 3 , and greater than 3 mg/L. In age- and sex-adjusted models , the traditional risk factors and elevated CRP levels indicated increased risk . The age- and sex-adjusted relative risk ( RR ) and 95 % confidence interval ( CI ) of CRP level greater than 3 mg/L for major CVD was elevated ( RR , 1.60 ; 95 % CI , 1.19 - 2.14 ) , with evidence of attenuation ( RR , 1.22 ; 95 % CI , 0.90 - 1.66 ) in multivariable models . The C statistic , a measure of the discriminatory capability of the prediction models , was 0.74 for prediction of major CVD with age and CRP level . In multivariable models that included traditional risk factors , the C statistic was 0.78 , a value that was unchanged with the addition of CRP to the multivariable model . Similar relations were noted for major coronary heart disease events . CONCLUSION Elevated CRP level provided no further prognostic information beyond traditional office risk factor assessment to predict future major CVD and major coronary heart disease in this population sample PURPOSE To investigate whether interleukin-6 and C-reactive protein levels predict all-cause and cause-specific mortality in a population -based sample of nondisabled older people . SUBJECTS AND METHODS A sample of 1,293 healthy , nondisabled participants in the Iowa 65 + Rural Health Study was followed prospect ively for a mean of 4.6 years . Plasma interleukin-6 and C-reactive protein levels were measured in specimens obtained from 1987 to 1989 . RESULTS Higher interleukin-6 levels were associated with a twofold greater risk of death [ relative risk ( RR ) for the highest quartile ( > or = 3.19 pg/mL ) compared with the lowest quartile of 1.9 [ 95 % confidence interval , CI , 1.2 to 3.1 ] ) . Higher C-reactive protein levels ( > or = 2.78 mg/L ) were also associated with increased risk ( RR = 1.6 ; CI , 1.0 to 2.6 ) . Subjects with elevation of both interleukin-6 and C-reactive protein levels were 2.6 times more likely ( CI , 1.6 to 4.3 ) to die during follow-up than those with low levels of both measurements . Similar results were found for cardiovascular and noncardiovascular causes of death , as well as when subjects were stratified by sex , smoking status , and prior cardiovascular disease , and for both early ( < 2.3 years ) and later follow-up . Results were independent of age , sex , body mass index , and history of smoking , diabetes , and cardiovascular disease , as well as known indicators of inflammation including fibrinogen and albumin levels and white blood cell count . CONCLUSIONS Higher circulating levels of interleukin-6 and C-reactive protein were associated with mortality in this population -based sample of healthy older persons . These measures may be useful for identification of high-risk subgroups for anti-inflammatory interventions The authors measured the relation between C-reactive protein , alpha 1 acid glycoprotein and albumin , an acute phase protein , and subsequent risk of myocardial infa rct ion and coronary heart disease death in a nested case-control study among the Multiple Risk Factor Intervention Trial ( MRFIT ) participants . There were 98 myocardial infa rct ion cases , 148 coronary heart disease deaths , and 491 controls . The cases and controls were followed for up to 17 years for deaths and 6 - 7 years for myocardial infa rct ion cases and controls . There was a significant association between available distribution of C-reactive protein and subsequent coronary heart disease mortality . For smokers at baseline , the risk of coronary heart disease deaths in quartile 4 of C-reactive protein as compared with quartile 1 was 4.3 ( 95 % confidence interval 1.74 - 10.8 ) . The association persisted when adjusted for characteristics related to smoking and smoking cessation during the trial and to pulmonary function . There was no relation between alpha 1 acid glycoprotein and either myocardial infa rct ion or coronary heart disease death . Albumin was inversely related to coronary heart disease death only for deaths that occurred between 7 and 13 years after baseline , consistent with previous MRFIT analyses . This is the first prospect i ve study in " healthy but high risk individuals " to document the relation between C-reactive protein and coronary heart disease mortality BACKGROUND C-reactive protein is an inflammatory marker believed to be of value in the prediction of coronary events . We report data from a large study of C-reactive protein and other circulating inflammatory markers , as well as up date d meta-analyses , to evaluate their relevance to the prediction of coronary heart disease . METHODS Measurements were made in sample s obtained at base line from up to 2459 patients who had a nonfatal myocardial infa rct ion or died of coronary heart disease during the study and from up to 3969 controls without a coronary heart disease event in the Reykjavik prospect i ve study of 18,569 participants . Measurements were made in paired sample s obtained an average of 12 years apart from 379 of these participants in order to quantify within-person fluctuations in inflammatory marker levels . RESULTS The long-term stability of C-reactive protein values ( within-person correlation coefficient , 0.59 ; 95 percent confidence interval , 0.52 to 0.66 ) was similar to that of both blood pressure and total serum cholesterol . After adjustment for base-line values for established risk factors , the odds ratio for coronary heart disease was 1.45 ( 95 percent confidence interval , 1.25 to 1.68 ) in a comparison of participants in the top third of the group with respect to base-line C-reactive protein values with those in the bottom third , and similar overall findings were observed in an up date d meta- analysis involving a total of 7068 patients with coronary heart disease . By comparison , the odds ratios in the Reykjavik Study for coronary heart disease were somewhat weaker for the erythrocyte sedimentation rate ( 1.30 ; 95 percent confidence interval , 1.13 to 1.51 ) and the von Willebr and factor concentration ( 1.11 ; 95 percent confidence interval , 0.97 to 1.27 ) but generally stronger for established risk factors , such as an increased total cholesterol concentration ( 2.35 ; 95 percent confidence interval , 2.03 to 2.74 ) and cigarette smoking ( 1.87 ; 95 percent confidence interval , 1.62 to 2.16 ) . CONCLUSIONS C-reactive protein is a relatively moderate predictor of coronary heart disease . Recommendations regarding its use in predicting the likelihood of coronary heart disease may need to be review ed PURPOSE To evaluate the distribution of lipoprotein(a ) ( Lp(a ) ) and assess its association to cardiovascular disease ( CVD ) in American Indians . METHODS Lp(a ) was measured in 3991 American Indians ( aged 45 - 74 years with no prior history of CVD at baseline ) from 13 communities in Arizona , Oklahoma , and South/North Dakota . They were followed prospect ively from 1989 to 1997 for CVD . The distribution of Lp(a ) was examined by center , sex , and diabetic status . Spearman correlation coefficients and Cox regression models were used to evaluate the association of Lp(a ) to CVD . RESULTS A total of 388 participants subsequently developed CVD . Median Lp(a ) concentration in American Indians was 3.0 mg/dl . This was almost half of that in whites and one sixth in blacks from the CARDIA study measured by the same method . Nondiabetic participants had significantly higher Lp(a ) levels than diabetic participants for both genders . Lp(a ) levels were higher in women than in men for nondiabetic participants , but there was no gender difference for diabetic participants . Correlation analysis showed Lp(a ) was significantly negatively correlated with the degree of Indian heritage , insulin , triglycerides ( TG ) , fasting plasma glucose ( FPG ) , and 2-hour plasma glucose ( 2hPG ) , and positively with low-density lipoproteins ( LDL ) , apoprotein B ( apoB ) , and fibrinogen ( FIB ) . In Cox regression models , adjusting for other risk factors , Lp(a ) was no longer a significant predictor of CVD in either diabetic or nondiabetic participants . CONCLUSIONS The lower concentration of Lp(a ) in American Indians and the high correlation with Indian heritage confirm the concept that Lp(a ) concentration is in large part genetically determined . Lp(a ) concentration is not an independent predictor of CVD among American Indians ; it is higher in those who develop CVD because of its positive correlation with LDL , apoB , and FIB A cross sectional and prospect i ve analysis of 3,745 British women aged 60 - 79 years at baseline was undertaken . Among these women there were 570 prevalent cases of coronary heart disease ( CHD ) and 151 new cases among 12,641 person-years of follow up of women who were free of CHD at baseline . Both fibrinogen and CRP were associated with indicators of socioeconomic position in childhood and adulthood and there was a cumulative effect of socioeconomic position from across the life course . The age-adjusted odds ratio ( 95 % confidence interval ) of prevalent CHD for a 1 unit ( 1 g/L ) increase in fibrinogen was 1.29 ( 1.12 , 1.49 ) ; with full adjustment for all potential confounding factors this attenuated to 1.09 ( 0.93 , 1.28 ) . The hazards ratio for incident CHD among those free of disease at baseline was 1.28 ( 1.00 , 1.64 ) ; with full adjustment for all potential confounding factors this attenuated to 1.09 ( 0.84 , 1.44 ) . Similar effects of adjustment for confounding factors were seen for the associations between CRP and both prevalent and incident CHD . By contrast , the strong positive association between smoking ( an established causal risk factor for CHD ) and CHD was not attenuated by adjustment for life course socioeconomic position or other risk factors . We conclude that fibrinogen and CRP predict CHD but may not be causally related to it BACKGROUND Plasma C-reactive protein ( CRP ) levels recently have been identified as an emerging risk factor for ischemic heart disease ( IHD ) . However , whether plasma CRP levels predict an increased risk for future IHD beyond traditional risk factors has yet to be evaluated in a large prospect i ve , population -based study . METHODS The association between elevated plasma CRP levels and the risk for future IHD was investigated in the prospect i ve , population -based cohort of 2037 IHD-free middle-aged men from the Quebec Cardiovascular Study . During a 5-year follow-up , 105 first IHD events were recorded . Baseline plasma CRP levels were measured using a highly sensitive assay . RESULTS High plasma CRP concentrations ( equal to or above vs below the median level of 1.77 mg/L ) were associated with a significant 1.8-fold increase in IHD risk ( 95 % confidence interval [ CI ] , 1.2 - 2.7 ) . This association remained significant after adjustment for lipid risk factors but not when the simultaneous contribution of nonlipid traditional risk factors was taken into account . Multivariate analyses indicated that CRP level predicted short-term risk for IHD ( events that occurred < or = 2 years after the baseline evaluation ) , but not long-term risk ( > 2 years ) . Moreover , high plasma CRP levels predicted an increased risk for IHD , independent of any other confounder , in younger ( < or = 55 years ) but not in older ( > 55 years ) individuals . CONCLUSION Plasma CRP levels may provide independent information on IHD risk only in younger middle-aged men and in the case of IHD events that may occur relatively soon after the baseline evaluation BACKGROUND Inflammation may be important in the pathogenesis of atherothrombosis . We studied whether inflammation increases the risk of a first thrombotic event and whether treatment with aspirin decreases the risk . METHODS We measured plasma C-reactive protein , a marker for systemic inflammation , in 543 apparently healthy men participating in the Physicians ' Health Study in whom myocardial infa rct ion , stroke , or venous thrombosis subsequently developed , and in 543 study participants who did not report vascular disease during a follow-up period exceeding eight years . Subjects were r and omly assigned to receive aspirin or placebo at the beginning of the trial . RESULTS Base-line plasma C-reactive protein concentrations were higher among men who went on to have myocardial infa rct ion ( 1.51 vs. 1.13 mg per liter , P<0.001 ) or ischemic stroke ( 1.38 vs. 1.13 mg per liter , P=0.02 ) , but not venous thrombosis ( 1.26 vs. 1.13 mg per liter , P=0.34 ) , than among men without vascular events . The men in the quartile with the highest levels of C-reactive protein values had three times the risk of myocardial infa rct ion ( relative risk , 2.9 ; P<0.001 ) and two times the risk of ischemic stroke ( relative risk , 1.9 ; P=0.02 ) of the men in the lowest quartile . Risks were stable over long periods , were not modified by smoking , and were independent of other lipid-related and non-lipid-related risk factors . The use of aspirin was associated with significant reductions in the risk of myocardial infa rct ion ( 55.7 percent reduction , P=0.02 ) among men in the highest quartile but with only small , nonsignificant reductions among those in the lowest quartile ( 13.9 percent , P=0.77 ) . CONCLUSIONS The base-line plasma concentration of C-reactive protein predicts the risk of future myocardial infa rct ion and stroke . Moreover , the reduction associated with the use of aspirin in the risk of a first myocardial infa rct ion appears to be directly related to the level of C-reactive protein , raising the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease BACKGROUND There has been interest in recent years in whether additional , and in particular novel , risk factors or blood markers , such as C-reactive protein , can enhance existing coronary heart disease ( CHD ) prediction models . METHODS Using a series of case-cohort studies , the prospect i ve Atherosclerosis Risk in Communities ( ARIC ) Study assessed the association of 19 novel risk markers with incident CHD in 15,792 adults followed up since 1987 - 1989 . Novel markers included measures of inflammation , endothelial function , fibrin formation , fibrinolysis , B vitamins , and antibodies to infectious agents . Change in the area under the receiver operating characteristic curve ( AUC ) was used to assess the additional contribution of novel risk markers to CHD prediction beyond that of traditional risk factors . RESULTS The basic risk factor model , which included traditional risk factors ( age , race , sex , total and high-density lipoprotein cholesterol levels , systolic blood pressure , antihypertensive medication use , smoking status , and diabetes ) , predicted CHD well , as evidence d by an AUC of approximately 0.8 . The C-reactive protein level did not add significantly to the AUC ( increase in AUC of 0.003 ) , and neither did most other novel risk factors . Of the 19 markers studied , lipoprotein-associated phospholipase A(2 ) , vitamin B(6 ) , interleukin 6 , and soluble thrombomodulin added the most to the AUC ( range , 0.006 - 0.011 ) . CONCLUSIONS Our findings suggest that routine measurement of these novel markers is not warranted for risk assessment . On the other h and , our findings reinforce the utility of major , modifiable risk factor assessment to identify individuals at risk for CHD for preventive action Previous studies have shown an association between serum C-reactive protein ( CRP ) and cardiovascular disease ( CVD ) risk . The roles of interleukin-6 ( IL-6 ) and tumor necrosis factor alpha ( TNFalpha ) are less well established . The aim of the present study was to analyze the associations of CRP , IL-6 and TNFalpha with incident coronary heart disease ( CHD ) events , CVD events , and total mortality . A r and om population sample , including men and women aged 25 - 64 years was examined in Finl and in 1992 . The sample size was 7,927 and 6,051 ( 76 % ) participated . The cohort was followed up until the end of 2001 . During the follow-up , 151 incident CHD events , 205 CVD events and 183 deaths from any cause were observed . A stratified r and om sub sample ( n=313 ) was used as the comparison group . After adjustment for conventional CVD risk factors , CRP showed a significant association with CHD risk in men ( HR=2.39 , 1.08 - 5.28 , comparing fourth quartile to the first quartile ) . This association remained significant after further adjustment for TNFalpha . TNFalpha also was a significant predictor of CHD among men , but the association was nonlinear ( HR=2.21 , 1.18 - 4.14 comparing the three upper quartiles to the first quartile ) . Further adjustment for CRP did not change this association substantially . Both CRP and TNFalpha predicted also all CVD events and total mortality among men . Among women the findings were nonsignificant . In conclusion , CRP and TNFalpha were significant , independent predictors of CHD and CVD events and total mortality among men . These findings provide further support to the important role of inflammation in the pathogenesis of CVD CONTEXT Postmenopausal hormone replacement therapy ( HRT ) has been shown to elevate C-reactive protein ( CRP ) levels . Several inflammatory biomarkers , including CRP , are associated with increased cardiovascular risk . However , whether the effect of HRT on CRP represents a clinical hazard is unknown . OBJECTIVES To assess the association between baseline levels of CRP and interleukin 6 ( IL-6 ) and incident coronary heart disease ( CHD ) and to examine the relationship between baseline use of HRT , CRP , and IL-6 levels as they relate to subsequent vascular risk . DESIGN , SETTING , AND PARTICIPANTS Prospect i ve , nested case-control study of postmenopausal women , forming part of the Women 's Health Initiative , a large , nationwide , observational study . Among 75 343 women with no history of cardiovascular disease or cancer , 304 women who developed incident CHD were defined as cases and matched by age , smoking status , ethnicity , and follow-up time with 304 study participants who remained event free during a median observation period of 2.9 years . MAIN OUTCOME MEASURE Incidence of first myocardial infa rct ion or death from CHD . RESULTS Median baseline levels of CRP ( 0.33 vs 0.25 mg/dL ; interquartile range [ IQR ] , 0.14 - 0.71 vs 0.10 - 0.47 ; P<.001 ) and IL-6 ( 1.81 vs 1.47 pg/mL ; IQR , 1.30 - 2.75 vs 1.05 - 2.15 ; P<.001 ) were significantly higher among cases compared with controls . In matched analyses , the odds ratio ( OR ) for incident CHD in the highest vs lowest quartile was 2.3 for CRP ( 95 % confidence interval [ CI ] , 1.4 - 3.7 ; P for trend = .002 ) and 3.3 for IL-6 ( 95 % CI , 2.0 - 5.5 ; P for trend < .001 ) . After additional adjustment for lipid and nonlipid risk factors , both inflammatory markers were significantly associated with a 2-fold increase in odds for CHD events . As anticipated , current use of HRT was associated with significantly elevated median CRP levels . However , there was no association between HRT and IL-6 . In analyses comparing individuals with comparable baseline levels of either CRP or IL-6 , those taking or not taking HRT had similar CHD ORs . In analyses stratified by HRT , we observed a positively grade d relationship between plasma CRP levels and the OR for CHD among both users and nonusers of HRT across the full spectrum of baseline CRP . CONCLUSIONS These prospect i ve findings indicate that CRP and IL-6 independently predict vascular events among apparently healthy postmenopausal women and that HRT increases CRP . However , use or nonuse of HRT had less importance as a predictor of cardiovascular risk than did baseline levels of either CRP or IL-6 |
13,686 | 28,723,527 | EVIDENCE SYNTHESIS Conventional US can not replace voiding cystourethrography in the detection of VUR .
Contrast enhanced voiding sonography and direct radionuclide cystography suggest acceptable detection rates of VUR with sensitivity of 71 - 100 % and specificity of 67 - 100 % .
Renal US and diuretic radioisotope renography with choice of technetium99 m mercaptocetyltriglycine are invaluable imaging modalities for the detection of UPJO .
Despite the concerns about the invasiveness and radiation exposure of conventional voiding cystourethrography , it is still the gold st and ard technique in the detection of VUR and is superior to the other options in depiction of anatomical details .
US and mercaptocetyltriglycine scintigraphy are also the gold st and ards and will continue to be so in the diagnosis of UPJO .
PATIENT SUMMARY New imaging modalities such as contrast enhanced voiding sonography and direct radionuclide cystography are promising in the detection of vesicoureteral reflux . | CONTEXT Although the imaging techniques used for diagnosing vesicoureteral reflux ( VUR ) and ureteropelvic junction obstruction ( UPJO ) are well determined , there is a need to decrease the numbers of unnecessary imaging and radiation exposure as most of the target population is children .
Newer imaging techniques are promising and could be eventually used for follow up in the near future .
OBJECTIVE To review the contemporary literature regarding the imaging techniques used for VUR and UPJO . | Purpose : The aim of this study is to compare the results of direct radionuclide cystography ( DRNC ) and voiding cystourethrography ( VCUG ) in a group of children with a high suspicion of vesicoureteral reflux ( VUR ) . Methods : For this purpose , 25 children were studied with both VCUG and DRNC . Among 50 ureter units able to be compared 39 ureter units did not show any VUR on either study . Eleven ureter units ( 10 children ) had VUR either on one study or on both ( VCUG and DRNC ) . In the children who had VUR on either study , a dimercaptosuccinic acid scintigraphy ( DMSA ) was performed to determine their cortical function . Results : We identified the following four patterns : 1 ) Five ureter units ( five children ) read positive on DRNC who were negative on VCUG and four of these children had positive findings on DMSA ; 2 ) Four ureter units ( four children ) read positive on VCUG who were negative on DRNC , and two of them had positive findings on DMSA ; 3 ) Two ureters ( one child ) read positive in both studies and also had abnormal DMSA findings ; 4 ) Thirtynine ureter units read as negative on both studies . Conclusion : Although the results of these two methods did not show a significant difference , DRNC offers a high sensitivity in the younger age group whereas VCUG seems to be more sensitive in the older age group . DRNC also offers continuous recording during the study , ease of assessment and lower radiation dose to the gonads , which makes it a preferable method for the initial diagnosis and follow-up of VUR PURPOSE When the st and ard cystogram does not show vesicoureteral reflux in children who have experienced febrile urinary tract infections ( UTIs ) , clinical management is controversial . We postulated that vesicoureteral reflux accounts for such UTIs but is " occult . " We tested this hypothesis by using a novel method , PIC cystography ( Positioning the Instillation of Contrast at the ureteral orifice ) at the time of cystoscopy . MATERIAL S AND METHODS We performed PIC cystography with instillation of contrast medium at the ureteral orifice consecutively and prospect ively in 57 children who underwent cystoscopy between November 1999 and February 2002 to evaluate febrile UTIs in 40 patients , dysfunctional voiding in 14 and hydronephrosis in 3 . The control group ( 27 patients , 54 renal units ) was used to assess the accuracy of PIC by comparing the results against those with the st and ard cystogram in children who did not have febrile infection and did not demonstrate vesicoureteral reflux ( 15 patients , 30 renal units ) , and in those who had febrile infection and vesicoureteral reflux ( 12 patients , 24 renal units ) . The study group ( 30 patients , 60 renal units ) served to assess the incidence of " occult " vesicoureteral reflux in children who experienced febrile UTIs yet did not have vesicoureteral reflux on st and ard cystography . RESULTS CONTROL GROUP In children without febrile UTIs all 30 ureteral orifices had a normal endoscopic appearance and no vesicoureteral reflux by PIC cystography . In children with febrile UTIs 15 ureteral orifices with known vesicoureteral reflux were lateral and /or patulous and demonstrated vesicoureteral reflux by PIC , 4 appeared normal and did not exhibit vesicoureteral reflux on st and ard cystography or by PIC , and 5 were lateral and /or patulous in appearance and did not display vesicoureteral reflux on st and ard cystography , but did show vesicoureteral reflux by PIC . These findings reveal that PIC cystography is 100 % sensitive at demonstrating reflux already known by st and ard cystogram , is 87 % specific as it showed reflux in 5 of 39 renal units not revealed by a st and ard cystogram and has an overall accuracy of 91 % . STUDY GROUP At cystoscopy all 30 children demonstrated an abnormal appearance of one or both ureteral orifices . PIC cystography showed vesicoureteral reflux in all 30 children ( 48 renal units , 12 unilateral and 18 bilateral ) . The remaining ureteral orifices ( 12 ) , which appeared normal , did not permit vesicoureteral reflux . Children with vesicoureteral reflux by PIC were treated with antimicrobial prophylaxis ( 26 ) or ureteral reimplantation ( 4 , 2 unilateral and 2 bilateral reimplantation ) Postoperatively , these children did not experience a febrile UTI during followup ( average 8 months ) . CONCLUSIONS PIC cystography is simple to perform using routinely available operating room equipment and does not artifactually induce vesicoureteral reflux . The incidence of " occult " vesicoureteral reflux in children who experience febrile UTIs without vesicoureteral reflux on st and ard cystography is 100 % by PIC cystography . PIC cystography should be done when vesicoureteral reflux is suspected in children who experience febrile UTIs but do not exhibit reflux on st and ard cystography BACKGROUND Fluoroscopic voiding cystourethrography ( VCUG ) is a widely used imaging test for the diagnosis of vesicoureteral reflux ( VUR ) . However , high gonadal radiation and intermittent imaging are the main disadvantages of VCUG . Direct radionuclide cystography ( DRC ) has been advocated for the detection of VUR with increased sensitivity and low radiation doses , however , having the disadvantage of providing less anatomical details for urethral evaluation . In this study , DRC has been compared with st and ard fluoroscopic VCUG for detection of VUR . METHODS A total of 41 children ( 82 kidney ureter units , KUU ) aged 1 month-126 months ( median , 15 months ) were studied sequentially using DRC and VCUG . The indications of VUR studied were urinary tract infection in 29 children , VUR follow up in eight children and antenatal dilatation history in four children . RESULTS A total of 18 refluxing ureters were detected by DRC , 22 refluxing ureters by VCUG and 14 refluxing ureters by both methods . The two methods were concordant for the detection and exclusion of VUR in 85 % of KUU . VUR was missed by VCUG in four KUU ( three severe , one mild ) whereas VUR was missed by DRC in eight KUU ( four grade I , four grade III ) . CONCLUSIONS There was a good correlation between DRC and VCUG in the evaluation of VUR . DRC provides continuous monitoring and low gonadal radiation exposure . DRC can be used in the diagnosis of VUR as an alternative to VCUG in selected cases PURPOSE Evaluation in children after febrile urinary tract infection involves voiding cystourethrogram , which emphasizes urinary reflux rather than renal risk . We believe that early dimercapto-succinic acid renal scan after febrile urinary tract infection predicts clinical ly significant reflux and which children should undergo voiding cystourethrogram . The criticism of this approach is that some reflux and preventable renal damage would be missed . This study vali date s the use of initial dimercapto-succinic scan and presents 5-year renal outcomes . MATERIAL S AND METHODS We prospect ively studied children with febrile urinary tract infection using initial dimercapto-succinic acid renal scan , voiding cystourethrogram and renal/bladder ultrasound . Children with anatomical or neurological genitourinary abnormality and protocol failures were excluded from analysis . Dimercapto-succinic acid scan was repeated at 6 months if initially abnormal . Followup was done every 6 months in all children for at least 5 years . RESULTS A total of 121 children fit study inclusion criteria and completed the 5-year study . Overall 88 initial dimercapto-succinic acid scans ( 73 % ) were abnormal and 78 children ( 64 % ) had urinary reflux . The OR of having clinical ly significant reflux predicted by abnormal initial scan was 35.4 . Abnormal followup scan did not predict clinical ly significant reflux . Overall subsequent urinary tract infection developed in 32 patients ( 26.5 % ) and 27 ( 85 % ) had an abnormal initial scan . No child with a normal initial scan had clinical ly significant reflux . CONCLUSIONS Dimercapto-succinic acid scan can predict clinical ly significant reflux and children at greatest renal risk . Initial dimercapto-succinic acid scan should be done in all children after febrile urinary tract infection while voiding cystourethrogram should be reserved for those with an abnormal initial dimercapto-succinic acid scan Background Vesicoureteric reflux ( VUR ) and its complications are common problems encountered in paediatric practice . Voiding cystourethrography ( VCU ) is the primary investigation of choice . Direct radionuclide cystography ( DRC ) is utilized in the follow-up evaluation of children diagnosed with VUR . However , VCU and DRC both require catheterization , which children do not tolerate well . Objective In this prospect i ve study we evaluated radionuclide cystography by direct supra-pubic puncture ( SDRC ) and instillation of the radiotracer into the bladder , avoiding catheterization . The results of this procedure were then compared with those of VCU . Patients and methods A total of 43 children ( eight females and 35 males ; mean age , 5.73±3.28 years ; range , 1.5–12 years ) were studied . Results Out of the total 86 renal units , SDRC showed VUR in 22 , whereas VCU showed VUR in 29 . The SDRC and VCU results were concordant in 77 ( 90 % ) out of 86 renal units in the detection of VUR . The sensitivity , specificity , positive predictive value , and negative predictive value of SDRC when compared to VCU were 75.86 % , 100 % , 100 % and 89 % , respectively . The overall accuracy of SDRC was 91.86 % . Conclusions The supra-pubic direct radionuclide cystography is a simple technique for detecting as well as grading VUR . The technique avoids catheterization , is well tolerated by children and is without significant side effects BACKGROUND This study was design ed to examine the capability of renal ultrasonography ( US ) for predicting vesicoureteral reflux ( VUR ) and renal scarring ( RS ) , and to assess , using initial US , the significant urologic abnormalities that impact on management of children hospitalized with a first febrile urinary tract infection ( UTI ) . METHODS Hospitalized children aged ≤ 2 years with a first febrile UTI were prospect ively evaluated using imaging studies , including (99m)Tc dimercaptosuccinic acid ( DMSA ) scan , US , and voiding cystourethrography . RESULTS Of the 310 children analyzed ( 195 boys and 115 girls ) , 105 ( 33.9 % ) had abnormal US . Acute DMSA scans were abnormal in 194 children ( 62.6 % ) , including 89 ( 45.9 % ) with concomitant abnormal US . There was VUR in 107 children ( 34.5 % ) , including 79 ( 25.5 % ) with Grade s III-V VUR . The sensitivity and negative predictive values of US were 52.3 % and 75.1 % , respectively , for Grade s I-V VUR and 68.4 % and 87.8 % , respectively , for Grade s III-V VUR . Eighty-five children ( 27.4 % ) had RS , including 55 ( 64.7 % ) with abnormal US . Of the 105 children with abnormal US , 33 ( 31.4 % ) needed subsequent management ( surgical intervention , parental counseling , or follow up of renal function ) . Nephromegaly on initial US and Grade s III-V VUR were risk factors of RS . CONCLUSION Abnormal US may carry a higher probability of Grade s III-V VUR and RS , and can affect subsequent management in a significant number of children . Nephromegaly on initial US and Grade s III-V VUR are strongly associated with an increased risk for RS . Thus , US should be performed on children after a first febrile UTI and children with normal US may not require voiding cystourethrography PURPOSE We investigated the prevalence and types of lower urinary tract dysfunction in children with vesicoureteral reflux grade s III and IV , and related improved dilating reflux , renal damage and recurrent urinary tract infection to dysfunction . MATERIAL S AND METHODS A total of 203 children between ages 1 to less than 2 years with reflux grade s III and IV were recruited into this open , r and omized , controlled , multicenter study . Voiding cystourethrography and dimercapto-succinic acid scintigraphy were done at study entry and 2-year followup . Lower urinary tract function was investigated by noninvasive methods , at study entry with 4-hour voiding observation in 148 patients and at 2 years by structured question naire and post-void residual flow measurement in 161 . RESULTS At study entry 20 % of patients had lower urinary tract dysfunction , characterized by high bladder capacity and increased post-void residual urine . At 2 years there was dysfunction in 34 % of patients . Subdivision into groups characteristic of children after toilet training revealed that 9 % had isolated overactive bladder and 24 % had voiding phase dysfunction . There was a negative correlation between dysfunction at 2 years and improved dilating reflux ( p = 0.002 ) . Renal damage at study entry and followup was associated with lower urinary tract dysfunction at 2 years ( p = 0.001 ) . Recurrent urinary tract infections were seen in 33 % of children with and in 20 % without dysfunction ( p = 0.084 ) . CONCLUSIONS After toilet training a third of these children with dilating reflux had lower urinary tract dysfunction , mainly voiding phase problems . Dysfunction was associated with persistent reflux and renal damage while dysfunction at study entry did not predict the 2-year outcome |
13,687 | 21,368,099 | The weak recommendations address the use of ib and ronate and strontium ranelate to prevent additional symptomatic fractures , the use of L2 nerve root blocks to treat the pain associated with L3 or L4 fractures , and the use of kyphoplasty to treat symptomatic fractures in patients who are neurologically intact | null | null |
13,688 | 29,019,796 | There was no mortality advantage of either modality versus st and ard care . | BACKGROUND Fluid administration in critically ill surgical patients must be closely monitored to avoid complications .
Resuscitation guided by invasive methods are not consistently associated with improved outcomes .
As such , there has been increased use of focused ultrasound and Arterial Pulse Waveform Analysis ( APWA ) to monitor and aid resuscitation .
An assessment of these methods using the Grading of Recommendations Assessment , Development , and Evaluation ( GRADE ) framework is presented . | Rationale : Assessment of fluid responsiveness relies on dynamic echocardiographic parameters that have not yet been compared in large cohorts . Objectives : To determine the diagnostic accuracy of dynamic parameters used to predict fluid responsiveness in ventilated patients with a circulatory failure of any cause . Methods : In this multicenter prospect i ve study , respiratory variations of superior vena cava diameter ( & Dgr;SVC ) measured using transesophageal echocardiography , of inferior vena cava diameter ( & Dgr;IVC ) measured using transthoracic echocardiography , of the maximal Doppler velocity in left ventricular outflow tract ( & Dgr;VmaxAo ) measured using either approach , and pulse pressure variations ( & Dgr;PP ) were recorded with the patient in the semirecumbent position . In each patient , a passive leg raise was performed and an increase of aortic velocity time integral greater than or equal to 10 % defined fluid responsiveness . Measurements and Main Results : Among 540 patients ( 379 men ; age , 65 ± 13 yr ; Simplified Acute Physiological Score II , 59 ± 18 ; Sequential Organ Failure Assessment , 10 ± 3 ) , 229 exhibited fluid responsiveness ( 42 % ) . & Dgr;PP , & Dgr;VmaxAo , & Dgr;SVC , and & Dgr;IVC could be measured in 78.5 % , 78.0 % , 99.6 % , and 78.1 % of cases , respectively . & Dgr;SVC greater than or equal to 21 % , & Dgr;VmaxAo greater than or equal to 10 % , and & Dgr;IVC greater than or equal to 8 % had a sensitivity of 61 % ( 95 % confidence interval , 57‐66 % ) , 79 % ( 75‐83 % ) , and 55 % ( 50‐59 % ) , respectively , and a specificity of 84 % ( 81‐87 % ) , 64 % ( 59‐69 % ) , and 70 % ( 66‐75 % ) , respectively . The area under the receiver operating characteristic curve of & Dgr;SVC was significantly greater than that of & Dgr;IVC ( P = 0.02 ) and & Dgr;PP ( P = 0.01 ) . Conclusions : & Dgr;VmaxAo had the best sensitivity and & Dgr;SVC the best specificity in predicting fluid responsiveness . & Dgr;SVC had a greater diagnostic accuracy than & Dgr;IVC and & Dgr;PP , but its measurement requires transesophageal echocardiography Introduction Acute hemodynamic instability increases morbidity and mortality . We investigated whether early non-invasive cardiac output monitoring enhances hemodynamic stabilization and improves outcome . Methods A multicenter , r and omized controlled trial was conducted in three European university hospital intensive care units in 2006 and 2007 . A total of 388 hemodynamically unstable patients identified during their first six hours in the intensive care unit ( ICU ) were r and omized to receive either non-invasive cardiac output monitoring for 24 hrs ( minimally invasive cardiac output/MICO group ; n = 201 ) or usual care ( control group ; n = 187 ) . The main outcome measure was the proportion of patients achieving hemodynamic stability within six hours of starting the study . Results The number of hemodynamic instability criteria at baseline ( MICO group mean 2.0 ( SD 1.0 ) , control group 1.8 ( 1.0 ) ; P = .06 ) and severity of illness ( SAPS II score ; MICO group 48 ( 18 ) , control group 48 ( 15 ) ; P = .86 ) ) were similar . At 6 hrs , 45 patients ( 22 % ) in the MICO group and 52 patients ( 28 % ) in the control group were hemodynamically stable ( mean difference 5 % ; 95 % confidence interval of the difference -3 to 14 % ; P = .24 ) . Hemodynamic support with fluids and vasoactive drugs , and pulmonary artery catheter use ( MICO group : 19 % , control group : 26 % ; P = .11 ) were similar in the two groups . The median length of ICU stay was 2.0 ( interquartile range 1.2 to 4.6 ) days in the MICO group and 2.5 ( 1.1 to 5.0 ) days in the control group ( P = .38 ) . The hospital mortality was 26 % in the MICO group and 21 % in the control group ( P = .34 ) . Conclusions Minimally-invasive cardiac output monitoring added to usual care does not facilitate early hemodynamic stabilization in the ICU , nor does it alter the hemodynamic support or outcome . Our results emphasize the need to evaluate technologies used to measure stroke volume and cardiac output -- especially their impact on the process of care -- before any large-scale outcome studies are attempted . Trial Registration The study was registered at Clinical Trials.gov ( Clinical Trials identifier NCT00354211 Introduction Several studies have shown that goal -directed hemodynamic and fluid optimization may result in improved outcome . However , the methods used were either invasive or had other limitations . The aim of this study was to perform intraoperative goal -directed therapy with a minimally invasive , easy to use device ( FloTrac/Vigileo ) , and to evaluate possible improvements in patient outcome determined by the duration of hospital stay and the incidence of complications compared to a st and ard management protocol . Methods In this r and omized , controlled trial 60 high-risk patients scheduled for major abdominal surgery were included . Patients were allocated into either an enhanced hemodynamic monitoring group using a cardiac index based intraoperative optimization protocol ( FloTrac/Vigileo device , GDT-group , n = 30 ) or a st and ard management group ( Control-group , n = 30 ) , based on st and ard monitoring data . Results The median duration of hospital stay was significantly reduced in the GDT-group with 15 ( 12 - 17.75 ) days versus 19 ( 14 - 23.5 ) days ( P = 0.006 ) and fewer patients developed complications than in the Control-group [ 6 patients ( 20 % ) versus 15 patients ( 50 % ) , P = 0.03 ] . The total number of complications was reduced in the GDT-group ( 17 versus 49 complications , P = 0.001 ) . Conclusions In high-risk patients undergoing major abdominal surgery , implementation of an intraoperative goal -directed hemodynamic optimization protocol using the FloTrac/Vigileo device was associated with a reduced length of hospital stay and a lower incidence of complications compared to a st and ard management protocol .Trial Registration Clinical trial registration information : Unique identifier : STUDY OBJECTIVE Annually , 38 million people are evaluated for trauma , the leading cause of death in persons younger than 45 years . The primary objective is to assess whether using a protocol inclusive of point-of-care , limited ultrasonography ( PLUS ) , compared to usual care ( control ) , among patients presenting to the emergency department ( ED ) with suspected torso trauma decreased time to operative care . METHODS The study was a r and omized controlled clinical trial conducted during a 6-month period at 2 Level I trauma centers . The intervention was PLUS conducted by verified clinician sonographers . The primary outcome measure was time from ED arrival to transfer to operative care ; secondary outcomes included computed tomography ( CT ) use , length of stay , complications , and charges . Regression models controlled for confounders and analyzed physician-to-physician variability . All analyses were conducted on an intention-to-treat basis . Results are presented as mean , first-quartile , median , and third-quartile , with multiplicative change and 95 % confidence intervals ( CIs ) , or percentage with odds ratio and 95 % CIs . RESULTS Four hundred forty-four patients with suspected torso trauma were eligible ; 136 patients lacked consent , and attending physicians refused enrollment of 46 patients . Two hundred sixty-two patients were enrolled : 135 PLUS patients and 127 controls . There were no important differences between groups . Time to operative care was 64 % ( 48 , 76 ) less for PLUS compared to control patients . PLUS patients underwent fewer CTs ( odds ratio 0.16 ) ( 0.07 , 0.32 ) , spent 27 % ( 1 , 46 ) fewer days in hospital , and had fewer complications ( odds ratio 0.16 ) ( 0.07 , 0.32 ) , and charges were 35 % ( 19 , 48 ) less compared to control . CONCLUSION A PLUS-inclusive protocol significantly decreased time to operative care in patients with suspected torso trauma , with improved re source use and lower charges This pilot trial aims at gaining support for the optimization of acute burn resuscitation through noninvasive continuous real-time hemodynamic monitoring using arterial pulse contour analysis . A group of 21 burned patients meeting preliminary criteria ( age range 18–75 years with second- third- degree burns and TBSA ≥10–75 % ) was r and omized during 2010 . A hemodynamic monitoring through lithium dilution cardiac output was used in 10 r and omized patients ( LiDCO group ) , whereas those without LiDCO monitoring were defined as the control group . The modified Brooke/Parkl and formula as a starting resuscitative formula , balanced crystalloids as the initial solutions , urine output of 0.5 ml/kg/hr as a crucial value of adequate intravascular filling were used in both groups . Additionally , the volume and vasopressor/inotropic support were based on dynamic preload parameters in the LiDCO group in the case of circulatory instability and oligouria . Statistical analysis was done using t-tests . Within the first 24 hours postburn , a significantly lower consumption of crystalloids was registered in LiDCO group ( P = .04 ) . The fluid balance under LiDCO control in combination with hourly diuresis contributed to reducing the cumulative fluid balance approximately by 10 % compared with fluid management based on st and ard monitoring parameters . The amount of applied solutions in the LiDCO group got closer to Brooke formula whereas the urine output was at the same level in both groups ( 0.8 ml/kg/hr ) . The new finding in this study is that when a fluid resuscitation is based on the arterial waveform analysis , the initial fluid volume provided was significantly lower than that delivered on the basis of physician-directed fluid resuscitation ( by urine output and mean arterial pressure ) . ( J Burn Care Res 2013;34:537–542 Pulse pressure variation can predict fluid responsiveness in strict applicability conditions . The purpose of this study was to describe the clinical applicability of pulse pressure variation during episodes of patient hemodynamic instability in the intensive care unit . We conducted a five-day , seven-center prospect i ve study that included patients presenting with an unstable hemodynamic event . The six predefined inclusion criteria for pulse pressure variation applicability were as follows : mechanical ventilation , tidal volume > 7 mL/kg , sinus rhythm , no spontaneous breath , heart rate/respiratory rate ratio > 3.6 , absence of right ventricular dysfunction , or severe valvulopathy . Seventy-three patients presented at least one unstable hemodynamic event , with a total of 163 unstable hemodynamic events . The six predefined criteria for the applicability of pulse pressure variation were completely present in only 7 % of these . This data indicates that PPV should only be used alongside a strong underst and ing of the relevant physiology and applicability criteria . Although these exclusion criteria appear to be profound , they likely represent an absolute contraindication of use for only a minority of critical care patients Background Fluid challenges ( FCs ) are one of the most commonly used therapies in critically ill patients and represent the cornerstone of hemodynamic management in intensive care units . There are clear benefits and harms from fluid therapy . Limited data on the indication , type , amount and rate of an FC in critically ill patients exist in the literature . The primary aim was to evaluate how physicians conduct FCs in terms of type , volume , and rate of given fluid ; the secondary aim was to evaluate variables used to trigger an FC and to compare the proportion of patients receiving further fluid administration based on the response to the FC . Methods This was an observational study conducted in ICUs around the world . Each participating unit entered a maximum of 20 patients with one FC . Results 2213 patients were enrolled and analyzed in the study . The median [ interquartile range ] amount of fluid given during an FC was 500 ml ( 500–1000 ) . The median time was 24 min ( 40–60 min ) , and the median rate of FC was 1000 [ 500–1333 ] ml/h . The main indication for FC was hypotension in 1211 ( 59 % , CI 57–61 % ) . In 43 % ( CI 41–45 % ) of the cases no hemodynamic variable was used . Static markers of preload were used in 785 of 2213 cases ( 36 % , CI 34–37 % ) . Dynamic indices of preload responsiveness were used in 483 of 2213 cases ( 22 % , CI 20–24 % ) . No safety variable for the FC was used in 72 % ( CI 70–74 % ) of the cases . There was no statistically significant difference in the proportion of patients who received further fluids after the FC between those with a positive , with an uncertain or with a negatively judged response . Conclusions The current practice and evaluation of FC in critically ill patients are highly variable . Prediction of fluid responsiveness is not used routinely , safety limits are rarely used , and information from previous failed FCs is not always taken into account Objective To investigate whether the respiratory variation in inferior vena cava diameter ( ΔDIVC ) could be related to fluid responsiveness in mechanically ventilated patients . Design Prospect i ve clinical study . Setting Medical ICU of a non-university hospital . Patients Mechanically ventilated patients with septic shock ( n=39 ) . Interventions Volume loading with 8 mL/kg of 6 % hydroxyethylstarch over 20 min . Measurements and results Cardiac output and ΔDIVC were assessed by echography before and immediately after the st and ardized volume load . Volume loading induced an increase in cardiac output from 5.7±2.0 to 6.4±1.9 L/min ( P<0.001 ) and a decrease in ΔDIVC from 13.8±13.6 vs 5.2±5.8 % ( P<0.001 ) . Sixteen patients responded to volume loading by an increase in cardiac output ≥15 % ( responders ) . Before volume loading , the ΔDIVC was greater in responders than in non-responders ( 25±15 vs 6±4 % , P<0.001 ) , closely correlated with the increase in cardiac output ( r=0.82 , P<0.001 ) , and a 12 % ΔDIVC cut-off value allowed identification of responders with positive and negative predictive values of 93 % and 92 % , respectively . Conclusion Analysis of ΔDIVC is a simple and non-invasive method to detect fluid responsiveness in mechanically ventilated patients with septic shock OBJECTIVES Sonographic measurement of the inferior vena cava ( IVC ) caval index predicts central venous pressure in ED patients . Fluid responsiveness ( FR ) is a measure of preload dependence defined as an increase in cardiac output secondary to volume expansion . We sought to determine if the caval index is an accurate measurement of FR in ED patients . METHODS We conducted a prospect i ve , observational trial at an urban , academic , adult ED with an annual census > 105 000 . Included patients were clinical ly suspected of eu- and hypovolemia . Excluded patients were < 18 years old , pregnant , incarcerated , sustained significant trauma or unable to consent . Supine IVC diameter was measured by bedside ultrasonography ( M-Turbo ; Sonosite , Bothwell , WA , USA ) . Caval index = [ ( expiratory IVC diameter - inspiratory IVC diameter)/expiratory IVC diameter ] × 100 . FR was defined as an increase in the cardiac index by > 10 % by impedance cardiography ( BioZ ; Sonosite ) following passive leg raise . The primary outcome was analysed using Spearman correlations for non-parametric data and the area under the receiver operating characteristics curve by Wilcoxon method . RESULTS Thirty patients were enrolled ; four were excluded because of incomplete data collection . Thirty-one per cent ( 95 % CI 13 - 48 ) of the patients were FR . The mean initial caval and cardiac index were 15.8 % ( 95 % CI 9.5 - 22 ) and 2.9 L/min/m(2 ) ( 95 % CI 2.6 - 3.2 ) , respectively . Caval index did not predict FR ( receiver operating curve = 0.46 , 95 % CI 0.21 - 0.71 , P = 0.63 ) . CONCLUSION Bedside sonographic measurement of IVC caval index does not predict FR in a heterogeneous ED patient population . Further research using this technique in targeted patient subsets and a variety of shock etiologies is needed Haemodynamic goal -directed therapies ( GDT ) may improve outcome following elective major surgery . So far , few data exist regarding haemodynamic optimization during emergency surgery . In this r and omized , controlled trial , 50 surgical patients with hypovolemic or septic conditions were enrolled and we compared two algorithms of GDTs based either on conventional parameters and pressure pulse variation ( control group ) or on cardiac index , global end-diastolic volume index and stroke volume variation as derived from the PiCCO monitoring system ( optimized group ) . Postoperative outcome was estimated by a composite index including major complications and by the Sequential Organ Failure Assessment ( SOFA ) Score within the first 3 days after surgery ( POD1 , POD2 and POD3 ) . Data from 43 patients were analyzed ( control group , N = 23 ; optimized group , N = 20 ) . Similar amounts of fluid were given in the two groups . Intraoperatively , dobutamine was given in 45 % optimized patients but in no control patients . Major complications occurred more frequently in the optimized group [ 19 ( 95 % ) versus 10 ( 40 % ) in the control group , P < 0.001 ] . Likewise , SOFA scores were higher in the optimized group on POD1 ( 10.2 ± 2.5 versus 6.6 ± 2.2 in the control group , P = 0.001 ) , POD2 ( 8.4 ± 2.6 vs 5.0 ± 2.4 in the control group , P = 0.002 ) and POD 3 ( 5.2 ± 3.6 and 2.2 ± 1.3 in the control group , P = 0.01 ) . There was no significant difference in hospital mortality ( 13 % in the control group and 25 % in the optimized group ) . Haemodynamic optimization based on volumetric and flow PiCCO-derived parameters was associated with a less favorable postoperative outcome compared with a conventional GDT protocol during emergency surgery Introduction Stroke volume variation ( SVV ) is a good and easily obtainable predictor of fluid responsiveness , which can be used to guide fluid therapy in mechanically ventilated patients . During major abdominal surgery , inappropriate fluid management may result in occult organ hypoperfusion or fluid overload in patients with compromised cardiovascular reserves and thus increase postoperative morbidity . The aim of our study was to evaluate the influence of SVV guided fluid optimization on organ functions and postoperative morbidity in high risk patients undergoing major abdominal surgery . Methods Patients undergoing elective intraabdominal surgery were r and omly assigned to a Control group ( n = 60 ) with routine intraoperative care and a Vigileo group ( n = 60 ) , where fluid management was guided by SVV ( Vigileo/FloTrac system ) . The aim was to maintain the SVV below 10 % using colloid boluses of 3 ml/kg . The laboratory parameters of organ hypoperfusion in perioperative period , the number of infectious and organ complications on day 30 after the operation , and the hospital and ICU length of stay and mortality were evaluated . The local ethics committee approved the study . Results The patients in the Vigileo group received more colloid ( 1425 ml [ 1000 - 1500 ] vs. 1000 ml [ 540 - 1250 ] ; P = 0.0028 ) intraoperatively and a lower number of hypotensive events were observed ( 2[1 - 2 ] Vigileo vs. 3.5[2 - 6 ] in Control ; P = 0.0001 ) . Lactate levels at the end of surgery were lower in Vigileo ( 1.78 ± 0.83 mmol/l vs. 2.25 ± 1.12 mmol/l ; P = 0.0252 ) . Fewer Vigileo patients developed complications ( 18 ( 30 % ) vs. 35 ( 58.3 % ) patients ; P = 0.0033 ) and the overall number of complications was also reduced ( 34 vs. 77 complications in Vigileo and Control respectively ; P = 0.0066 ) . A difference in hospital length of stay was found only in per protocol analysis of patients receiving optimization ( 9 [ 8 - 12 ] vs. 10 [ 8 - 19 ] days ; P = 0.0421 ) . No difference in mortality ( 1 ( 1.7 % ) vs. 2 ( 3.3 % ) ; P = 1.0 ) and ICU length of stay ( 3 [ 2 - 5 ] vs. 3 [ 0.5 - 5 ] ; P = 0.789 ) was found . Conclusions In this study , fluid optimization guided by SVV during major abdominal surgery is associated with better intraoperative hemodynamic stability , decrease in serum lactate at the end of surgery and lower incidence of postoperative organ complications . Trial registration Current Controlled Trials IS RCT N95085011 Background : Stroke volume variation ( SVV ) has been shown to be a reliable predictor of fluid responsiveness . However , the predictive role of SVV measured by FloTrac/Vigileo system in prediction of fluid responsiveness was unproven in patients undergoing ventilation with low tidal volume . Methods : Fifty patients undergoing elective gastrointestinal surgery were r and omly divided into two groups : Group C [ n1=20 , tidal volume ( Vt ) = 8 ml/kg , frequency ( F ) = 12/min ] and Group L [ n2=30 , Vt= 6 ml/kg , F=16/min ] . After anesthesia induction , 6 % hydroxyethyl starch130/0.4 solution ( 7 ml/kg ) was intravenously transfused . Besides st and ard haemodynamic monitoring , SVV , cardiac output , cardiac index ( CI ) , stroke volume ( SV ) , stroke volume index ( SVI ) , systemic vascular resistance ( SVR ) and systemic vascular resistance index ( SVRI ) were determined with the FloTrac/Vigileo system before and after fluid loading . Results : After fluid loading , the MAP , CVP , SVI and CI increased significantly , whereas the SVV and SVR decreased markedly in both groups . SVI was significantly correlated to the SVV , CVP but not the HR , MAP and SVR . SVI was significantly correlated to the SVV before fluid loading ( Group C : r = 0.909 ; Group L : r = 0.758 ) but not the HR , MAP , CVP and SVR before fluid loading . The largest area under the ROC curve ( AUC ) was found for SVV ( Group C , 0.852 ; Group L , 0.814 ) , and the AUC for other preloading indices in two groups ranged from 0.324 to 0.460 . Conclusion : SVV measured by FloTrac/Vigileo system can predict fluid responsiveness in patients undergoing ventilation with low tidal volumes during gastrointestinal surgery Introduction We have almost no information concerning the value of inferior vena cava ( IVC ) respiratory variations in spontaneously breathing ICU patients ( SBP ) to predict fluid responsiveness . Methods SBP with clinical fluid need were included prospect ively in the study . Echocardiography and Doppler ultrasound were used to record the aortic velocity-time integral ( VTI ) , stroke volume ( SV ) , cardiac output ( CO ) and IVC collapsibility index ( cIVC ) ( ( maximum diameter (IVCmax)– minimum diameter (IVCmin))/ IVCmax ) at baseline , after a passive leg-raising maneuver ( PLR ) and after 500 ml of saline infusion . Results Fifty-nine patients ( 30 males and 29 females ; 57 ± 18 years-old ) were included in the study . Of these , 29 ( 49 % ) were considered to be responders ( ≥10 % increase in CO after fluid infusion ) . There were no significant differences between responders and nonresponders at baseline , except for a higher aortic VTI in nonresponders ( 16 cm vs. 19 cm , p = 0.03 ) . Responders had a lower baseline IVCmin than nonresponders ( 11 ± 5 mm vs. 14 ± 5 mm , p = 0.04 ) and more marked IVC variations ( cIVC : 35 ± 16 vs. 27 ± 10 % , p = 0.04 ) . Prediction of fluid-responsiveness using cIVC and IVCmax was low ( area under the curve for cIVC at baseline 0.62 ± 0.07 ; 95 % , CI 0.49 - 0.74 and for IVCmax at baseline 0.62 ± 0.07 ; 95 % CI 0.49 - 0.75 ) . In contrast , IVC respiratory variations > 42 % in SBP demonstrated a high specificity ( 97 % ) and a positive predictive value ( 90 % ) to predict an increase in CO after fluid infusion . Conclusions In SBP with suspected hypovolemia , vena cava size and respiratory variability do not predict fluid responsiveness . In contrast , a cIVC > 42 % may predict an increase in CO after fluid infusion BACKGROUND Fluid management guided by oesophageal Doppler monitor has been reported to improve perioperative outcome . Stroke volume variation ( SVV ) is considered a reliable clinical predictor of fluid responsiveness . Consequently , the aim of the present trial was to evaluate the accuracy of SVV determined by arterial pulse contour ( APCO ) analysis , using the FloTrac/Vigileo system , to predict fluid responsiveness as measured by the oesophageal Doppler . METHODS Patients undergoing major abdominal surgery received intraoperative fluid management guided by oesophageal Doppler monitoring . Fluid boluses of 250 ml each were administered in case of a decrease in corrected flow time ( FTc ) to < 350 ms . Patients were connected to a monitoring device , obtaining SVV by APCO . Haemodynamic variables were recorded before and after fluid bolus application . Fluid responsiveness was defined as an increase in stroke volume index > 10 % . The ability of SVV to predict fluid responsiveness was assessed by calculation of the area under the receiver operating characteristic ( ROC ) curve . RESULTS Twenty patients received 67 fluid boluses . Fifty-two of the 67 fluid boluses administered result ed in fluid responsiveness . SVV achieved an area under the ROC curve of 0.512 [ confidence interval ( CI ) 0.32 - 0.70 ] . A cut-off point for fluid responsiveness was found for SVV > or = 8.5 % ( sensitivity : 77 % ; specificity : 43 % ; positive predictive value : 84 % ; and negative predictive value : 33 % ) . CONCLUSIONS This prospect i ve , interventional observer-blinded study demonstrates that SVV obtained by APCO , using the FloTrac/Vigileo system , is not a reliable predictor of fluid responsiveness in the setting of major abdominal surgery Objectives The aim of this study was to assess and compare the ability of the automatically and continuously measured stroke volume variation ( SVV ) obtained by FloTrac/Vigileo , and pulse pressure variation ( PPV ) measured by an IntelliVue MP monitor , to predict fluid responsiveness in mechanically ventilated septic shock patients . Method We conducted a prospect i ve study on 42 septic shock patients . SVV , PPV and other haemodynamic data were recorded before and after fluid administration of 500 ml of 6 % hydroxyethyl starch . Responders were defined as patients with an increase in stroke volume index of at least 15 % after fluid loading . Results Twenty-four ( 57.1 % ) patients were classified as fluid responders . The baseline SVV correlated with the baseline PPV ( r = 0.96 , P < 0.001 ) . SVV and PPV were significantly higher in responders than in nonresponders ( 15.5 ± 4.5 vs. 8.2 ± 3.3 % and 16.4 ± 5.2 vs. 8.3 ± 3.5 , respectively , P < 0.001 for both ) . There was no difference between the area under the receiver operating characteristic curves of SVV [ 0.92 , 95 % confidence interval 0.832–1.00 ] and PPV ( 0.916 , 95 % confidence interval 0.829–1.00 ) . The optimal threshold values in predicting fluid responsiveness were 10 % for SVV ( sensitivity 91.7 % and specificity 83.3 % ) and 12 % for PPV ( sensitivity 83.3 % and specificity 83.3 % ) . Our results were independent of the site of arterial catheterisation . Conclusion The SVV , obtained by FloTrac/Vigileo , and the automated PPV , obtained by the IntelliVue MP monitor , showed comparable performance in terms of predicting fluid responsiveness in passively ventilated septic shock patients , with a regular cardiac rhythm and a tidal volume not less than 8 ml kg−1 PURPOSE The purpose of the study was to compare the effect of limited echocardiography (LE)-guided therapy to st and ard management on 28-day mortality , intravenous fluid prescription , and inotropic dosing following early resuscitation for shock . MATERIAL S AND METHODS Two hundred twenty critically ill patients with undifferentiated shock from a quaternary intensive care unit were included in the study . The LE group consisted of 110 consecutive patients prospect ively studied over a 12-month period receiving LE-guided management . The st and ard management group consisted of 110 consecutive patients retrospectively studied with shock immediately prior to the LE intervention . RESULTS In the LE group , fluid restriction was recommended in 71 ( 65 % ) patients and initiation of dobutamine in 27 ( 25 % ) . Fluid prescription during the first 24 hours was significantly lower in LE patients ( 49 [ 33 - 74 ] vs 66 [ 42 - 100 ] mL/kg , P = .01 ) , whereas 55 % more LE patients received dobutamine ( 22 % vs 12 % , P = .01 ) . The LE patients had improved 28-day survival ( 66 % vs 56 % , P = .04 ) , a reduction in stage 3 acute kidney injury ( 20 % vs 39 % ) , and more days alive and free of renal support ( 28 [ 9.7 - 28 ] vs 25 [ 5 - 28 ] , P = .04 ) . CONCLUSIONS Limited echocardiography-guided management following early resuscitation is associated with improved survival , less fluid , and increased inotropic prescription . A prospect i ve r and omized control trial is required to verify these results Objective In mechanically ventilated patients inspiratory increase in pleural pressure during lung inflation may produce complete or partial collapse of the superior vena cava . Occurrence of this collapse suggests that at this time external pressure exerted by the thoracic cavity on the superior vena cava is greater than the venous pressure required to maintain the vessel fully open . We tested the hypothesis that measurement of superior vena caval collapsibility would reveal the need for volume expansion in a given septic patient . Design and setting Prospect i ve data collection for 66 successive patients in septic shock admitted in a medical intensive care unit and mechanically ventilated for an associated acute lung injury . Measurements and results We simultaneously measured superior vena caval collapsibility by echocardiography and cardiac index by the Doppler technique at baseline and after a 10 ml/kg volume expansion by 6 % hydroxyethyl starch in 30 min . The threshold superior vena caval collapsibility of 36 % , calculated as ( maximum diameter on expiration−minimum diameter on inspiration)/maximum diameter on expiration , allowed discrimination between responders ( defined by an increase in cardiac index of at least 11 % induced by volume expansion ) and nonresponders , with a sensitivity of 90 % and a specificity of 100 % . Conclusions Superior vena cava measurement should be systematic ally performed during routine echocardiography in septic shock as it gives an accurate index of fluid responsiveness OBJECTIVES To evaluate the therapeutic effect of early fluid resuscitation under the guidance of Pulse indicator Continuous Cardiac Output ( PiCCO ) on patients with severe acute pancreatitis ( SAP ) . METHODS Clinical data of 18 SAP patients ( the study group ) , who had undergone fluid resuscitation under the guidance of PiCCO from October 2011 to October 2013 , were analyzed prospect ively . Clinical data of 25 cases ( control group ) who had undergone fluid resuscitation without the guidance of PiCCO from January 2009 to September 2011 were collected . Then , retrospective and prospect i ve case-control study was carried out . RESULTS During the first 6 h , 0 - 24 h , 24 - 48 h , and 0 - 72 h of admission , the study group received more volume of fluid than the control group . There were significantly faster decline of APACHE II score and the value of blood lactate in study group , as well as the length of ICU stay and the proportion of renal failure at 72 h of admission . According to the 2012 Atlanta classification , six cases in study group turned into moderate SAP ( 33.30 % ) , significantly higher than the control group ( 8.00 % ) ( p = 0.0049 ) . The volume of fluid infusion and clinical parameters were linearly relative . CONCLUSIONS The PiCCO device may be a useful adjunct for fluid resuscitation monitoring in patients with SAP in the early stage . Early fluid resuscitation under the guidance of PiCCO can improve tissue perfusion , reduce the SIRS persistence time and the length of ICU stay . This program did not increase the risk of respiratory failure and influence the mortality OBJECTIVES The aim of this study was to assess the feasibility and effects on perioperative management of a focused transthoracic echocardiogram performed by anesthesiologists . DESIGN A prospect i ve observational study of all patients having a focused cardiovascular ultrasound ( FoCUS ) . SETTING A single tertiary referral university teaching hospital . PARTICIPANTS Fifty consecutive perioperative patients who had a clinical indication for a FoCUS . INTERVENTIONS After performing a FoCUS , relevant clinical information was communicated to the anesthesiologist in charge of the case , who then decided on the appropriate management of the patient including the choice of anesthesia , invasive monitoring , fluids , vasoactive drugs , and postoperative care . If indicated , patients were referred for a formal cardiology-based transthoracic echocardiogram . MEASUREMENTS AND MAIN RESULTS Anesthesiologists were able to obtain diagnostic- quality images during a FoCUS in 98 % of patients . The most common indication for a FoCUS was an undifferentiated ejection systolic murmur in 50 % of cases , with 38 % of all patients having aortic stenosis . In 84 % of patients , some change in their perioperative care occurred as a result of the FoCUS study . Major findings correlated with a formal cardiology-based transthoracic echocardiogram in 87 % of cases . CONCLUSION Anesthesiologists with a cardiac and echocardiography background can successfully perform a FoCUS in almost all patients when indicated , which provides valuable new diagnostic information guiding changes in perioperative management in the majority of patients BACKGROUND The term secondary abdominal compartment syndrome ( ACS ) has been applied to describe trauma patients who develop ACS but do not have abdominal injuries . The purpose of this study was to describe major trauma victims who developed secondary ACS during st and ardized shock resuscitation . METHODS Our prospect i ve data base for st and ardized shock resuscitation was review ed to obtain before and after abdominal decompression shock related data for secondary ACS patients . Focused chart review was done to confirm time-related outcomes . RESULTS Over the 30 months period ending May 2001 , 11 ( 9 % ) of 128 st and ardized shock resuscitation patients developed secondary ACS . All presented in severe shock ( systolic blood pressure 85 + /- 5 mm Hg , base deficit 8.6 + /- 1.6 mEq/L ) , with severe injuries ( injury severity score 28 + /- 3 ) and required aggressive shock resuscitation ( 26 + /- 2 units of blood , 38 + /- 3 L crystalloid within 24 hours ) . All cases of secondary ACS were recognized and decompressed within 24 hours of hospital admission . After decompression , the bladder pressure and the systemic vascular resistance decreased , while the mean arterial pressure , cardiac index , and static lung compliance increased . The mortality rate was 54 % . Those who died failed to respond to decompression with increased cardiac index and did not maintain decreased bladder pressure . CONCLUSIONS Secondary ACS is an early but , if appropriately monitored , recognizable complication in patients with major nonabdominal trauma who require aggressive resuscitation Perioperative hemodynamic optimisation improves postoperative outcome for patients undergoing high-risk surgery ( HRS ) . In this prospect i ve r and omized multicentre study we studied the effects of an individualized , goal -directed fluid management based on continuous stroke volume variation ( SVV ) and stroke volume ( SV ) monitoring on postoperative outcomes . 64 patients undergoing HRS were r and omized either to a control group ( CON , n = 32 ) or a goal -directed group ( GDT , n = 32 ) . In GDT , SVV and SV were continuously monitored ( FloTrac/Vigileo ) and patients were brought to and maintained on the plateau of the Frank-Starling curve ( SVV < 10 % and SV increase < 10 % in response to fluid loading ) . Organ dysfunction was assessed using the SOFA score and re source utilization using the TISS score . Patients were followed up to 28 days for postoperative complications . Main outcome measures were the number of complications ( infectious , cardiac , respiratory , renal , hematologic and abdominal post-operative complications ) , maximum SOFA score and cumulative TISS score during ICU stay , duration of mechanical ventilation , length of ICU stay , and time until fit for discharge . 12 patients had to be excluded from final analysis ( 6 in each group ) . During surgery , GDT received more colloids than CON ( 1,589 vs. 927 ml , P < 0.05 ) and SVV decreased in GDT ( from 9.0 to 8.0 % , P < 0.05 ) but not in CON . The number of postoperative wound infections was lower in GDT ( 0 vs. 7 , P < 0.01 ) . Although not statistically significant , the proportion of patients with at least one complication ( 46 vs. 62 % ) , the number of postoperative complications per patient ( 0.65 vs. 1.40 ) , the maximum sofa score ( 5.9 vs. 7.2 ) , and the cumulative TISS score ( 69 vs. 83 ) tended to be lower . This multicentre study shows that fluid management based on a SVV and SV optimisation protocol is feasible and decreases postoperative wound infections . Our findings also suggest that a goal -directed strategy might decrease postoperative organ dysfunction The hypothesis of this study states that in emergency department ( ED ) patients with non-traumatic symptomatic hypotension , the presence of hyperdynamic left ventricular function ( LVF ) is specific for sepsis as the etiology of shock . We performed a secondary analysis of patients with non-traumatic symptomatic hypotension enrolled in a r and omized , clinical diagnostic trial . The study was done in an urban tertiary ED with a census over 100,000 visits per year . Inclusion criteria were non-trauma ED patients aged > 17 years , initial vital signs consistent with shock ( systolic blood pressure < 100 mm Hg or shock index > 1.0 ) , and agreement of two independent observers for one sign and symptom of circulatory shock . All patients underwent focused ED echocardiography ( echo ) during initial resuscitation . Echos were review ed post-hoc by a blinded physician and categorized by qualitative LVF as hyperdynamic ( ejection fraction [ EF ] > 55 % ) , normal to moderate impairment ( EF 30%-55 % ) , and severe impairment ( EF < 30 % ) . Main outcome was the criterion st and ard diagnosis of septic shock . Analyses include the diagnostic performance of LVF , Cohen 's kappa for interobserver agreement of LVF , and logistic regression for independent predictors of sepsis . There were 103 echos that were adequate for analysis . The mean age was 57+/-16.7 years , 59 % were male , and the mean initial systolic blood pressure was 83+/-11.3 mm Hg . A final diagnosis of septic shock was made in 38 % ( 39/103 ) of patients . Seventeen of 103 ( 17 % ) patients had hyperdynamic LVF with an interobserver agreement of kappa=0.8 . The sensitivity and specificity of hyperdynamic LVF for predicting sepsis were 33 % ( 95 % CI 19%-50 % ) and 94 % ( 85%-98 % ) , respectively . Hyperdynamic LVF had a positive likelihood ratio of 5.3 for the diagnosis of sepsis and was a strong independent predictor of sepsis as the final diagnosis with an odds ratio of 5.5 ( 95 % CI 1.1 - 45 ) . Among ED patients with non-traumatic undifferentiated symptomatic hypotension , the presence of hyperdynamic LVF on focused echo is highly specific for sepsis as the etiology of shock BACKGROUND Critically ill patients often require invasive monitoring to evaluate and optimize cardiac function and preload . With question able outcomes associated with pulmonary artery catheters ( PACs ) , some have evaluated the role of less invasive monitors . We hypothesized that the Bedside Echocardiographic Assessment in Trauma ( BEAT ) examination would generate cardiac index ( CI ) and central venous pressure ( CVP ) estimates that correlate with that of a PAC . METHODS BEAT was performed on all SICU patients with a PAC in place . Prospect i ve data included stroke volume and the inferior vena cava ( IVC ) diameter . The CI was calculated and correlated with that from the PAC . Each CI was then categorized as low , normal , or high . The IVC diameter was used to estimate the CVP . The association between the BEAT and PAC estimates of CI and CVP was evaluated using chi . RESULTS Eighty-five BEAT examinations were performed , 57 % on trauma and 37 % on general surgery patients . Fifty-nine percent of the CI examinations and 97 % of the IVC examinations contained quality images . Of these , the overall correlation coefficient was 0.70 ( p < 0.0001 ) . When CI was categorized , there was a significant association between the BEAT and PAC ( p = 0.021 ) . There was a significant association between the CVP estimate from the BEAT examination and the PAC ( p = 0.031 ) . CONCLUSION Our data show a significant correlation between the CI and CVP estimates obtained from the BEAT examination and that from a PAC . BEAT provides a noninvasive method of evaluating cardiac function and volume status . Bedside echocardiography is teachable and should become a part of future critical care curricula Background : Stroke volume variation ( SVV ) – as measured by the pulse contour cardiac output ( PiCCO ® ) system – predicts the cardiac output response to a fluid challenge in patients on controlled ventilation . Whether this applies to patients on pressure support ventilation is unknown Objective : We examined a physician-performed , goal -directed ultrasound protocol for the emergency department management of nontraumatic , symptomatic , undifferentiated hypotension . Design : R and omized , controlled trial of immediate vs. delayed ultrasound . Setting : Urban , tertiary emergency department , census > 100,000 . Patients : Nontrauma emergency department patients , aged > 17 yrs , and initial emergency department vital signs consistent with shock ( systolic blood pressure < 100 mm Hg or shock index > 1.0 ) , and agreement of two independent observers for at least one sign and symptom of inadequate tissue perfusion . Interventions : Group 1 ( immediate ultrasound ) received st and ard care plus goal -directed ultrasound at time 0 . Group 2 ( delayed ultrasound ) received st and ard care for 15 mins and goal -directed ultrasound with st and ard care between 15 and 30 mins after time 0 . Measurements and Main Results : Outcomes included the number of viable physician diagnoses at 15 mins and the rank of their likelihood of occurrence at both 15 and 30 mins . One hundred eighty-four patients were included . Group 1 ( n = 88 ) had a smaller median number of viable diagnoses at 15 mins ( median = 4 ) than did group 2 ( n = 96 , median = 9 , Mann-Whitney U test , p < .0001 ) . Physicians indicated the correct final diagnosis as most likely among their viable diagnosis list at 15 mins in 80 % ( 95 % confidence interval , 70–87 % ) of group 1 subjects vs. 50 % ( 95 % confidence interval , 40–60 % ) in group 2 , difference of 30 % ( 95 % confidence interval , 16–42 % ) . Conclusions : Incorporation of a goal -directed ultrasound protocol in the evaluation of nontraumatic , symptomatic , undifferentiated hypotension in adult patients results in fewer viable diagnostic etiologies and a more accurate physician impression of final diagnosis Purpose To compare treatment based on either PiCCO-derived physiological values or central venous pressure ( CVP ) monitoring , we performed a prospect i ve r and omized controlled trial with group sequential analysis . Methods Consecutive critically ill patients with septic shock and /or ARDS were included . The planned total sample size was 715 . The primary outcome was 28-day mortality after r and omization . Participants underwent stratified r and omization according to the classification of ARDS and /or septic shock . Caregivers were not blinded to the intervention , but participants and outcome assessors were blinded to group assignment . Results The study was stopped early because of futility after enrollment of 350 patients including 168 in the PiCCO group and 182 in the control group . There was no loss to follow-up and data from all enrolled participants were analyzed . The result showed that treatment based on PiCCO-derived physiological values was not able to reduce the 28-day mortality risk ( odds ratio 1.00 , 95 % CI 0.66–1.52 ; p = 0.993 ) . There was no difference between the two groups in secondary outcomes such as 14-day mortality ( 40.5 vs. 41.2 % ; p = 0.889 ) , ICU length of stay ( median 9 vs. 7.5 days ; p = 0.598 ) , days free of vasopressors ( median 14.5 vs. 19 days ; p = 0.676 ) , and days free of mechanical ventilation ( median 3 vs. 6 days ; p = 0.168 ) . No severe adverse event was reported in both groups . Conclusion On the basis of our study , PICCO-based fluid management does not improve outcome when compared to CVP-based fluid management Objective To evaluate the extent to which respiratory changes in inferior vena cava ( IVC ) diameter can be used to predict fluid responsiveness . Design Prospect i ve clinical study . Setting Hospital intensive care unit . Patients Twenty-three patients with acute circulatory failure related to sepsis and mechanically ventilated because of an acute lung injury . Measurements Inferior vena cava diameter ( D ) at end-expiration ( Dmin ) and at end-inspiration ( Dmax ) was measured by echocardiography using a subcostal approach . The distensibility index of the IVC ( dIVC ) was calculated as the ratio of Dmax − Dmin / Dmin , and expressed as a percentage . The Doppler technique was applied in the pulmonary artery trunk to determine cardiac index ( CI ) . Measurements were performed at baseline and after a 7 ml/kg volume expansion using a plasma exp and er . Patients were separated into responders ( increase in CI ≥15 % ) and non-responders ( increase in CI < 15 % ) . Results Using a threshold dIVC of 18 % , responders and non-responders were discriminated with 90 % sensitivity and 90 % specificity . A strong relation ( r=0.9 ) was observed between dIVC at baseline and the CI increase following blood volume expansion . Baseline central venous pressure did not accurately predict fluid responsiveness . Conclusion Our study suggests that respiratory change in IVC diameter is an accurate predictor of fluid responsiveness in septic patients OBJECTIVE To determine the accuracy of the Focused Assessment for the Sonographic examination of the Trauma patient ( FAST ) when performed by trauma team members during a 3-year period , and to determine the clinical conditions in which the FAST is most accurate in the assessment of injured patients . SUMMARY BACKGROUND DATA The FAST is a rapid test that sequentially surveys the pericardial region for hemopericardium and then the right and left upper quadrants and pelvis for hemoperitoneum in patients with potential truncal injuries . The clinical conditions in which the FAST is most accurate in the assessment of injured patients have yet to be determined . METHODS FAST examinations were performed on patients with precordial or transthoracic wounds or blunt abdominal trauma . Patients with a positive ultrasound ( US ) examination for hemopericardium underwent immediate surgery , whereas those with a positive US for hemoperitoneum underwent a computed tomography scan ( if they were hemodynamically stable ) or immediate celiotomy ( if they were hemodynamically unstable- blood pressure < or = 90 mmHg ) . RESULTS FAST examinations were performed in 1540 patients ( 1227 with blunt injuries , 313 with penetrating injuries ) . There were 1440 true-negative results , 80 true-positive results , 16 false-negative results , and 4 false-positive results ; the sensitivity was 83.3 % , the specificity 99.7 % . US was most sensitive and specific for the evaluation of patients with precordial or transthoracic wounds ( sensitivity 100 % , specificity 99.3 % ) and hypotensive patients with blunt abdominal trauma ( sensitivity 100 % , specificity 100 % ) . CONCLUSIONS US should be the initial diagnostic modality for the evaluation of patients with precordial wounds and blunt truncal injuries because it is rapid and accurate . Because of the high sensitivity and specificity of US in the evaluation of patients with precordial wounds and hypotensive patients with blunt torso trauma , immediate surgical intervention is justified when those patients have a positive US examination Background : Both occult hypoperfusion and volume overload are associated with increased morbidity and mortality in critically ill patients . Accurately predicting fluid responsiveness ( FRes ) allows for optimization of cardiac performance while avoiding fluid overload and prolonged mechanical ventilation . Objective : To simultaneously assess the ability to predict FRes using the stroke volume variation ( SVV ) obtained with the Vigileo/Flotrac monitor and inferior vena cava respiratory variation ( ΔIVC ) measured by st and ard echocardiography ( [ ECHO ) during mechanical ventilation . Methods : We included medical intensive care unit ( ICU ) patients undergoing mechanical ventilation that required vasopressors , had worsening organ function , and that were well adapted to the ventilator . We excluded patients requiring escalating doses of vasopressors , hemodialysis , with ascites and patients with atrial fibrillation or a heart rate > 120/min . Stroke volume index ( SVI ) and SVV were obtained from the Vigileo monitor whereas ΔIVC was obtained with ECHO ( M-mode ) . Doppler ECHO was used to measure SVI and used to determine FRes ( defined by SVI increase ≥10 % ) . A data set was obtained before and 30 minutes after a 10-minute fluid challenge ( FC ) with 500 mL of saline . Results : In all , 25 patients were prospect ively enrolled over an 8-month period . A total of 12 patients had acute respiratory distress syndrome ( ARDS ) , 3 had a cardiac arrest , and 10 had sepsis . The patients ’ mean age was 61.36 years ( ±13.7 ) , study enrollment since ICU admission was 3.4 days ( ±3.39 ) , the Sequential Organ Failure Assessment ( SOFA ) score was 12.44 ( ±2.59 ) , and the tidal volume 8.6 mL/kg ( ±1.68 ) . Of the 25 patients , 8 ( 32 % ) were FRes . The correlation coefficient between the baseline ΔIVC and percentage increase in SVI ( by ECHO ) after an FC was R2 = .51 with a receiver operating characteristic ( ROC ) curve of 0.81 while that for the baseline SVV by Vigileo was R2 = .12 with an ROC curve of 0.57 . The mean SVI bias between ECHO and Vigileo was -2 mL/m2 , the precision was -18 to 14 and the mean error was 46 % . Conclusions : ECHO assessment of the IVC variation during mechanical ventilation may prove to be a useful technique to predict FRes and guide fluid resuscitation in the ICU . The SVV obtained with the Vigileo monitor failed to predict FRes likely due to lack of calibration and the use of a complex algorithm that may be unreliable in patients with sepsis OBJECTIVE To assess validity of respiratory variation of inferior vena cava ( IVC ) diameter to predict fluid responsiveness and guide fluid therapy in mechanically ventilated patients during the first 6 hours after elective cardiac surgery . DESIGN Prospect i ve observational case series study . SETTING Single-center hospital . PATIENTS 50 consecutive patients undergoing elective cardiac surgery . INTERVENTIONS Transthoracic bedside echocardiography . MEASUREMENTS AND MAIN RESULTS Parameters derived from ultrasonographic assessment of the IVC diameter ( collapsibility index [ CI ] , distensibility index [ DI ] , and IVC/aorta index ) . In the whole study group , change in fluid balance correlated with change in IVC maximum diameter ( p = 0.034 , r = 0.176 ) . IVC-CI and IVC-DI correlated with IVC/aorta index . A weak correlation between central venous pressure ( CVP ) and IVC-derived parameters ( IVC-CI and IVC-DI ) was noticed . Despite statistical significance ( p<0.05 ) , all observed correlations expressed low statistical power ( r<0.21 ) . There were no statistically significant differences between fluid responders and nonresponders in relation to clinical parameters , CVP , ultrasound IVC measurement , and IVC-derived indices . CONCLUSION Dynamic IVC-derived parameters ( IVC-CI , IVC-DI , and IVC/aorta index ) and CVP are not reliable predictors of fluid responsiveness in the first 6 hours after cardiac surgery . Complexity of physiologic factors modulating cardiac performance in this group may be responsible for the difficulty in finding a plausible monitoring tool for fluid guidance . Bedside ultrasonographic measurement of IVC is unable to predict fluid responsiveness in the first 6 hours after cardiac surgery BACKGROUND We hypothesize that limited transthoracic echocardiogram ( LTTE ) is a useful tool to guide therapy during the initial phase of resuscitation in trauma patients . METHODS All highest-level alert patients with at least one measurement of systolic blood pressure less than 100 mm Hg , a mean arterial pressure less than 60 mm Hg , and /or a heart rate greater than 120 beats per minute who arrived to the trauma bay ( TB ) were r and omized to have either LTTE performed ( LTTEp ) or not performed ( non-LTTE ) as part of their initial evaluation . Images were stored , and results were reported regarding contractility ( good vs. poor ) , fluid status ( empty inferior vena cava [ hypovolemic ] vs. full inferior vena cava [ not hypovolemic ] ) , and pericardial effusion ( present vs. absent ) . Time from TB to operating room , intravenous fluid administration , blood product requirement , intensive care unit admission , and mortality were examined in both groups . RESULTS A total of 240 patients were r and omized . Twenty-five patients were excluded since they died upon arrival to the TB , leaving 215 patients in the study . Ninety-two patients were in the LTTEp group with 123 patients in the non-LTTE group . The LTTEp and non-LTTE groups were similar in age ( 38 years vs. 38.8 years , p = 0.75 ) , Injury Severity Score ( ISS ) ( 19.2 vs. 19.0 , p = 0.94 ) , Revised Trauma Score ( RTS ) ( 5.5 vs. 6.0 , p = 0.09 ) , lactate ( 4.2 vs. 3.6 , p = 0.14 ) , and mechanism of injury ( p = 0.44 ) . Strikingly , LTTEp had significantly less intravenous fluid than non-LTTE patients ( 1.5 L vs. 2.5 L , p < 0.0001 ) , less time from TB to operating room ( 35.6 minutes vs. 79.1 min , p = 0.0006 ) , higher rate of intensive care unit admission ( 80.4 % vs. 67.2 % , p = 0.04 ) , and a lower mortality rate ( 11 % vs. 19.5 % , p = 0.09 ) . Mortality differences were particularly evident in the traumatic brain injury patients ( 14.7 % in LTTEp vs. 39.5 % in non-LTTE , p = 0.03 ) . CONCLUSION LTTE is a useful guide for therapy in hypotensive trauma patients during the early phase of resuscitation . LEVEL OF EVIDENCE Therapeutic study , level II IMPORTANCE Small trials suggest that postoperative outcomes may be improved by the use of cardiac output monitoring to guide administration of intravenous fluid and inotropic drugs as part of a hemodynamic therapy algorithm . OBJECTIVE To evaluate the clinical effectiveness of a perioperative , cardiac output-guided hemodynamic therapy algorithm . DESIGN , SETTING , AND PARTICIPANTS OPTIMISE was a pragmatic , multicenter , r and omized , observer-blinded trial of 734 high-risk patients aged 50 years or older undergoing major gastrointestinal surgery at 17 acute care hospitals in the United Kingdom . An up date d systematic review and meta- analysis were also conducted including r and omized trials published from 1966 to February 2014 . INTERVENTIONS Patients were r and omly assigned to a cardiac output-guided hemodynamic therapy algorithm for intravenous fluid and inotrope ( dopexamine ) infusion during and 6 hours following surgery ( n=368 ) or to usual care ( n=366 ) . MAIN OUTCOMES AND MEASURES The primary outcome was a composite of predefined 30-day moderate or major complications and mortality . Secondary outcomes were morbidity on day 7 ; infection , critical care-free days , and all-cause mortality at 30 days ; all-cause mortality at 180 days ; and length of hospital stay . RESULTS Baseline patient characteristics , clinical care , and volumes of intravenous fluid were similar between groups . Care was nonadherent to the allocated treatment for less than 10 % of patients in each group . The primary outcome occurred in 36.6 % of intervention and 43.4 % of usual care participants ( relative risk [ RR ] , 0.84 [ 95 % CI , 0.71 - 1.01 ] ; absolute risk reduction , 6.8 % [ 95 % CI , -0.3 % to 13.9 % ] ; P = .07 ) . There was no significant difference between groups for any secondary outcomes . Five intervention patients ( 1.4 % ) experienced cardiovascular serious adverse events within 24 hours compared with none in the usual care group . Findings of the meta- analysis of 38 trials , including data from this study , suggest that the intervention is associated with fewer complications ( intervention , 488/1548 [ 31.5 % ] vs control , 614/1476 [ 41.6 % ] ; RR , 0.77 [ 95 % CI , 0.71 - 0.83 ] ) and a nonsignificant reduction in hospital , 28-day , or 30-day mortality ( intervention , 159/3215 deaths [ 4.9 % ] vs control , 206/3160 deaths [ 6.5 % ] ; RR , 0.82 [ 95 % CI , 0.67 - 1.01 ] ) and mortality at longest follow-up ( intervention , 267/3215 deaths [ 8.3 % ] vs control , 327/3160 deaths [ 10.3 % ] ; RR , 0.86 [ 95 % CI , 0.74 - 1.00 ] ) . CONCLUSIONS AND RELEVANCE In a r and omized trial of high-risk patients undergoing major gastrointestinal surgery , use of a cardiac output-guided hemodynamic therapy algorithm compared with usual care did not reduce a composite outcome of complications and 30-day mortality . However , inclusion of these data in an up date d meta- analysis indicates that the intervention was associated with a reduction in complication rates . TRIAL REGISTRATION is rct n.org Identifier : IS RCT N04386758 |
13,689 | 29,282,363 | Our results indicate the functional importance of −163C > A polymorphism on CYP1A2 inducibility in humans | A large interindividual variation in the activity of cytochrome P450 1A2 ( CYP1A2 ) raises concern about therapeutic failure or toxicity when medical professionals prescribe drugs extensively metabolized by CYP1A2 .
To date , a number of studies have assessed the association between genetic polymorphisms and CYP1A2 activity ; however , there are controversies as to the functional importance of CYP1A2 polymorphisms on the metabolism of CYP1A2 substrates . | The impact of gender , use of oral contraceptive steroids ( OCS ) , coffee consumption and of smoking on the metabolism of sparteine , caffeine , and paracetamol was studied in 194 r and omly selected subjects ( 98 male and 95 female ) . Thirty-eight of the male volunteers were cigarette smokers , 40 of the female subjects were smokers and /or users of OCS . The metabolic ratio of sparteine oxidation ( MRs ) showed a trimodal distribution . 7.7 % of the subjects had a MRs > 20 and thus were poor metabolizers ( PMs ) . Within the extensive metabolizer ( EM ) subjects , a distinct subgroup accounting for 11 % was observed with 20 > MRs > 1.2 . Six of the 15 phenotypical PMs were heterozygous EMs by genotyping . This indicates the existence of one or several CYP2D6 mutations which can not be identified by the currently employed genotyping methods . In each subgroup , i.e. smokers/OCS and non-smokers/non-OCS , the cumulative frequency distribution of the heterozygous ( wt/B ) phenotype caused a shift to higher MRs compared with the wild-type homozygotes ( wt/wt ) . Thus , for the in vivo activity of CYP2D6 , genetic determinants prevail over environmental factors . Smoking , use of oral contraceptive steroids , caffeine consumption , or gender had no influence on sparteine metabolism . The distribution of the paracetamol glucuronide/paracetamol metabolic ratio appeared to be unimodal although skewed . Glucuronidation capacity was clearly affected by gender , OCS use and smoking . It was higher in male than in female subjects . Male smokers had the highest , and female non-smokers/non-OCS users the lowest metabolic ratio . CYP1A2 activity , as determined by a caffeine metabolic ratio ( ( AFMU + 1X + 1U)/1 , 7U ) , was multimodally distributed and was clearly increased in smokers . It was significantly correlated to paracetamol glucoronidation in male heavy smokers ( r=0.85 ) , suggesting an element of co-regulation of CYP1A2 and of paracetamol conjugating UDP-glucuronosyltransferase isozymes , including UGTI.6 AIMS To study the potential utility of caffeine based probes of CYP1A2 enzyme activity in predicting the pharmokinetics of tacrine in patients with Alzheimer 's disease . METHODS The pharmokinetics of a single 40 mg oral dose of tacrine were measured in 19 patients with Alzheimer 's disease . Each patient also received 2 mg kg(-1 ) [ 13C-3-methyl ] caffeine orally and had breath and urine sample s collected . RESULTS Tacrine oral clearance ( CL F(-1 ) kg(-1 ) ) , which varied 15-fold among the patients , correlated significantly with the 2 h total production of 13CO2 in breath ( r=0.56 , P=0.01 ) , and with each of two commonly used urinary caffeine metabolite ratios : the ' paraxanthine/caffeine ratio ' ( 1,7X + 1 , 7U)/1,3,7X ) ( r=0.76 , P=0.0002 ) and the ' caffeine metabolic ratio ' ( AFMU + 1X + 1U)/1 , 7U)(r=0.76 , P=0.0001 ) . CONCLUSIONS These observations support a central role for CYP1A2 in the in vivo disposition of tacrine and the potential for drug interactions when tacrine treated patients receive known inducers or inhibitors of this enzyme . The magnitude of the correlations we observed , however , are probably not sufficient to be clinical ly useful in individualizing tacrine therapy |
13,690 | 23,853,046 | When we carried out sensitivity analysis ( temporarily removing a study at high risk of bias ) the differences between groups were no longer statistically significantThere were no significant differences between high- and low-dose regimens for instrumental vaginal birth , epidural analgesia , hyperstimulation , postpartum haemorrhage , chorioamnionitis or women 's perceptions of experiences .
For neonatal outcomes , there was no significant difference between groups for Apgar scores , umbilical cord pH , admission to special care baby unit , or neonatal mortality .
AUTHORS ' CONCLUSIONS Higher-dose regimens of oxytocin ( 4 mU per minute or more ) were associated with a reduction in the length of labour and in caesarean section , and an increase in spontaneous vaginal birth . | BACKGROUND A major cause of failure to achieve spontaneous vaginal birth is delay in labour due to presumed inefficient uterine action .
Oxytocin is given to increase contractions and high-dose regimens may potentially increase the number of spontaneous vaginal births , but as oxytocin can cause hyperstimulation of the uterus , there is a possibility of increased adverse events .
OBJECTIVES To compare starting dose and increment dose of oxytocin for augmentation for women delayed in labour to determine whether augmentation by high-dose regimens of oxytocin improves labour outcomes and to examine the effect on both maternal/neonatal outcomes and women 's birth experiences . | OBJECTIVE To test the hypothesis that high-dose oxytocin , when used in a masked fashion , would result in shorter labors and less need for cesarean delivery . METHODS We conducted r and omized , double-masked trials of high-dose compared with low-dose oxytocin for augmentation and induction of labor . Patients were r and omly assigned to receive oxytocin by either a low-dose protocol ( 1.5 mU/minute initially , increased by 1.5 mU/minute every 30 minutes ) or a high-dose protocol ( 4.5 mU/minute initially , increased by 4.5 mU/minute every 30 minutes ) . Oxytocin solutions were prepared by a central pharmacy and infusion volumes ( mL/hour ) were identical , thus ensuring double masking . RESULTS A total of 1307 patients were r and omized ( induction , 816 ; augmentation , 491 ) . In the group receiving oxytocin for induction , high-dose oxytocin was associated with a significant shortening of labor ( oxytocin to complete dilatation : 9.7+/-0.3 compared with 7.8+/-0.2 hours , P<.001 ; oxytocin to delivery : 10.5+/-0.3 compared with 8.5+/-0.3 hours , P<.001 ) . The cesarean delivery rate with low-dose oxytocin was 15.0 % , compared with 11.3 % with high-dose oxytocin ( P = .17 ) . For nulliparous women undergoing induction , cesarean delivery rates were as follows : Total 17.3 % ( low dose ) compared with 11.7 % ( high dose ) , P = .15 ; cephalopelvic disproportion 11.9 % ( low dose ) compared with 5.9 % ( high dose ) , P = .06 . When used for augmentation , high-dose oxytocin again was associated with a significant shortening of labor without a significant difference in cesarean birth rates . No differences in neonatal outcomes were noted between the groups for either augmentation or induction . CONCLUSION When used in a double-masked fashion , high-dose oxytocin is associated with significantly shorter labors without any demonstrable adverse fetal or neonatal effects STUDY OBJECTIVE : To determine the extent of intrapartum intervention received by primigravidas . DESIGN : Cross sectional survey of NHS hospitals in the UK . SETTING : One hundred and one r and omly selected hospital maternity units . PARTICIPANTS : Forty consecutive primigravid women , judged to be at low risk at the start of labour , in each hospital . MAIN OUTCOME MEASURES : Seven groups of interventions or monitoring procedures were identified from the first , second , and third stages of labour : fetal monitoring , vaginal examinations , artificial rupture of membranes , augmentation of labour , pain relief , type of delivery , and episiotomy . Data were collected during 1993 . MAIN RESULTS : Ninety eight hospitals took part in the study and data were collected on 3160 low risk primigravidas . Seventy four per cent of these women had continuous cardiotocography . The proportion of women having restrictive or invasive fetal monitoring showed appreciable geographical variation for both the first and second stages of labour . Using the criterion of a vaginal examination every four hours and allowing for the length of each woman 's labour , 72 % had more vaginal examinations than expected ; there was a significant geographical variation in the number of women receiving more than five examinations . Fifty three per cent had artificial rupture of membranes ; the procedure was performed over a wide range of cervical dilatations ( 0 cm-10 cm ) . Thirty eight per cent of labours were augmented , most commonly by intravenous syntocinon ; the procedure showed significant geographical variation . Twenty eight per cent had a spinal block or epidural analgesia for the relief of pain ; this intervention varied by geographical region only for the second stage of labour . Over one quarter of the women required instrumental delivery . Forty six per cent had an episiotomy ; the frequency of this intervention varied substantially by region . There were no infant deaths . Twelve babies were recorded at birth as having a congenital anomaly . CONCLUSIONS : The rates of several interventions seem high for this low risk group and there was substantial geographical variation in the use of six interventions . Clinical trials are needed to evaluate the optimum criteria for using these interventions from which guidelines should be drawn up by local groups and the Royal College OBJECTIVE To compare high and low starting dose of oxytocin infusion for effectiveness and safety in augmentation of labour in nulliparous women . DESIGN An open r and omised controlled clinical trial . SETTING Harare Maternity Hospital , Zimbabwe . SUBJECTS 258 nulliparous women , with spontaneous onset of labour , who required augmentation . MAIN OUTCOMES MEASURES Duration of augmentation , mode of delivery , maternal and neonatal complications . INTERVENTIONS Women were r and omly allocated to either low dose ( starting at 4 mIU/minute ) or high dose ( starting at 10 mIU/minute ) oxytocin group . RESULTS Of the 258 women enrolled , 133 were r and omized to the low and 125 to the high starting oxytocin dose groups . The groups were comparable for maternal and gestational age . There was no difference in mean cervical dilatation before augmentation of labour ; six cm in both groups ( p = 0.167 ) . The mean augmentation to delivery interval was shorter in the high dose group , 218 versus 326 minutes ( p < 0.001 ) . There was no difference in the mode of delivery and fetal outcome in terms of birthweight , five minute Apgar score , admission to neonatal unit and perinatal death . CONCLUSION A high starting dose of oxytocin infusion is as safe but more effective for augmentation of labour in nulliparous women , compared to a low starting dose OBJECTIVE Our purpose was to perform a r and omized trial comparing intravaginal misoprostol to intravaginal prostagl and in E2 gel for preinduction cervical ripening evaluating efficacy and side effects . STUDY DESIGN Seventy-five women seen for induction of labor were r and omized to receive 100 micrograms of intravaginal misoprostol or 5 mg of pharmacy-prepared intravaginal prostagl and in E2 gel for cervical ripening before oxytocin induction . Six hours after placement of the study agent , patients were given oxytocin if they were not in labor . The primary outcome measure was induction-to-delivery time ; secondary measures were change in Bishop score , delivery mode , and side effects . Results were analyzed by the Student t test and Fisher 's exact test , with p < 0.05 considered significant . RESULTS There was no difference in the incidence of primiparity or the median initial Bishop score between the two study groups . The mean time to delivery and the need for oxytocin was significantly less for subjects receiving misoprostol . There was no difference in the incidence of uterine hyperstimulation syndrome or cesarean delivery between the groups . CONCLUSIONS This r and omized clinical trial indicates that misoprostol is efficacious for preinduction cervical ripening . Misoprostol use result ed in a significantly shorter induction-to-delivery time compared with prostagl and in E2 gel use . The side effects associated with misoprostol may be dose related , and further studies to identify the optimum dosage and interval are needed Objective : To compare two low-dose oxytocin protocol s in terms of fetal distress , uterine hyperstimulation , cesarean delivery rate , maximum dose of oxytocin , and length of labor . Methods : We r and omized 865 patients into 15-minute ( incremental dose 1 mU/minute until 5 mU/minute , then 1 or 2 mU/minute ) or 40-minute ( incremental dose 1.5 mU/minute until 7 mU/minute , then 1.5 or 3.0 mU/minute ) low-dose protocol s. Before oxytocin use , all subjects were stratified according to parity and purpose of oxytocin , ie , for induction or augmentation of labor . Results : The 40-minute dosing protocol had a significantly lower maximum dose of oxytocin ( augmentation , 6.5 versus 8.2 mU/minute , P < .001 ; induction , 11.5 versus 14.5 mU/minute , P < .001 ) , a lower incidence of uterine hyperstimulation ( augmentation , 18.8 versus 31.8 % , P < .001 ; induction , 19.1 versus 33.0 % , P < .002 ) , and less fetal distress ( augmentation , 15.5 versus 26.1 % , P < .005 ) . No significant differences were found in the cesarean rate or length of labor . Conclusion : A dosing interval of 40 minutes led to lower incidences of uterine hyperstimulation and fetal distress , and decreased the maximum dose of oxytocin , without affecting the length of labor or the cesarean rate Objective : To determine whether an increase in the oxytocin dosing interval would decrease the incidence of uterine hypers timulation . Methods : This study included 1801 consecutive pregnancies receiving high-dose oxytocin . Oxytocin was used for labor augmentation in 1167 and induction in 634 women . Twenty- and 40-minute dosage intervals were compared . The study period was based on an 80 % likelihood of detecting S and 10 % differences in the cesarean and hyperstimulation rates , respectively . Statistics were analyzed with X1 , Fisher , and Wilcoxon rank-sum tests where appropriate . Multivariate logistic regression and analysis of covariance were used to control for confounding demographic variables . Results : Comparison of the 20- and 40-minute regimens for labor induction yielded no differences in the rates of cesarean delivery for dystocia ( 16 versus 19%% ) or fetal distress ( 5 versus 6 % ) . The 20-minute regimen for augmentation was associated with a significant reduction in cesarean for dystocia ( 8 versus 12 % P=.05 ) . The incidence of uterine hyperstimulation was greater with the 20-minute than the 40-minute regimen for induction ( 40 versus 31 % P=.02 ) , but not for augmentation ( 31 versus 28 % ) . Neonatal outcomes were unaffected by the dosage interval for both augmentation and induction . Conclusion : A 40-minute dosing interval for high-dose oxytocin offers no clear advantage over a 20-minute interval . Both regimens were safe and efficient , with no differences in perinatal outcome . The 20-minute interval was associated with fewer cesareans for dystocia when used for labor augmentation , whereas the 40-minute interval result ed in less hyperstimulation when used for labor induction . ( Obstet Gynecol 1994;83:234r4 OBJECTIVE To compare the efficacy and safety of high dose oxytocin in the augmentation of labor . METHOD Two hundred pregnant women requiring augmentation of labor were r and omly assigned to receive oxytocin by either a low dose protocol ( 1.5 microm/min initially , increased by 1.5 microm/min every 30 min ) or a high dose protocol ( 4.5 microm/min initially , increased by 4.5 microm/min every 30 min ) . RESULTS High dose of oxytocin was associated with a significant shortening of labor 4 ( 1.10 - 10 ) vs. 6 ( 1 - 10 ) h , p<0.0001 without a significant difference in cesarean delivery rate , neonatal and maternal outcome . CONCLUSION The use of high dose oxytocin is associated with significantly shorter labor without any adverse fetal and maternal effects OBJECTIVE Our purpose was to compare the efficacy and safety of low-dose versus high-dose oxytocin regimens in the augmentation of labor . STUDY DESIGN Three hundred ten term pregnancies requiring augmentation of labor underwent r and omization to receive either a low-dose or high-dose oxytocin augmentation regimen . Maternal demographics , labor-delivery data , and neonatal outcome were compared . RESULTS The high-dose oxytocin group had a significantly lower cesarean section rate , regardless of parity ( 10.4 % vs 25.7 % , p < 0.001 ) , with no differences in maternal complications and neonatal outcomes . The time needed to correct the labor abnormality was also significantly decreased ( 1.24 + /- 1.4 hours vs 3.12 + /- 1.6 hours , p < 0.001 ) in the high-dose group . CONCLUSIONS The use of high-dose oxytocin regimen benefits both nulliparous and multiparous women requiring labor augmentation by significantly lowering both the time necessary to correct the labor abnormality and the need for cesarean section Uterine activity was measured in 60 women whose first labour was progressing slowly in the active phase . The mean level of active contraction area ( uterine activity integral , UAI ) before oxytocin augmentation was 898 ( SD 458 ) kPas/15 min . UAI increased significantly with time , even in women not given oxytocin . UAI increased logarithmically with increasing oxytocin infusion rate . Levels of uterine activity before and after oxytocin infusion are correlated positively such that the higher the initial level of UAI the higher the UAI in response to oxytocin . However , the regression line approaches the line of identity such that even with high doses of oxytocin UAI would not be likely to exceed 2500 kPas/15 min . There is a positive correlation between uterine activity and cervical dilatation rate in unstimulated labour ; however , this is less evident following oxytocin infusion . Increases in uterine activity below 1200 kPas/15 min result from both higher frequency and active pressure , whereas above 1200 kPas/15 min any increase is due mainly to a rise in frequency The value of quantifying active contraction area to guide oxytocin titration in augmentation of labour was investigated by a r and omised trial . Sixty-eight nulliparae with slow progress of labour had oxytocin titrated to achieve preset " optimal " active contraction area or " optimal " frequency of contractions in a r and omised manner . There was no difference in maternal characteristics of age and height , pre-augmentation period of observed labour or cervical dilatation at the onset of augmentation between the 2 groups . The maximum dose of oxytocin , post-augmentation period and the number of operative deliveries were similar . There was no difference in the mean birth weight of neonates , or in the number of neonates who had low Apgar score or acidotic cord arterial blood pH. Our results suggest that there may be no advantage in oxytocin titration to achieve preset " optimal " active contraction area compared with " optimal " frequency of uterine contractions in nulliparae with slow progress of labour |
13,691 | 23,114,947 | Subsequently in agreement with these evidence levels , different degree recommendations are established being potentially useful to design food guides as part of strategies addressed to the treatment overweight and obesity | This study is a consensus document of two Spanish scientific associations , FESNAD ( Spanish Federation of Nutrition , Food and Dietetic Associations ) and SEEDO ( Spanish Association for the Study of Obesity ) , about the role of the diet in the treatment of overweight and obesity in adults . | OBJECTIVE The objectives of this study were to compare the effects of diets rich in medium-chain triglycerides ( MCTs ) or long-chain triglycerides ( LCTs ) on body composition , energy expenditure , substrate oxidation , subjective appetite , and ad libitum energy intake in overweight men . RESEARCH METHODS AND PROCEDURES Twenty-four healthy , overweight men with body mass indexes between 25 and 31 kg/m(2 ) consumed diets rich in MCT or LCT for 28 days each in a crossover r and omized controlled trial . At baseline and after 4 weeks of each dietary intervention , energy expenditure was measured using indirect calorimetry , and body composition was analyzed using magnetic resonance imaging . RESULTS Upper body adipose tissue ( AT ) decreased to a greater extent ( p < 0.05 ) with functional oil ( FctO ) compared with olive oil ( OL ) consumption ( -0.67 + /- 0.26 kg and -0.02 + /- 0.19 kg , respectively ) . There was a trend toward greater loss of whole-body subcutaneous AT volume ( p = 0.087 ) with FctO compared with OL consumption . Average energy expenditure was 0.04 + /- 0.02 kcal/min greater ( p < 0.05 ) on day 2 and 0.03 + /- 0.02 kcal/min ( not significant ) on day 28 with FctO compared with OL consumption . Similarly , average fat oxidation was greater ( p = 0.052 ) with FctO compared with OL intake on day 2 but not day 28 . DISCUSSION Consumption of a diet rich in MCTs results in greater loss of AT compared with LCTs , perhaps due to increased energy expenditure and fat oxidation observed with MCT intake . Thus , MCTs may be considered as agents that aid in the prevention of obesity or potentially stimulate weight loss BACKGROUND The effects of a carbohydrate-restricted diet on weight loss and risk factors for atherosclerosis have been incompletely assessed . METHODS We r and omly assigned 132 severely obese subjects ( including 77 blacks and 23 women ) with a mean body-mass index of 43 and a high prevalence of diabetes ( 39 percent ) or the metabolic syndrome ( 43 percent ) to a carbohydrate-restricted ( low-carbohydrate ) diet or a calorie- and fat-restricted ( low-fat ) diet . RESULTS Seventy-nine subjects completed the six-month study . An analysis including all subjects , with the last observation carried forward for those who dropped out , showed that subjects on the low-carbohydrate diet lost more weight than those on the low-fat diet ( mean [ + /-SD ] , -5.8+/-8.6 kg vs. -1.9+/-4.2 kg ; P=0.002 ) and had greater decreases in triglyceride levels ( mean , -20+/-43 percent vs. -4+/-31 percent ; P=0.001 ) , irrespective of the use or nonuse of hypoglycemic or lipid-lowering medications . Insulin sensitivity , measured only in subjects without diabetes , also improved more among subjects on the low-carbohydrate diet ( 6+/-9 percent vs. -3+/-8 percent , P=0.01 ) . The amount of weight lost ( P<0.001 ) and assignment to the low-carbohydrate diet ( P=0.01 ) were independent predictors of improvement in triglyceride levels and insulin sensitivity . CONCLUSIONS Severely obese subjects with a high prevalence of diabetes or the metabolic syndrome lost more weight during six months on a carbohydrate-restricted diet than on a calorie- and fat-restricted diet , with a relative improvement in insulin sensitivity and triglyceride levels , even after adjustment for the amount of weight lost . This finding should be interpreted with caution , given the small magnitude of overall and between-group differences in weight loss in these markedly obese subjects and the short duration of the study . Future studies evaluating long-term cardiovascular outcomes are needed before a carbohydrate-restricted diet can be endorsed Context In 2003 , the authors reported that severely obese adults lost more weight and had better serum lipid patterns after 6 months of a low-carbohydrate diet rather than a conventional low-fat diet . Contribution After 1 year , these same patients still had more favorable triglyceride and high-density lipoprotein cholesterol levels on the low-carbohydrate diet than on the conventional diet . However , weight loss and the other metabolic parameters were similar in the 2 diet groups . Caution s The effect of the modest improvements in high-density lipoprotein cholesterol and triglyceride levels on the development of diabetes and cardiovascular disease is unknown . The Editors The prevalence of obesity and its associated metabolic abnormalities has increased markedly over the past 2 decades ( 1 , 2 ) . Although guidelines to follow a highcomplex carbohydrate , low-fat , energy-deficient diet to achieve weight loss are generally accepted ( 3 ) , considerable public interest has focused on low-carbohydrate diets ( 4 ) . We recently reported that persons with severe obesity lost more weight and had greater improvements in triglyceride levels , insulin sensitivity , and glycemic control after 6 months of a low-carbohydrate diet as compared with a conventional weight loss diet based on calorie and fat restriction ( 5 ) . However , these findings were preliminary because of the short duration of that study ( 6 ) . A simultaneously published study by Foster and colleagues suggested that persons on a low-carbohydrate diet tended to regain weight by 1 year ( 7 ) . These findings were limited , however , because few participants completed the study and because the study used a self-help approach , which is less effective than direct counseling for maintaining weight loss ( 8) . Foster and colleagues also excluded persons with diabetes , which is highly prevalent in the obese population . During the development of this study , we decided to analyze and report preliminary results at 6 months and final results at 1 year . We thought that the short-term results would be important , given the high-risk nature of our study sample , but that long-term outcomes would provide more information about the sustainability of any diet-related outcomes . We now report our findings 1 year after r and omization to a low-carbohydrate diet versus a low-fat weight loss diet ( conventional diet ) in severely obese adults with a high prevalence of diabetes or the metabolic syndrome . Methods Study Participants The study design has been previously described ( 5 ) . Participants were recruited from the outpatient practice s of the Philadelphia Veterans Affairs Medical Center and included persons 18 years of age and older with a body mass index ( BMI ) of 35 kg/m2 or greater . The exclusion criteria were a serum creatinine level greater than 133 mol/L ( > 1.5 mg/dL ) , hepatic disease , severe life-limiting medical illness , inability to self-monitor glucose levels , or active use of a weight loss program or weight loss medication . Between May 2001 and November 2001 , 132 persons were r and omly assigned to either a low-carbohydrate diet ( n = 64 ) or a conventional diet ( n = 68 ) . The Institutional Review Committee at the Philadelphia Veterans Affairs Medical Center approved the study , and all participants provided written informed consent . Interventions Diet groups met in weekly counseling sessions for 4 weeks , followed by 11 monthly sessions . Participants on the low-carbohydrate diet were instructed only to reduce carbohydrate intake to less than 30 g per day . Participants on the conventional diet were instructed to reduce caloric intake by 500 calories per day , with less than 30 % of calories derived from fat , in accordance with the National Heart , Lung , and Blood Institute guidelines ( 3 ) . Outcome Measures We collected data , including weight ( single calibrated scale , SR Instruments , Inc. , Tonaw and a , New York ) , medical history ( self-reported ) , and blood pressure , at baseline , 6 months , and 1 year . Fasting blood specimens were obtained for glucose , hemoglobin A1c , and serum lipid levels ( Synchron LX20 , Beckman Coulter , Inc. , Fullerton , California ) . Low-density lipoprotein ( LDL ) cholesterol level was calculated by using the Friedewald formula ( 9 ) . We defined the presence of diabetes by a historical fasting blood glucose level greater than 6.94 mmol/L ( > 125 mg/dL ) or use of antidiabetic medications . The metabolic syndrome was considered present if a participant had 3 or more of the following ( 10 ) : central obesity , fasting blood glucose level of 6.11 mmol/L ( 110 mg/dL ) or greater , fasting triglyceride level of 1.70 mmol/L ( 150 mg/dL ) or greater , high-density lipoprotein ( HDL ) cholesterol level less than 1.04 mmol/L ( < 40 mg/dL ) for men or less than 1.30 mmol/L ( < 50 mg/dL ) for women , blood pressure of 130/85 mm Hg or greater , or antihypertensive therapy . We assumed that all participants had central obesity because of the uniform severity of their obesity ( BMI range , 35.0 to 79.4 kg/m2 ) . Serum insulin was measured by radioimmunoassay ( Laboratory Corporation of America Holdings [ LabCorp ] , Burlington , North Carolina ] ) . Insulin resistance in nondiabetic persons was estimated by the quantitative insulin sensitivity check ( QUICK ) index : 1/[(log ( fasting insulin ( U/mL ) ) + ( log fasting glucose(mg/dL ) ) ] . Statistical Analysis Our primary end point was total weight loss at 1 year . Secondary analyses included the change from baseline in serum lipid levels , insulin sensitivity , and glycemic control . We estimated that we would need 100 persons ( 50 per group ) , assuming a 2-sided type I error of 5 % , for the study to have 80 % power to detect a 5-kg greater mean weight loss in the low-carbohydrate group than in the conventional diet group . These calculations were based on an anticipated maximum weight loss by 6 months , with weight stabilization in both diet groups between 6 months and 1 year . To compensate for an anticipated dropout rate of 25 % , we set our enrollment target at 135 persons . R and omization was performed by using a pre-established algorithm generated from a r and om set of numbers that was constructed and held in a separate center and concealed from those enrolling persons during r and omization . We used stratified r and omization , with blocking within strata , to ensure assignment of approximately equal numbers of women , diabetic persons , and severely obese persons ( BMI 40 kg/m2 ) to each study group . Changes in weight , dietary intake , and metabolic data were compared between the 2 diets by r and om-coefficient analysis ( 11 ) . This type of analysis was selected to allow for a variable number of observations for participants and to take into account that the repeated observations of the outcome variables over time for individuals were correlated . The r and om-coefficient analysis model takes these correlations into account by allowing the intercept to vary r and omly among persons . We used a restricted maximum likelihood analysis , which assumed that changes were distributed according to a bivariate normal distribution and that data were missing at r and om . The outcome variables were changes from baseline in weight , dietary macronutrient consumption , and metabolic measurements . For all of these analyses , the covariates included an indicator variable for time ( 6 months and 1 year ) , diet group , and a diet group by time interaction term . This diet group by time interaction term was kept in the model , regardless of its statistical significance ( P = 0.063 for the weight loss analysis ) . Separate analyses to adjust for baseline differences between diet groups were also made by entering the following covariates to each of these models : age ; race ( white or African American ) ; sex ; baseline BMI ; baseline caloric intake ; and the presence or absence of hypertension , use of lipid-lowering therapy , diabetes , active smoking , and sleep apnea ( 12 ) . All variables were assessed for normality before entry into the analyses . Triglyceride , insulin , and glucose levels were skewed and thus were log-transformed before the analyses . Baseline differences between diet groups were compared by chi-square analysis for dichotomous variables and by the unpaired t-test for continuous variables . All P values are 2-sided , and a P value of 0.05 was considered statistically significant . Analyses were performed with SPSS statistical software , version 11.1 ( SPSS , Inc. , Chicago , Illinois ) . Missing Data Of the 132 enrolled persons , follow-up was done at 6 months for 79 persons and at 1 year for 87 persons . For measurements at 6 months , we retrieved weights on an additional 16 persons on the low-carbohydrate diet and 23 persons on the conventional diet ( total , 39 persons at a mean [ SD ] of 6.6 1.2 months ) . For measurements at 1 year , we retrieved weights on 18 persons on the low-carbohydrate diet and 21 persons on the conventional diet ( total , 39 persons at a mean [ SD ] of 13.5 3.2 months ) . Thus , we had 6-month weights on 118 of 132 persons ( 89 % ) and 1-year weights on 126 of 132 persons ( 96 % ) . Of the 18 persons who missed the 6-month visit but returned for the 1-year visit ( 6 in the low-carbohydrate group and 12 in the conventional diet group ) , all but 2 had 6-month weights retrieved from medical records . Of the 6 persons for whom no 1-year weights were available , 2 were in the low-carbohydrate group and 4 in the conventional diet group . The weights retrieved from medical records were obtained on scales that were different from those used for the study and were probably obtained in a nonuniform manner with regard to clothing . We used several approaches to h and le the 45 participants with missing data for diet recall and metabolic measurements . For the primary analysis by r and om-coefficient analysis , we assumed data were missing at r and om . To verify this assumption , we performed sensitivity analyses based on comparisons of baseline characteristics and weight loss differences between those who dropped out and those who completed the study . We also performed 2 additional sensitivity Subjects with obesity and elevated fasting blood glucose are at high risk of developing type 2 diabetes which may be reduced by a dietary intervention leading to an improvement of insulin resistance . We investigated the potential of a whole-grain based dietary product ( WG ) with reduced starch content derived from double-fermented wheat during a hypo-energetic diet to positively influence body weight , fasting blood glucose , insulin resistance and lipids in comparison to a nutrient-dense meal replacement product ( MR ) in a r and omized two-way cross-over study with two 4-week treatment periods separated by a 2-week wash-out . Subjects replaced at least two daily meals with WG and MR , respectively , targeting for a consumption of 200 g of either product per day . Total daily energy intake was limited to 7120 kJ. Thirty-one subjects ( BMI 33.9 ( SD 2.7 ) kg/m2 , fasting blood glucose 6.3 ( SD 0.8 ) mmol/l ) completed the study . In both treatment groups body weight ( -2.5 ( SD 2.0 ) v. - 3.2 ( SD 1.6 ) kg for WG v. MR ) , fasting blood glucose ( -0.4 ( SD 0.3 ) v. -0.5 ( SD 0.5 ) mmol/l ) , total cholesterol ( -0.5 ( SD 0.5 ) v. -0.6 ( SD 0.5 ) mmol/l ) , TAG ( -0.3 ( SD 0.9 ) v. -0.3 ( SD 1.2 ) mmol/l ) and homeostasis model assessment ( HOMA ) insulin resistance score ( -0.7 ( SD 0.8 ) v. -1.1 ( SD 1.7 ) microU/ml x mmol/l ) improved ( P < 0.05 ) with no significant differences between the treatments . After statistical adjustment for the amount of body weight lost , however , the comparison between both groups revealed that fasting serum insulin ( P = 0.031 ) and HOMA insulin resistance score ( P = 0.049 ) improved better with WG than with MR . We conclude that WG favourably influences metabolic risk factors for type 2 diabetes independent from the amount of body weight lost during a hypo-energetic diet Gallstone disease is a major health problem throughout the Western world . Approximately 12 % of adults in the United States have gallstones [ 1 , 2 ] . Although most of these persons are asymptomatic [ 3 ] , more than 500 000 cholecystectomies are done yearly for treatment of symptomatic gallstones and associated complications [ 1 ] . Laparoscopic cholecystectomy has made it much easier to manage symptomatic patients , but the annual cost of caring for such patients exceeds $ 5 billion [ 1 ] . Preventing gallstones from forming is therefore an important goal . The development of cholesterol gallstones is associated with certain well-defined risk factors [ 1 , 4 - 6 ] . For most adults , the most important of these factors appear to be obesity and active weight reduction . Several studies have clearly shown that the risk for gallstones increases stepwise with increasing body weight [ 7 - 11 ] . The prevalence of gallstones is two- to threefold greater in persons who weigh as little as 20 % more than their ideal body weight and as much as eightfold greater in patients who exceed their ideal body weight by twofold or more [ 7 - 9 ] . The risk for developing gallstones during active weight reduction is also well accepted [ 9 - 17 ] . Ten percent to 25 % of persons having rapid weight reduction through very-low-calorie dieting develop gallstones [ 12 - 14 ] . In addition , 35 % of patients with morbid obesity develop gallstones as they lose weight after bariatric surgery [ 15 - 18 ] . Ursodeoxycholic acid is a bile salt that reduces cholesterol secretion into bile and improves biliary cholesterol solubility . It is used to dissolve cholesterol gallstones [ 19 - 22 ] . Its properties have led to the hypothesis that it could prevent the formation of cholesterol gallstones in certain high-risk population s. Two previous studies showed that ursodeoxycholic acid could reduce the incidence of gallstone formation in persons participating in a very-low-calorie diet program [ 12 ] and after bariatric surgery [ 18 ] . These preliminary reports inspired two multicenter , r and omized , double-blind , placebo-controlled trials to determine the optimum dose at which ursodeoxycholic acid could prevent gallstone formation in patients having rapid weight reduction . We evaluated approximately 1000 patients participating in a very-low-calorie liquid protein diet program . A similar study [ 23 ] done in parallel with ours evaluated the effects of ursodeoxycholic acid during weight reduction in more than 300 patients having proximal gastric bypass surgery at 10 surgical weight loss centers . Taken together , these studies clearly show that the prophylactic use of ursodeoxycholic acid is highly effective for the prevention of gallstone formation in patients having rapid weight reduction . Methods Patients We recruited patients from 31 Health Management Re sources -affiliated diet centers throughout the United States that agreed to collaborate in this trial . All patients at these centers were informed of the risk for gallstone formation while dieting and were asked whether they would participate in a study to prevent gallstone formation . To be accepted into this trial , all patients had to 1 ) have a body mass index of 38 kg or more ; 2 ) be between 18 and 70 years of age ; 3 ) be willing to participate in the Health Management Re sources very-low-calorie diet plan for 16 weeks ; and 4 ) have normal serum potassium and calcium levels . Women of childbearing age had to have a negative serum pregnancy test result . Patients were excluded from the study if they had any one the following : 1 ) previous cholecystectomy ; 2 ) gallstones or gallbladder sludge on ultrasonogram ; 3 ) hypersensitivity to bile acids or eggs ; 4 ) a history of hypothyroidism or the Cushing syndrome ; 5 ) an eating disorder or other psychological problem that would interfere with participation in the diet program ; 6 ) use of oral bile salt preparations , aluminum-based antacids , or lithium ; 7 ) long-term use of nonsteroidal anti-inflammatory agents ( including aspirin ) or antihyperlipidemic agents [ including cholestyramine ] within 2 weeks of entering into the trial ; and 8) a total bilirubin level of more than 2.0 mg/dL , a serum creatinine level of more than 2.0 mg/dL , or an alanine aminotransferase level of more than 133 kat/L. Diuretic therapy had to be discontinued at least 1 day before trial entry . A total of 1004 consecutive patients who met all entry criteria and agreed to participate were enrolled in the trial . The study was approved by the human investigations review committee at each of the participating centers and by the medical review boards of Health Management Re sources , Inc. , and Ciba-Geigy Pharmaceutical Company . Informed consent was obtained from all participants before study entry . Study Design If a patient met all entry criteria and agreed to participate in the study , a baseline ultrasonogram of the gallbladder was obtained and all exclusion criteria were review ed . If gallstones , gallbladder sludge , or both were identified , or if any other exclusion criteria were present , the patient was not entered into the trial . All other patients were entered into the study and r and omly assigned to receive either placebo , 300 mg of ursodeoxycholic acid once daily , 600 mg of ursodeoxycholic acid in two divided doses daily , or 1200 mg of ursodeoxycholic acid in two divided doses daily . Blocks of four patients at each of the 31 centers were used in the r and omization . Treatment groups were blinded using a double-dummy technique . All patients were provided with two coded medication bottles ( one for the morning and one for the evening ) ; each bottle contained either placebo or ursodeoxycholic acid in capsules that were identical in appearance . Patients were instructed to take two pills from the morning bottle and two pills from the evening bottle daily . Thus , each patient took two capsules twice daily . Each patient began taking coded medication on the first day that he or she began the Health Management Re sources diet plan and continued to take it throughout the entire 16-week program . The Health Management Re sources diet was a 520-kcal/d liquid protein diet containing 50 g of protein , 79 g of carbohydrate , and 1 to 3 g of fat ( depending on the particular preparation selected ) . All patients consumed this diet 3 to 5 times daily for 16 weeks and were instructed not to consume any other food . Supplements providing 100 % to 150 % of the U.S. recommended daily allowance of vitamins and minerals were supplied for each patient . Consumption of noncaloric fluids ( water and diet or club sodas ) was not limited . Each patient was evaluated biweekly throughout the study . At each visit , body weight and all adverse experiences that had occurred since the previous visit were recorded . Patients were instructed to return all medication bottles and unused medications to their study center . Compliance with study medication was assessed by pill count . Gallbladder ultrasonography was repeated after 8 weeks of dieting and after 16 weeks of dieting or termination from the trial , or both . Gallstones and gallbladder sludge were defined using st and ard and well-accepted criteria [ 24 ] . Radiologists from each of the 31 participating centers met and agreed to these criteria before the start of the study . Although the radiologists were aware that the patients were participants in this study , they were blinded to the particular group to which each patient had been assigned . The reading of the radiologist at each site was considered final , and these findings were not review ed by a single central radiologist . If a patient was found to have developed one or more gallstones , his or her participation in the trial was complete . No further weight loss data were collected from these patients as part of the trial . Gallbladder sludge was not considered a primary end point . Patients who developed sludge were informed of this and were continued in the trial . Bile Analysis Thirty-two patients from a single Health Management Re sources center ( Austin Diagnostic Center , Austin , Texas ) volunteered to participate in bile analysis . Each of these patients had endoscopy to obtain bile for analysis before starting the diet and at the completion of the trial . All patients had routine upper endoscopy while under conscious sedation ( midazolam , 2 mg to 4 mg ) in the morning , after an overnight fast . The tip of the endoscope was advanced into the second portion of the duodenum , and the ampulla of Vater was visualized . An intravenous dose of sincalide ( Kinevac , 0.02 to 0.06 g/kg ) was then administered to stimulate gallbladder contraction . As bile entered the duodenum , it was aspirated through the suction port of the endoscope and collected . Bile sample s were immediately centrifuged at 25 000 g for 30 minutes , and a sample of the sediment was examined for cholesterol crystals with a polarizing microscope ( magnification , 400 ) . The supernatant was frozen for later analysis by the primary investigator . All bile sample s were thawed and analyzed as a single batch . Total phospholipid levels were determined by the method of Bartlett [ 25 ] . Cholesterol was determined in whole bile after appropriate dilution with an assay kit ( Sigma Chemical Co. , St. Louis , Missouri ) . The bile salt composition of each bile sample was determined using reverse-phase , high-performance liquid chromatography in a Waters model 600 system ( Waters Chromatography , Milford , Massachusetts ) as described previously [ 26 ] . The percentage of total bile acids that were conjugates of ursodeoxycholic acid ( tauro-plus glyco- ) was assessed . The cholesterol saturation index of each bile sample was calculated from tables developed by Carey [ 27 ] using the computer program of Kuroki and colleagues [ 28 ] . Four patients did not have enough bile collected to allow paired analysis of cholesterol saturation and assessment of the percentage of ursodeoxycholic acid . Statistical Analysis The Ciba-Geigy Pharmaceutical Company was responsible for overseeing data collection and data analysis . Background There is concern that recommending protein-enriched meal replacements as part of a weight management program could lead to changes in biomarkers of liver or renal function and reductions in bone density . This study was design ed as a placebo-controlled clinical trial utilizing two isocaloric meal plans utilizing either a high protein-enriched ( HP ) or a st and ard protein ( SP ) meal replacement in an outpatient weight loss program . Subjects/ methods 100 obese men and women over 30 years of age with a body mass index ( BMI ) between 27 to 40 kg/m2 were r and omized to one of two isocaloric weight loss meal plans 1 ) . HP group : providing 2.2 g protein/kg of lean body mass (LBM)/day or 2 ) . SP group : providing 1.1 g protein/kg LBM/day . Meal replacement ( MR ) was used twice daily ( one meal , one snack ) for 3 months and then once a day for 9 months . Body weight , lipid profiles , liver function , renal function and bone density were measured at baseline and 12 months . Results Seventy subjects completed the study . Both groups lost weight ( HP -4.29 ± 5.90 kg vs. SP -4.66 ± 6.91 kg , p < 0.01 ) and there was no difference in weight loss observed between the groups at one year . There was no significant change noted in liver function [ AST ( HP -2.07 ± 10.32 U/L , p = 0.28 ; SP 0.27 ± 6.67 U/L , p = 0.820 ) , ALT ( HP -1.03 ± 10.08 U/L , p = 0.34 ; SP -2.6 ± 12.51 U/L , p = 0.24 ) , bilirubin ( HP 0.007 ± 0.33 , U/L , p = 0.91 ; SP 0.07 ± 0.24 U/L , p = 0.120 ) , alkaline phosphatase ( HP 2.00 ± 9.07 U/L , p = 0.240 ; SP -2.12 ± 11.01 U/L , p = 0.280 ) ] , renal function [ serum creatinine ( HP 0.31 ± 1.89 mg/dL , p = 0.380 ; SP -0.05 ± 0.15 mg/dL , p = 0.060 ) , urea nitrogen ( HP 1.33 ± 4.68 mg/dL , p = 0.130 ; SP -0.24 ± 3.03 mg/dL , p = 0.650 ) , 24 hour urine creatinine clearance ( HP -0.02 ± 0.16 mL/min , p = 0.480 ; SP 1.18 ± 7.53 mL/min , p = 0.400 ) , and calcium excretion ( HP -0.41 ± 9.48 mg/24 hours , p = 0.830 ; SP -0.007 ± 6.76 mg/24 hours , p = 0.990 ) ] or in bone mineral density by DEXA ( HP 0.04 ± 0.19 g/cm2 , p = 0.210 ; SP -0.03 ± 0.17 g/cm2 , p = 0.320 ) in either group over one year . Conclusions These studies demonstrate that protein-enriched meals replacements as compared to st and ard meal replacements recommended for weight management do not have adverse effects on routine measures of liver function , renal function or bone density at one year . Clinical trial.gov : NCT01030354 The aim of the present study was to test the hypothesis that a prolonged refeeding duration after successful very-low-energy diet (VLED)-induced weight loss beneficially affects weight development and eating behaviour . Patients ( n 269 ) were recruited to a 1-year obesity treatment programme with 12 weeks of an initial VLED . After the VLED , patients with > or= 10 % weight loss were r and omly allocated to 1 week ( group 1 ) or 6 weeks ( group 6 ) refeeding to an ordinary , energy-reduced diet , and thereafter followed and actively treated for an additional 40 weeks . Eating behaviour ( revised twenty-one-item Three-Factor Eating Question naire ) was measured at baseline , during and after refeeding , and at week 52 . Weight change over time in the two treatment groups was tested by repeated- measures analysis in completers and by intention to treat ( ITT ) . Of the patients , 169 ( 109 women ) lost > or= 10 % during the VLED and were r and omised . At r and omisation , weight loss was - 16.5 ( SD 3.7 ) % in group 1 and - 16.7 ( SD 4.3 ) % in group 6 ( P = 0.73 ) . Between weeks 12 and 52 , completers in group 6 regained significantly less weight ( 3.9 ( SD 9.1 ) % ) as compared with group 1 ( 8.2 ( SD 8.3 ) % ; P = 0.006 ) ( ITT , P = 0.05 ) . Completers in group 6 also maintained a higher level of dietary restraint after refeeding was completed , but eating behaviour did not differ at week 52 . Weight change after the refeeding periods were completed did not differ significantly between the groups ( P = 0.06 ) . Overall , longer refeeding duration after successful weight loss with a VLED improves weight maintenance in a 1-year perspective CONTEXT Reduced intake of saturated fat is widely recommended for prevention of cardiovascular disease . The type of macronutrient that should replace saturated fat remains uncertain . OBJECTIVE To compare the effects of 3 healthful diets , each with reduced saturated fat intake , on blood pressure and serum lipids . DESIGN , SETTING , AND PARTICIPANTS R and omized , 3-period , crossover feeding study ( April 2003 to June 2005 ) conducted in Baltimore , Md , and Boston , Mass. Participants were 164 adults with prehypertension or stage 1 hypertension . Each feeding period lasted 6 weeks and body weight was kept constant . INTERVENTIONS A diet rich in carbohydrates ; a diet rich in protein , about half from plant sources ; and a diet rich in unsaturated fat , predominantly monounsaturated fat . MAIN OUTCOME MEASURES Systolic blood pressure and low-density lipoprotein cholesterol . RESULTS Blood pressure , low-density lipoprotein cholesterol , and estimated coronary heart disease risk were lower on each diet compared with baseline . Compared with the carbohydrate diet , the protein diet further decreased mean systolic blood pressure by 1.4 mm Hg ( P = .002 ) and by 3.5 mm Hg ( P = .006 ) among those with hypertension and decreased low-density lipoprotein cholesterol by 3.3 mg/dL ( 0.09 mmol/L ; P = .01 ) , high-density lipoprotein cholesterol by 1.3 mg/dL ( 0.03 mmol/L ; P = .02 ) , and triglycerides by 15.7 mg/dL ( 0.18 mmol/L ; P<.001 ) . Compared with the carbohydrate diet , the unsaturated fat diet decreased systolic blood pressure by 1.3 mm Hg ( P = .005 ) and by 2.9 mm Hg among those with hypertension ( P = .02 ) , had no significant effect on low-density lipoprotein cholesterol , increased high-density lipoprotein cholesterol by 1.1 mg/dL ( 0.03 mmol/L ; P = .03 ) , and lowered triglycerides by 9.6 mg/dL ( 0.11 mmol/L ; P = .02 ) . Compared with the carbohydrate diet , estimated 10-year coronary heart disease risk was lower and similar on the protein and unsaturated fat diets . CONCLUSION In the setting of a healthful diet , partial substitution of carbohydrate with either protein or monounsaturated fat can further lower blood pressure , improve lipid levels , and reduce estimated cardiovascular risk . Clinical Trials Registration Clinical Trials.gov Identifier : NCT00051350 To determine the optimal energy intake of very-low-calorie diets ( VLCDs ) , 76 obese women were r and omly assigned , in a double-blind fashion , to one of three liquid-formula diets : 1758 kJ/d ( 420 kcal/d ) , 2763 kJ/d ( 660 kcal/d ) , or 3349 kJ/d ( 800 kcal/d ) . Weight , body composition , symptoms , mood , and acceptability of the diet were assessed throughout the 6-mo study . There were no significant differences in weight losses or changes in body composition among the three dietary conditions at the end of treatment , nor were there significant differences among conditions in acceptability of the diet , symptoms , or mood . These results suggest that there is no clinical advantage to using VLCDs that provide less than 3349 kJ/d ( 800 kcal/d ) BACKGROUND Consuming foods low in energy density ( kcal/g ) decreases energy intake over several days , but the effectiveness of this strategy for weight loss has not been tested . OBJECTIVE The effects on weight loss of 2 strategies for reducing the energy density of the diet were compared over 1 y. DESIGN Obese women ( n = 97 ) were r and omly assigned to groups counseled either to reduce their fat intake ( RF group ) or to reduce their fat intake and increase their intake of water-rich foods , particularly fruit and vegetables ( RF+FV group ) . No goals for energy or fat intake were assigned ; the subjects were instructed to eat ad libitum amounts of food while following the principles of their diet . RESULTS After 1 y , study completers ( n = 71 ) in both groups had significant decreases in body weight ( P < 0.0001 ) . Subjects in the RF+FV group , however , had a significantly different pattern of weight loss ( P = 0.002 ) than did subjects in the RF group . After 1 y , the RF+FV group lost 7.9 + /- 0.9 kg and the RF group lost 6.4 + /- 0.9 kg . Analysis of all r and omly assigned subjects also showed a different pattern of weight loss between groups ( P = 0.021 ) . Diet records indicated that both groups had similar reductions in fat intake . The RF+FV group , however , had a lower dietary energy density than did the RF group ( P = 0.019 ) as the result of consuming a greater weight of food ( P = 0.025 ) , especially fruit and vegetables ( P = 0.037 ) . The RF+FV group also reported less hunger ( P = 0.003 ) . CONCLUSION Reducing dietary energy density , particularly by combining increased fruit and vegetable intakes with decreased fat intake , is an effective strategy for managing body weight while controlling hunger BACKGROUND The role of glycemic index ( GI ) in appetite and body-weight regulation is still not clear . OBJECTIVE The objective of the study was to investigate the long-term effects of a low-fat , high-carbohydrate diet with either low glycemic index ( LGI ) or high glycemic index ( HGI ) on ad libitum energy intake , body weight , and composition , as well as on risk factors for type 2 diabetes and ischemic heart disease in overweight healthy subjects . DESIGN The study was a 10-wk parallel , r and omized , intervention trial with 2 matched groups . The LGI or HGI test foods , given as replacements for the subjects ' usual carbohydrate-rich foods , were equal in total energy , energy density , dietary fiber , and macronutrient composition . Subjects were 45 ( LGI diet : n = 23 ; HGI diet : n = 22 ) healthy overweight [ body mass index ( in kg/m(2 ) ) : 27.6 + /- 0.2 ] women aged 20 - 40 y. RESULTS Energy intake , mean ( + /- SEM ) body weight ( LGI diet : -1.9 + /- 0.5 kg ; HGI diet : -1.3 + /- 0.3 kg ) , and fat mass ( LGI diet : -1.0 + /- 0.4 kg ; HGI diet : -0.4 + /- 0.3 kg ) decreased over time , but the differences between groups were not significant . No significant differences were observed between groups in fasting serum insulin , homeostasis model assessment for relative insulin resistance , homeostasis model assessment for beta cell function , triacylglycerol , nonesterified fatty acids , or HDL cholesterol . However , a 10 % decrease in LDL cholesterol ( P < 0.05 ) and a tendency to a larger decrease in total cholesterol ( P = 0.06 ) were observed with consumption of the LGI diet as compared with the HGI diet . CONCLUSIONS This study does not support the contention that low-fat LGI diets are more beneficial than HGI diets with regard to appetite or body-weight regulation as evaluated over 10 wk . However , it confirms previous findings of a beneficial effect of LGI diets on risk factors for ischemic heart disease This study investigated the acceptability of two very-low-calorie diets in 16 moderately overweight persons participating in a weight reduction program . Subjects were prescribed a 1000 - 1200 kcal balanced diet the first month and asked to complete appetite and mood scales on a weekly basis . They were then r and omly assigned to either a protein-sparing-modified fast ( PSMF ) or a protein-formula-liquid diet , each of which provided about 400 kcal daily . Analysis of the appetite data showed that PSMF subjects reported significantly less hunger and preoccupation with eating than did liquid diet subjects during 2 of the 4 weeks on a very-low-calorie diet . Subjects in both conditions reported significant reductions in anxiety . Results are discussed in terms of possible advantages of PSMF BACKGROUND Dietary energy density ( ED ) reductions are associated with energy intake ( EI ) reductions . Little is known about influences on body weight ( BW ) . OBJECTIVES We examined the effects of behavioral interventions on ED values and explored how 6-mo ED changes relate to BW . DESIGN Prehypertensive and hypertensive persons were r and omly assigned to 1 of 3 groups : the established group received an 18-session intervention implementing well-established hypertension recommendations ( eg , weight loss , sodium reduction , and physical activity ) , the established+Dietary Approaches to Stop Hypertension ( DASH ) group received an 18-session intervention also implementing the DASH diet , and the advice group received 1 session on these topics . Two 24-h dietary recalls were collected ( n=658 ) . RESULTS Each group had significant declines in EI , ED , and BW . The established and established+DASH groups had the greatest EI and BW reductions . The established+DASH group had the greatest ED reduction and the greatest increase in the weight of food consumed . When groups were combined and analyzed by ED change tertiles , participants in the highest tertile ( ie , largest ED reduction ) lost more weight ( 5.9 kg ) than did those in the middle ( 4.0 kg ) or lowest ( 2.4 kg ) tertile . Participants in the highest and middle tertiles increased the weight of food they consumed ( 300 and 80 g/d , respectively ) but decreased their EI ( 500 and 250 kcal/d ) . Conversely , those in the lowest tertile decreased the weight of food consumed ( 100 g/d ) , with little change in EI . The highest and middle tertiles had favorable changes in fruit , vegetable , vitamin , and mineral intakes . CONCLUSION Both large and modest ED reductions were associated with weight loss and improved diet quality BACKGROUND Lowering the dietary glycemic load and increasing protein intake may be advantageous for weight management . OBJECTIVE This r and omized controlled trial was design ed to evaluate the effects of an ad libitum reduced-glycemic-load ( RGL ) diet on body weight , body composition , and cardiovascular disease ( CVD ) risk markers in overweight and obese adults during an initial weight-loss phase ( 12 wk ) and a weight-loss maintenance phase ( weeks 24 - 36 ) . DESIGN Subjects were assigned to RGL ( n = 43 ) or low-fat , portion-controlled ( control ; n = 43 ) diet groups . The RGL group was instructed to eat until satisfied , maintaining a low carbohydrate intake during weeks 0 - 2 and adding low-glycemic-index carbohydrate thereafter . Control subjects were instructed to reduce fat intake and decrease portion sizes , with a targeted energy deficit of 500 to 800 kcal/d . RESULTS The RGL group had lost significantly more weight than did the control group at week 12 ( -4.9 and -2.5 kg , respectively ; P = 0.002 ) , but the 2 groups did not differ significantly at week 36 ( -4.5 and -2.6 kg , respectively ; P = 0.085 ) . Changes in fat mass differed between the groups at week 12 ( -1.9 and -0.9 kg , respectively ; P = 0.016 ) but not at week 36 ( -2.0 and -1.3 kg , respectively ; P = 0.333 ) . At the end of the study , no differences were found in responses for CVD risk markers except a larger mean change in HDL cholesterol in the RGL group than in the control group ( 3.8 and 1.9 mg/dL , respectively ; P = 0.037 ) . CONCLUSION These findings provide evidence that an ad libitum RGL diet is a reasonable alternative to a low-fat , portion-controlled eating plan for weight management BACKGROUND Some investigators fear that dieting may precipitate binge eating and other adverse behavioral consequences . OBJECTIVE The objective of the study was to examine whether dieting would elicit binge eating and mood disturbance in individuals free of these complications before treatment . DESIGN A total of 123 obese women were r and omly assigned to 1 ) a 1000 kcal/d diet that included 4 servings/d of a liquid meal replacement ( MR ) ; 2 ) a 1200 - 1500 kcal/d balanced deficit diet ( BDD ) of conventional foods ; or 3 ) a nondieting ( ND ) approach that discouraged energy restriction . All women attended weekly group sessions for 20 wk and biweekly sessions from week 20 to week 40 . RESULTS At week 20 , participants in the MR , BDD , and ND groups lost 12.1 + /- 6.7 % , 7.8 + /- 6.0 % , and 0.1 + /- 2.4 % of initial weight , respectively ( P < 0.001 ) . During the first 20 wk , there were no significant differences among groups in the number of persons who had objective binge episodes or in reports of hunger or dietary disinhibition . Symptoms of depression decreased significantly more ( P < 0.001 ) in the MR and BDD groups than in ND participants . At week 28 , significantly more ( P < 0.003 ) cases of binge eating were observed in MR participants than in the 2 other groups . No differences , however , were observed between groups at weeks 40 or 65 ( a follow-up visit ) . At no time did any participant meet criteria for binge-eating disorder . CONCLUSION Concerns about possible adverse behavioral consequences of dieting should not dissuade primary care providers from recommending modest energy restriction to obese individuals Noncompliance with therapeutic diets remains a major obstacle to achieving improvements in cardiovascular disease ( CVD ) morbidity and mortality . This study compared dietary compliance and CVD risk factor response to two dietary interventions design ed to treat hypertension , dyslipidemia , and diabetes mellitus . In a multicenter trial , 560 adults were r and omly assigned to either a self-selected , mixed-food plan ( n = 277 ) , or a nutrient-fortified prepared meal plan ( n = 283 ) ; each was design ed to provide 15 - 20 % of energy from fat , 55 - 60 % from carbohydrate , and 15 - 20 % from protein . Nutrient intake was estimated from 3-d food records collected biweekly throughout the 10-wk intervention . Compliance was determined by evaluating the participants ' ability to meet specific criteria for energy intake [ + /-420 kJ ( 100 kcal ) from the midpoint of the prescribed energy range ] , fat intake ( < 20 % , < 25 % , or < 30 % of energy from total fat ) , and the National Cholesterol Education Program/American Heart Association Step 1 and 2 diet recommendations . Compliance with energy , fat , and Step 1 and 2 criteria was better in participants who followed the prepared meal plan than in those who followed the self-selected diet ( P < 0.0001 ) . Compliant participants in both groups achieved greater reductions in body weight , systolic and diastolic blood pressure , and total and low-density-lipoprotein cholesterol than noncompliant participants ( P < 0.05 ) . In general , better endpoint responses were observed with lower fat intakes regardless of group assignment . The prepared meal plan is a simple and effective strategy for meeting the many nutrient recommendations for CVD risk reduction and improving dietary compliance and CVD endpoints BACKGROUND The optimal nutritional approach for the prevention of cardiovascular disease among obese persons remains a topic of intense controversy . Available approaches range from conventional low-fat to very-low-carbohydrate diets . OBJECTIVE The aim of this pilot study was to evaluate the efficacy of an ad libitum low-glycemic load diet , without strict limitation on carbohydrate intake , as an alternative to a conventional low-fat diet . DESIGN A r and omized controlled trial compared 2 dietary treatments in obese young adults ( n = 23 ) over 12 mo . The experimental treatment emphasized ad libitum consumption of low-glycemic-index foods , with 45 - 50 % of energy from carbohydrates and 30 - 35 % from fat . The conventional treatment was restricted in energy ( 250 - 500 kcal/d deficit ) and fat ( < 30 % of energy ) , with 55 - 60 % of energy from carbohydrate . We compared changes in study outcomes by repeated- measures analysis of log-transformed data and expressed the results as mean percentage change . RESULTS Body weight decreased significantly over a 6-mo intensive intervention in both the experimental and conventional diet groups ( -8.4 % and -7.8 % , respectively ) and remained below baseline at 12 mo ( -7.8 % and -6.1 % , respectively ) . The experimental diet group showed a significantly greater mean decline in plasma triacylglycerols than did the conventional diet group ( -37.2 % and -19.1 % , respectively ; P = 0.005 ) . Mean plasminogen activator inhibitor 1 concentrations decreased ( -39.0 % ) in the experimental diet group but increased ( 33.1 % ) in the conventional diet group ( P = 0.004 ) . Changes in cholesterol concentrations , blood pressure , and insulin sensitivity did not differ significantly between the groups . CONCLUSION An ad libitum low-glycemic load diet may be more efficacious than a conventional , energy-restricted , low-fat diet in reducing cardiovascular disease risk BACKGROUND Despite interest in the glycemic index diets as an approach to weight control , few long-term evaluations are available . OBJECTIVE The objective was to investigate the long-term effect of a low-glycemic-index ( LGI ) diet compared with that of a high-glycemic-index ( HGI ) diet ; all other dietary components were equal . DESIGN After a 6-wk run-in , we r and omly assigned 203 healthy women [ body mass index ( in kg/m2 ) : 23 - 30 ] aged 25 - 45 y to an LGI or an HGI diet with a small energy restriction . The primary outcome measure was weight change at 18 mo . Secondary outcomes included hunger and fasting insulin and lipids . RESULTS Despite requiring a run-in and the use of multiple incentives , only 60 % of the subjects completed the study . The difference in glycemic index between the diets was approximately 35 - 40 units ( 40 compared with 79 ) during all 18 mo of follow-up , and the carbohydrate intake from energy remained at approximately 60 % in both groups . The LGI group had a slightly greater weight loss in the first 2 mo of follow-up ( -0.72 compared with -0.31 kg ) , but after 12 mo of follow-up both groups began to regain weight . After 18 mo , the weight change was not significantly different ( P = 0.93 ) between groups ( LGI : -0.41 kg ; HGI : -0.26 kg ) . A greater reduction was observed in the LGI diet group for triacylglycerol ( difference = -16.4 mg/dL ; P = 0.11 ) and VLDL cholesterol ( difference = -3.7 mg/dL ; P = 0.03 ) . CONCLUSIONS Long-term weight changes were not significantly different between the HGI and LGI diet groups ; therefore , this study does not support a benefit of an LGI diet for weight control . Favorable changes in lipids confirmed previous results BACKGROUND When substituted for carbohydrate in an energy-reduced diet , dietary protein enhances fat loss in women . It is unknown whether the effect is due to increased protein or reduced carbohydrate . OBJECTIVE We compared the effects of 2 isocaloric diets that differed in protein and fat content on weight loss , lipids , appetite regulation , and energy expenditure after test meals . DESIGN This was a parallel , r and omized study in which subjects received either a low-fat , high-protein ( LF-HP ) diet ( 29 + /- 1 % fat , 34 + /- 0.8 % protein ) or a high-fat , st and ard-protein ( HF-SP ) diet ( 45 + /- 0.6 % fat , 18 + /- 0.3 % protein ) during 12 wk of energy restriction ( 6 + /- 0.1 MJ/d ) and 4 wk of energy balance ( 7.4 + /- 0.3 MJ/d ) . Fifty-seven overweight and obese [ mean body mass index ( in kg/m(2 ) ) : 33.8 + /- 0.9 ] volunteers with insulin concentrations > 12 mU/L completed the study . RESULTS Weight loss ( LF-HP group , 9.7 + /- 1.1 kg ; HF-SP group , 10.2 + /- 1.4 kg ; P = 0.78 ) and fat loss were not significantly different between diet groups even though the subjects desired less to eat after the LF-HP meal ( P = 0.02 ) . The decrease in resting energy expenditure was not significantly different between diet groups ( LF-HP , -342 + /- 185 kJ/d ; HF-SP , -349 + /- 220 kJ/d ) . The decrease in the thermic effect of feeding with weight loss was smaller in the LF-HP group than in the HF-SP group ( -0.3 + /- 1.0 % compared with -3.6 + /- 0.7 % ; P = 0.014 ) . Glucose and insulin responses to test meals improved after weight loss ( P < 0.001 ) with no significant diet effect . Bone turnover , inflammation , and calcium excretion did not change significantly . CONCLUSION The magnitude of weight loss and the improvements in insulin resistance and cardiovascular disease risk factors did not differ significantly between the 2 diets , and neither diet had any detrimental effects on bone turnover or renal function After a baseline period of free-feeding , 20 obese out patients alternated between four 2-wk periods of minimal-carbohydrate diet ( 800 kcal ; 58 % protein and 42 % fat by weight ) and of a carbohydrate-supplemented diet ( 1,000 kcal ; 42 % protein , 30 % fat , and 28 % carbohydrate ) . In a comparison of psychological adjustment during the baseline and low-calorie diets , the initial 2 wk of dieting was associated with a decrease in appetite and elevation of psychological well-being , regardless of the composition of the diet . Thereafter , appetite and mood approached basal levels . Further changes in these psychological reactions to dieting did not vary with the type of diet . There was no support for the idea that a minimal-carbohydrate , protein-supplemented fast decreases appetite and elevates mood more in comparison with a similar diet containing enough carbohydrate to minimize ketosis BACKGROUND It is not clear whether varying the protein-to-carbohydrate ratio of weight-loss diets benefits body composition or metabolism . OBJECTIVE The objective was to compare the effects of 2 weight-loss diets differing in protein-to-carbohydrate ratio on body composition , glucose and lipid metabolism , and markers of bone turnover . DESIGN A parallel design included either a high-protein diet of meat , poultry , and dairy foods ( HP diet : 27 % of energy as protein , 44 % as carbohydrate , and 29 % as fat ) or a st and ard-protein diet low in those foods ( SP diet : 16 % of energy as protein , 57 % as carbohydrate , and 27 % as fat ) during 12 wk of energy restriction ( 6 - 6.3 MJ/d ) and 4 wk of energy balance ( approximately 8.2 MJ/d ) . Fifty-seven overweight volunteers with fasting insulin concentrations > 12 mU/L completed the study . RESULTS Weight loss ( 7.9 + /- 0.5 kg ) and total fat loss ( 6.9 + /- 0.4 kg ) did not differ between diet groups . In women , total lean mass was significantly ( P = 0.02 ) better preserved with the HP diet ( -0.1 + /- 0.3 kg ) than with the SP diet ( -1.5 + /- 0.3 kg ) . Those fed the HP diet had significantly ( P < 0.03 ) less glycemic response at weeks 0 and 16 than did those fed the SP diet . After weight loss , the glycemic response decreased significantly ( P < 0.05 ) more in the HP diet group . The reduction in serum triacylglycerol concentrations was significantly ( P < 0.05 ) greater in the HP diet group ( 23 % ) than in the SP diet group ( 10 % ) . Markers of bone turnover , calcium excretion , and systolic blood pressure were unchanged . CONCLUSION Replacing carbohydrate with protein from meat , poultry , and dairy foods has beneficial metabolic effects and no adverse effects on markers of bone turnover or calcium excretion BACKGROUND A very-low-energy diet ( VLED ) can result in substantial , rapid weight loss and is increasingly prescribed before obesity surgery to minimize risk and difficulty by reducing liver size and abdominal adiposity . Despite its growing popularity , a VLED in this setting has received little attention . OBJECTIVE The aim of this study was to investigate the efficacy and acceptability of a preoperative VLED . DESIGN In a prospect i ve observational study , 32 subjects ( n = 19 men and 13 women ) with a mean ( + /-SD ) age of 47.5 + /- 8.3 y and a body mass index ( in kg/m(2 ) ) of 47.3 + /- 5.3 consumed a VLED for 12 wk . Primary outcomes included changes in liver volume ( LV ) and in visceral and subcutaneous adipose tissue ( VAT/SAT ) . Changes in body weight , anthropometric measures , and biochemical variables were also recorded , and compliance with , acceptability of , and side effects of treatment were assessed . Changes in LV and VAT/SAT area were measured by computed tomography and magnetic resonance imaging at baseline and weeks 2 , 4 , 8 , and 12 . RESULTS Mean ( + /-SD ) LV , VAT/SAT , and body weight decreased significantly ( P < 0.001 for all ) . The degree of LV reduction was directly related to the reduction in relative body weight ( r = 0.54 , P = 0.001 ) and initial LV ( r = 0.43 , P = 0.015 ) . Eighty percent of the reduction in LV occurred between weeks 0 and 2 ( P < 0.001 ) . Reductions in body weight and VAT were uniform over the 12-wk period . Attrition was 14 % . Acceptability was adequate but waned over time , and mild transitory side effects occurred . CONCLUSIONS Given the observed early reduction in LV and the progressive reduction in VAT , we suggest that the minimum duration for a preoperative VLED be 2 wk . Ideally , the duration should be 6 wk to achieve maximal LV reduction and significant reductions in VAT and body weight without compromising compliance and acceptability The determine the effect of different foods on the blood glucose , 62 commonly eaten foods and sugars were fed individually to groups of 5 to 10 healthy fasting volunteers . Blood glucose levels were measured over 2 h , and expressed as a percentage of the area under the glucose response curve when the same amount of carbohydrate was taken as glucose . The largest rises were seen with vegetables ( 70 + /- 5 % ) , followed by breakfast cereals ( 65 + /- 5 % ) , cereals and biscuits ( 60 + /- 3 % ) , fruit ( 50 + /- 5 % ) , dairy products ( 35 + /- 1 % ) , and dried legumes ( 31 + /- 3 % ) . A significant negative relationship was seen between fat ( p less than 0.01 ) and protein ( p less than 0.001 ) and postpr and ial glucose rise but not with fiber or sugar content BACKGROUND Meat intake may be related to weight gain because of its high energy and fat content . Some observational studies have shown that meat consumption is positively associated with weight gain , but intervention studies have shown mixed results . OBJECTIVE Our objective was to assess the association between consumption of total meat , red meat , poultry , and processed meat and weight gain after 5 y of follow-up , on average , in the large European population who participated in the European Prospect i ve Investigation into Cancer and Nutrition-Physical Activity , Nutrition , Alcohol , Cessation of Smoking , Eating Out of Home and Obesity ( EPIC-PANACEA ) project . DESIGN A total of 103,455 men and 270,348 women aged 25 - 70 y were recruited between 1992 and 2000 in 10 European countries . Diet was assessed at baseline with the use of country-specific vali date d question naires . A dietary calibration study was conducted in a representative sub sample of the cohort . Weight and height were measured at baseline and self-reported at follow-up in most centers . Associations between energy from meat ( kcal/d ) and annual weight change ( g/y ) were assessed with the use of linear mixed models , controlled for age , sex , total energy intake , physical activity , dietary patterns , and other potential confounders . RESULTS Total meat consumption was positively associated with weight gain in men and women , in normal-weight and overweight subjects , and in smokers and nonsmokers . With adjustment for estimated energy intake , an increase in meat intake of 250 g/d ( eg , one steak at approximately 450 kcal ) would lead to a 2-kg higher weight gain after 5 y ( 95 % CI : 1.5 , 2.7 kg ) . Positive associations were observed for red meat , poultry , and processed meat . CONCLUSION Our results suggest that a decrease in meat consumption may improve weight management BACKGROUND Long-term weight loss and cardiometabolic effects of a very-low-carbohydrate , high-saturated-fat diet ( LC ) and a high-carbohydrate , low-fat diet ( LF ) have not been evaluated under isocaloric conditions . OBJECTIVE The objective was to compare an energy-controlled LC diet with an LF diet at 1 y. DESIGN Men and women ( n = 118 ) with abdominal obesity and at least one additional metabolic syndrome risk factor were r and omly assigned to either an energy-restricted ( approximately 6 - 7 MJ ) LC diet ( 4 % , 35 % , and 61 % of energy as carbohydrate , protein , and fat , respectively ) or an isocaloric LF diet ( 46 % , 24 % , and 30 % of energy as carbohydrate , protein , and fat , respectively ) for 1 y. Weight , body composition , and cardiometabolic risk markers were assessed . RESULTS Sixty-nine participants ( 59 % ) completed the trial : 33 in the LC group and 36 in the LF group . Both groups lost similar amounts of weight ( LC : -14.5 + /- 1.7 kg ; LF : -11.5 + /- 1.2 kg ; P = 0.14 , time x diet ) and body fat ( LC : -11.3 + /- 1.5 kg ; LF : -9.4 + /- 1.2 kg ; P = 0.30 ) . Blood pressure , fasting glucose , insulin , insulin resistance , and C-reactive protein decreased independently of diet composition . Compared with the LF group , the LC group had greater decreases in triglycerides ( -0.36 + /- 0.15 mmol/L ; 95 % CI : -0.67 , -0.05 mmol/L ; P = 0.011 ) , increases in HDL cholesterol ( 0.23 + /- 0.09 mmol/L ; 95 % CI : 0.06 , 0.40 mmol/L ; P = 0.018 ) and LDL cholesterol ( 0.6 + /- 0.2 mmol/L ; 95 % CI : 0.2 , 1.0 mmol/L ; P = 0.001 ) , and a greater but nonsignificant increase in apolipoprotein B ( 0.08 + /- 0.04 g/L ; 95 % CI : -0.004 , 0.171 g/L ; P = 0.17 ) . CONCLUSIONS Under planned isoenergetic conditions , as expected , both dietary patterns result ed in similar weight loss and changes in body composition . The LC diet may offer clinical benefits to obese persons with insulin resistance . However , the increase in LDL cholesterol with the LC diet suggests that this measure should be monitored . This trial was registered with the Australian New Zeal and Clinical Trials Registry at ( http://www.anzctr.org.au ) as ACTR 12606000203550 CONTEXT The prevalence of overweight and obesity in the United States remains high . Commercial weight loss programs may contribute to efforts to reduce the prevalence of overweight and obesity , although few studies have examined their efficacy in controlled trials . OBJECTIVE To test whether a free prepared meal and incentivized structured weight loss program promotes greater weight loss and weight loss maintenance at 2 years compared with usual care . DESIGN , SETTING , AND PARTICIPANTS A r and omized controlled trial of weight loss and weight loss maintenance in 442 overweight or obese women ( body mass index , 25 - 40 ) aged 18 to 69 years ( mean age , 44 years ) conducted at US institutions over 2 years with follow-up between November 2007 and April 2010 . INTERVENTION The program , which involves in-person center-based or telephone-based one-to-one weight loss counseling , was available over a 2-year period . Behavioral goals were an energy-reduced , nutritionally adequate diet , facilitated by the inclusion of prepackaged food items in a planned menu during the initial weight loss phase , and increased physical activity . Participants assigned to usual care received 2 individualized weight loss counseling sessions with a dietetics professional and monthly contacts . MAIN OUTCOME MEASURES Weight loss and weight loss maintenance . RESULTS Weight data were available at 24 months for 407 women ( 92.1 % of the study sample ) . In an intent-to-treat analysis with baseline value substitution , mean weight loss was 7.4 kg ( 95 % confidence interval [ CI ] , 6.1 - 8.7 kg ) or 7.9 % ( 95 % CI , 6.5%-9.3 % ) of initial weight at 24 months for the center-based group , 6.2 kg ( 95 % CI , 4.9 - 7.6 kg ) or 6.8 % ( 95 % CI , 5.2%-8.4 % ) for the telephone-based group , and 2.0 kg ( 95 % CI , 0.6 - 3.3 kg ) or 2.1 % ( 95 % CI , 0.7%-3.5 % ) for the usual care control group after 24 months ( P < .001 for intervention effect ) . CONCLUSION Compared with usual care , this structured weight loss program result ed in greater weight loss over 2 years . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00640900 OBJECTIVE To evaluate the effectiveness of meal replacements ( MRs ) in weight loss interventions in premenopausal women . RESEARCH METHODS AND PROCEDURES Overweight premenopausal women ( n = 113 ; body mass index : 25 to 35 kg/m(2 ) ; 30 to 50 years old ) were r and omized into three interventions : group A , a dietitian-led intervention ; group B , a dietitian-led intervention incorporating MRs ; and group C , a clinical office-based intervention incorporating MRs . In year 1 , groups A and B attended 26 group sessions , whereas group C received the same educational material s during 26 10-minute office visits with a physician-nurse team . In year 2 , participants attended monthly group seminars and drop-in visits with a dietitian . RESULTS For the 74 subjects completing year 1 , weight loss in the office-based group C was as effective as the traditional dietitian-led group A ( 4.3 + /- 6.5 % vs. 4.1 + /- 6.4 % ) , while group B maintained a significantly greater weight loss ( 9.1 + /- 8.9 % ; p < 0.02 ; mean + /- SD ) . For the 43 subjects completing year 2 , group B showed significant differences in the percentage of weight loss ( -8.5 + /- 7.0 % ) compared with group A ( -1.5 + /- 5.0 % ) and group C ( -3.0 + /- 7.0 % ; p < 0.001 ) . DISCUSSION Study results showed that a traditional weight loss intervention incorporating MRs was effective as a weight loss tool in the medical office practice and in the dietitian-led group setting The Mediterranean diet is receiving increasing attention in cardiovascular epidemiology . The association of adherence to the Mediterranean diet with the incidence of hypertension was evaluated among 9,408 men and women enrolled in a dynamic Spanish prospect i ve cohort study during 1999 - 2005 . Dietary intake was assessed at baseline with a vali date d semiquantitative food frequency question naire , and a 9-point Mediterranean diet score was constructed . During a median follow-up period of 4.2 years ( range , 1.9 - 7.9 ) , 501 incident cases of hypertension were identified . After adjustment for major hypertension risk factors and nutritional covariates , adherence to the Mediterranean diet was not associated with hypertension ( the hazard ratio was 1.10 ( 95 % confidence interval ( CI ) : 0.81 , 1.41 ) for moderate adherence and 1.12 ( 95 % CI : 0.79 , 1.60 ) for high adherence ) . However , it was associated with reduced changes in mean levels of systolic blood pressure ( moderate adherence , -2.4 mm Hg ( 95 % CI : -4.0 , -0.8 ) ; high adherence , -3.1 mm Hg ( 95 % CI : -5.4 , -0.8 ) ) and diastolic blood pressure ( moderate adherence , -1.3 mm Hg ( 95 % CI : -2.5 , -0.1 ) ; high adherence , -1.9 mm Hg ( 95 % CI : -3.6 , -0.1 ) ) after 6 years of follow-up . These results suggest that adhering to a Mediterranean-type diet could contribute to the prevention of age-related changes in blood pressure OBJECTIVE To compare a meal replacement ( MR ) program with a conventional reduced-calorie diet ( RCD ) for weight management using the pharmacy as the setting and the pharmacist as the point of contact for dietary advice . DESIGN R and omized , controlled , open-label trial . SETTING Travis Pharmacy in Shen and oah , Iowa . PATIENTS Ninety-five patients from southwestern iowa and southeastern Nebraska were enrolled , of whom 88 were considered eligible for comparison ( by continuing through week 2 of the study ) . INTERVENTION Patients were r and omized to an MR plan or a traditional RCD plan . Patients were followed for a 3-month period of active weight loss and a 10-week period of weight maintenance . Patients returned every 3 weeks for follow-up with the pharmacist , for a total of 13 visits . MAIN OUTCOME MEASURE Weight changes . RESULTS During the active weight loss phase , the MR ( n = 45 ) and RCD ( n = 43 ) groups lost a significant amount of weight , although no significant difference was found between the groups ( mean + /- st and ard error = 4.90 + /- 0.30 kg MR versus 4.30 + /- 0.30 kg RCD ; P = .16 ) . In the weight maintenance phase , the MR group lost 0.70 + /- 0.40 kg and the RCD group lost 0.90 + /- 0.40 kg ( P = .60 ) . Significant improvements were observed in waist circumference , systolic and diastolic blood pressure , and triglyceride levels . No significant changes were seen in high-density lipoprotein cholesterol or low-density lipoprotein cholesterol levels in either group . CONCLUSION Successful weight management can be achieved in a pharmacy setting . Both MR and RCD programs were effective BACKGROUND Roux-en-Y gastric bypass surgery is the leading surgical treatment of morbid obesity in the United States . The role of preoperative weight loss in gastric bypass surgery remains controversial . We performed a prospect i ve r and omized trial to determine whether preoperative weight loss results in better outcomes after laparoscopic gastric bypass . METHODS A total of 100 patients undergoing laparoscopic gastric bypass surgery from May 2004 to October 2005 were r and omized preoperatively to either a weight loss group with a 10 % weight loss requirement or a group that had no weight loss requirements . The patients were followed prospect ively . The variables analyzed included perioperative complications , operative time , postoperative weight loss , and resolution of co-morbidities . RESULTS Data were available for 26 patients in the weight loss group and 35 in the nonweight loss group . The 2 groups had similar preoperative characteristics , conversion and complication rates , and resolution of co-morbidities . The initial body mass index was 48.7 kg/m(2 ) and 49.3 kg/m(2 ) for the weight loss group and nonweight loss group , respectively ( P = NS ) . The preoperative body mass index was 44.5 kg/m(2 ) and 50.7 kg/m(2 ) for the weight loss group and nonweight loss group , respectively ( P = 0.0027 ) . The operative time was 220.2 and 257.6 minutes for the 2 groups ( P = 0.0084 ) . The percentage of excess weight loss at 3 and 6 months for the weight loss group and nonweight loss group was 44.1 % and 33.1 % ( P = 0.0267 ) and 53.9 % and 50.9 % ( P = NS ) , respectively . The interval to surgery from the initial consultation was 5.4 months and 5.2 months for the 2 groups ( P = NS ) . CONCLUSIONS Preoperative weight loss before laparoscopic Roux-en-Y gastric bypass was associated with a decrease in the operating room time and an improved percentage of excess weight loss in the short term . Preoperative weight loss , however , did not affect the major complication or conversion rates , and its long-term effects were not apparent through this study . Also , preoperative weight loss did not have any bearing on the resolution of co-morbidities The glycaemic index ( GI ) has been developed in order to classify food according to the postpr and ial glycaemic response . This parameter is of interest , especially for people prone to glucose intolerance ; however , the effects of a low-GI ( LGI ) diet on body weight , carbohydrate and lipid metabolism remain controversial . We studied the effects of either a LGI or high-GI ( HGI ) diet on weight control and cardiovascular risk factors in overweight , non-diabetic subjects . The study was a r and omized 5-week intervention trial . The thirty-eight subjects ( BMI 27.3 ( sem 0.2 ) kg/m2 ) followed an intervention diet in which usual starch was replaced ad libitum with either LGI or HGI starch . Mean body weight decrease was significant in the LGI group ( - 1.1 ( sEM 0.3 ) kg , P = 0.004 ) and was significantly greater than in the HGI group ( - 0.3 ( sEM 0.2 ) kg , P = 0.04 between groups ) . Hunger sensation scales showed a trend towards a decrease in hunger sensation before lunch and dinner in the LGI group when compared with the HGI group ( P = 0.09 ) . No significant increase in insulin sensitivity was noticed . The LGI diet also decreased total cholesterol by 9.6 % ( P < 0.001 ) , LDL-cholesterol by 8.6 % ( P = 0.01 ) and both LDL-:HDL-cholesterol ratio ( 10.1 % , P = 0.003 ) and total : HDL-cholesterol ratio ( 8.5 % , P = 0.001 ) while no significant changes were observed in the HGI group . Lowering the GI of daily meals with simple dietary recommendations results in increased weight loss and improved lipid profile and is relatively easy to implement with few constraints . These potential benefits of consuming a LGI diet can be useful to develop practical dietetic advice Objective To assess the effect of weight loss induced by a very low energy diet on moderate and severe obstructive sleep apnoea in obese men . Design Single centre , two arm , parallel , r and omised , controlled , open label trial . Blocked r and omisation procedure used for treatment allocation . Setting Outpatient obesity clinic in a university hospital in Stockholm , Sweden . Participants 63 obese men ( body mass index 30 - 40 , age 30 - 65 years ) with moderate to severe obstructive sleep apnoea ( apnoea-hypopnoea index ( AHI ) ≥15 ) , treated with continuous positive airway pressure . Interventions The intervention group received a liquid very low energy diet ( 2.3 MJ/day ) for seven weeks to promote weight loss , followed by two weeks of gradual introduction of normal food , reaching 6.3 MJ/day at week 9 . The control group adhered to their usual diet during the nine weeks of follow-up . Main outcome measure AHI , the major disease severity index for obstructive sleep apnoea . Data from all r and omised patients were included in an intention to treat analysis ( baseline carried forward for missing data ) . Results Of the 63 eligible patients , 30 were r and omised to intervention and 33 to control . Two patients in the control group were dissatisfied with allocation and immediately discontinued . All other patients completed the trial . Both groups had a mean AHI of 37 events/h ( SD 15 ) at baseline . At week 9 , the intervention group ’s mean body weight was 20 kg ( 95 % confidence interval 18 to 21 ) lower than that of the control group , while its mean AHI was 23 events/h ( 15 to 30 ) lower . In the intervention group , five of 30 ( 17 % ) were disease free after the energy restricted diet ( AHI < 5 ) , with 15 of 30 ( 50 % ) having mild disease ( AHI 5 - 14.9 ) , whereas the AHI of all patients in the control group except one remained at 15 or higher . In a subgroup analysis of the intervention group , baseline AHI significantly modified the effectiveness of treatment , with a greater improvement in AHI in patients with severe obstructive sleep apnoea ( AHI > 30 ) at baseline compared with those with moderate ( AHI 15 - 30 ) sleep apnoea ( AHI −38 v −12 , P<0.001 ) , despite similar weight loss ( −19.2 v −18.2 kg , P=0.55 ) . Conclusion Treatment with a low energy diet improved obstructive sleep apnoea in obese men , with the greatest effect in patients with severe disease . Long term treatment studies are needed to vali date weight loss as a primary treatment strategy for obstructive sleep apnoea . Trial registration Current Controlled Trials IS RCT N70090382 BACKGROUND Since many successful dieters regain the weight they lose , programs that teach maintenance skills are needed . We developed a maintenance program based on self-regulation theory and tested the efficacy of delivering the program face to face or over the Internet . METHODS We r and omly assigned 314 participants who had lost a mean of 19.3 kg of body weight in the previous 2 years to one of three groups : a control group , which received quarterly newsletters ( 105 participants ) , a group that received face-to-face intervention ( 105 ) , and a group that received Internet-based intervention ( 104 ) . The content of the programs in the two intervention groups was the same , emphasizing daily self-weighing and self-regulation , as was the frequency of contact with the groups . The primary outcome was weight gain over a period of 18 months . RESULTS The mean ( + /-SD ) weight gain was 2.5+/-6.7 kg in the face-to-face group , 4.7+/-8.6 kg in the Internet group , and 4.9+/-6.5 kg in the control group , with a significant difference between the face-to-face group and the control group ( 2.4 kg ; 95 % confidence interval [ CI ] , 0.002 to 10.8 ; P=0.05 ) . The proportion of participants who regained 2.3 kg or more over the 18-month period was significantly higher in the control group ( 72.4 % ) than in the face-to-face group ( 45.7 % ; absolute difference , 27 % ; 95 % CI , 14 to 39 ; P<0.001 ) or the Internet group ( 54.8 % ; absolute difference , 18 % ; 95 % CI , 5 to 30 ; P=0.008 ) . Daily self-weighing increased in both intervention groups and was associated with a decreased risk of regaining 2.3 kg or more ( P<0.001 ) . CONCLUSIONS As compared with receiving quarterly newsletters , a self-regulation program based on daily weighing improved maintenance of weight loss , particularly when delivered face to face . ( Clinical Trials.gov number , NCT00067145 [ Clinical Trials.gov ] . CONTEXT The results of clinical trials involving diet in the treatment of obesity have been inconsistent , possibly due to inherent physiological differences among study participants . OBJECTIVE To determine whether insulin secretion affects weight loss with 2 popular diets . DESIGN , SETTING , AND PARTICIPANTS R and omized trial of obese young adults ( aged 18 - 35 years ; n = 73 ) conducted from September 2004 to December 2006 in Boston , Mass , and consisting of a 6-month intensive intervention period and a 12-month follow-up period . Serum insulin concentration at 30 minutes after a 75-g dose of oral glucose was determined at baseline as a measure of insulin secretion . Outcomes were assessed at 6 , 12 , and 18 months . Missing data were imputed conservatively . INTERVENTIONS A low-glycemic load ( 40 % carbohydrate and 35 % fat ) vs low-fat ( 55 % carbohydrate and 20 % fat ) diet . MAIN OUTCOME MEASURES Body weight , body fat percentage determined by dual-energy x-ray absorptiometry , and cardiovascular disease risk factors . RESULTS Change in body weight and body fat percentage did not differ between the diet groups overall . However , insulin concentration at 30 minutes after a dose of oral glucose was an effect modifier ( group x time x insulin concentration at 30 minutes : P = .02 for body weight and P = .01 for body fat percentage ) . For those with insulin concentration at 30 minutes above the median ( 57.5 microIU/mL ; n = 28 ) , the low-glycemic load diet produced a greater decrease in weight ( -5.8 vs -1.2 kg ; P = .004 ) and body fat percentage ( -2.6 % vs -0.9 % ; P = .03 ) than the low-fat diet at 18 months . There were no significant differences in these end points between diet groups for those with insulin concentration at 30 minutes below the median level ( n = 28 ) . Insulin concentration at 30 minutes after a dose of oral glucose was not a significant effect modifier for cardiovascular disease risk factors . In the full cohort , plasma high-density lipoprotein cholesterol and triglyceride concentrations improved more on the low-glycemic load diet , whereas low-density lipoprotein cholesterol concentration improved more on the low-fat diet . CONCLUSIONS Variability in dietary weight loss trials may be partially attributable to differences in hormonal response . Reducing glycemic load may be especially important to achieve weight loss among individuals with high insulin secretion . Regardless of insulin secretion , a low-glycemic load diet has beneficial effects on high-density lipoprotein cholesterol and triglyceride concentrations but not on low-density lipoprotein cholesterol concentration . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00130299 Objective : To investigate whether addition of modified guar gum ( GG ) to a low-energy semisolid meal might be effective on appetite by modifying the response of blood glucose and other blood parameters . Design : Three intervention periods of 2 weeks each , separated by washout periods of 4 weeks . R and omized and cross-over design .Subjects : Fifteen overweight male subjects ( mean±s.d . ; age , 44±9 y ; body mass index , 28.6±1.8 kg/m2).Intervention : Subjects consumed a low-energy diet divided over three times a day , consisting of a semisolid meal with ( SSM+ ) or without ( SSM ) addition of 2.5 g GG , or a solid meal ( SM ) with the same energy content ( 947 kJ ) and macronutrient composition , plus a dinner of the subject 's own choice . At the end of each intervention , time and number of meal initiations , dynamics of blood glucose and other blood parameters , and appetite ratings such as hunger and satiety were determined in a time-blinded situation . Results : The changes in blood glucose from meal initiation to blood glucose peak and from peak to nadir were smaller with SSM+ and SM compared to SSM . Satiety before the third meal was higher with SSM+ and SM compared to SSM ( P<0.01 ) . Meal pattern , general appetite and total energy intake were similar for all treatments . Conclusions : We conclude that , similar to SM , SSM+ result ed in a more moderate change in blood glucose compared to SSM and positively affected satiety before the third meal , while general appetite , total energy intake and meal pattern did not differ OBJECTIVE Very-low-calorie diets ( VLCDs ) are an effective method for weight reduction in Caucasians . This study investigated the efficacy and safety of two different VLCDs ( 450 or 800kcal/d ) in obese Taiwanese . METHODS 132 participants with BMI > or = 30kg/m(2 ) were r and omized to two VLCD groups for body weight reduction for 12 weeks . Each group had 66 participants . Anthropometric and metabolic parameters were measured . RESULTS The intention-to-treat analysis revealed that the percentage change in body weight over the 12-week treatment period was -9.14 % in the VLCD-450 group and -8.98 % in the VLCD-800 group . A total of 27 ( 40.9 % ) participants in the VLCD-450 group and 29 ( 43.9 % ) participants in the VLCD-800 group achieved 10 % or more weight loss at the end of treatment . The body weight , waist circumference , hip circumference , fat mass , blood pressure , triglycerides , and blood glucose were statistically improved from baseline but not between the two groups . The improvement rate of nonalcoholic fatty liver disease ( NAFLD ) was 41.5 % in the VLCD-450 group and 50.0 % in the VLCD-800 group . The incidence of adverse events did not differ significantly between the groups and no serious adverse events were reported in either group . CONCLUSION Both the VLCD-450 and 800kcal/d can effectively and safely reduce body weight and improve NAFLD in 12 weeks in obese Taiwanese participants . However , there is no additional benefit in prescribing the more restrictive diet intervention in Taiwanese Context Low-carbohydrate weight reduction diets are popular despite a dearth of data on long-term efficacy and adverse effects . Contribution Community-dwelling hyperlipidemic persons were r and omly assigned to either a low-carbohydrate , ketogenic diet or a low-fat , low-cholesterol , reduced-calorie diet for 24 weeks . Compared to the low-fat group , patients in the low-carbohydrate group lost more weight , had a greater decrease in triglyceride levels , and had higher high-density lipoprotein cholesterol levels . Levels of low-density lipoprotein cholesterol remained stable in both groups . Side effects were more common in the low-cholesterol group but were generally mild . Caution s While the study suggests the efficacy and relative safety of the low-cholesterol diet , the high dropout rate , self-directed adherence to the diet , and relatively short observation period challenge the generalizability of the findings . The Editors As the prevalence of obesity has increased over the past 20 years ( 1 ) , the difficulties faced by overweight patients and their health care practitioners have become apparent . Fewer than 25 % of Americans who attempt to lose weight actually reduce caloric intake and increase exercise as currently recommended ( 2 ) . Persons who successfully lose weight have difficulty maintaining their weight loss ( 3 ) . Therefore , it is not surprising that consumers spend $ 33 billion yearly on weight loss products and services in search of effective therapies ( 2 ) . Because many weight loss interventions are unproven and untested , practitioners often lack information with which to recommend a certain therapy or to monitor a patient once a therapy is chosen . One approach to weight loss that has gained recognition in the face of modest supportive scientific evidence is the low-carbohydrate diet . A popular version of this diet recommends extreme restriction of carbohydrate intake to less than 20 g/d initially ( 4 ) . This level of carbohydrate restriction can induce serum and urinary ketones and weight loss ( 5 , 6 ) . However , until recently , available data on low-carbohydrate diets came from small studies of short duration , most of which were uncontrolled ( 5 , 7 - 10 ) . We examined body weight , body composition , serum lipid levels , and adverse effects over 24 weeks in hyperlipidemic persons who were r and omly assigned to follow a low-carbohydrate , ketogenic diet or a low-fat , low-cholesterol , reduced-calorie diet commonly used to induce weight loss and decrease serum lipid levels . Methods Participants Generally healthy persons were recruited from the community . Inclusion criteria were age 18 to 65 years , body mass index of 30 to 60 kg/m2 , desire to lose weight , elevated lipid levels ( total cholesterol level > 5.17 mmol/L [ > 200 mg/dL ] , low-density lipoprotein [ LDL ] cholesterol level > 3.36 mmol/L [ > 130 mg/dL ] , or triglyceride level > 2.26 mmol/L [ 200 mg/dL ] ) , and no serious medical condition . Exclusion criteria were use of any prescription medication in the previous 2 months ( except for oral contraceptives , estrogen therapy , and stable thyroid medication ) , pregnancy or breastfeeding , use of any weight loss diet or diet pills in the previous 6 months , and baseline ketonuria . All participants provided written informed consent , and the institutional review board of Duke University Health System approved the study . Participants received no monetary incentive . Interventions By using a computer-generated simple r and omization list , participants were allocated to receive the low-carbohydrate diet or low-fat diet . The intervention for both groups included group meetings , diet instruction , and an exercise recommendation . Group meetings took place at an outpatient research clinic twice monthly for 3 months , then monthly for 3 months . These meetings typically lasted 1 hour and consisted of diet instruction , supportive counseling , question naires , and biomedical measurements . During the study , participants selected their own menus and prepared or bought their own meals according to the guidelines presented to them . Participants were encouraged to exercise for 30 minutes at least 3 times weekly , but no formal exercise program or incentives were provided . Low-Carbohydrate Diet Using a popular diet book published by a lay press and additional h and outs , trained research staff instructed participants to restrict intake of carbohydrates to less than 20 g/d ( 4 ) . Participants were permitted unlimited amounts of animal foods ( meat , fowl , fish , and shellfish ) , unlimited eggs , 4 oz of hard cheese , 2 cups of salad vegetables ( such as lettuce , spinach , or celery ) , and 1 cup of low-carbohydrate vegetables ( such as broccoli , cauliflower , or squash ) daily . Participants were encouraged to drink 6 to 8 glasses of water daily . When participants were halfway to their goal body weight ( determined at the week 10 visit with assistance from research personnel ) , they were advised to add approximately 5 g of carbohydrates to their daily intake each week until they reached a level at which body weight was maintained . To simulate the practice of the study sponsor , the low-carbohydrate diet group also received daily nutritional supplements ( multivitamin , essential oils , diet formulation , and chromium picolinate ; for a list of the composition of these supplements , see the Appendix ) ( 6 ) . Low-Fat Diet Using a commonly available booklet and additional h and outs , a registered dietitian instructed participants in a diet consisting of less than 30 % of daily energy intake from fat , less than 10 % of daily energy intake from saturated fat , and less than 300 mg of cholesterol daily ( 11 , 12 ) . The recommended energy intake was 2.1 to 4.2 MJ ( 500 to 1000 kcal ) less than the participant 's calculated energy intake for weight maintenance ( body weight in pounds 10 ) ( 13 ) . Primary Outcome Measure Body weight and body mass index were the primary outcome measures . At each visit , participants were weighed on the same calibrated scale while wearing lightweight clothing and no shoes . Body mass index was calculated as body weight in kilograms divided by height in meters squared . Secondary Outcome Measures Adherence Adherence to the diet was measured by self-report , food records , and , for the low-carbohydrate diet group , urinary ketone assessment . Diet Composition All participants completed a 24-hour recall of food intake at baseline and take-home food records ( 5 consecutive days , including a weekend ) that were collected at each meeting during the study . Participants were instructed on how to document food intake and were given h and outs with examples of how to complete the records . A sample of participants ( 13 in the low-carbohydrate diet group and 7 in the low-fat diet group ) who completed the study was selected for food record analysis by the research staff on the basis of adequacy of detail in their records . A registered dietitian analyzed the food records by using a nutrition software program ( Nutritionist Five , version 1.6 [ First Data Bank , Inc. , San Bruno , California ] ) . Ketonuria Restriction of dietary intake of carbohydrates to less than 40 g/d typically results in ketonuria that is detectable by dipstick analysis , which can be used to monitor adherence to the low-carbohydrate diet ( 14 , 15 ) . At each return visit , participants provided a fresh urine specimen for analysis . The following semi-quantitative scale was used to categorize ketone content : none , trace ( up to 0.9 mmol/L [ 5 mg/dL ] ) , small ( 0.9 to 6.9 mmol/L [ 5 to 40 mg/dL ] ) , moderate ( 6.9 to 13.8 mmol/L [ 40 to 80 mg/dL ] ) , large80 ( 13.8 to 27.5 mmol/L [ 80 to 160 mg/dL ] ) , and large160 ( > 27.5 mmol/L [ > 160 mg/dL ] ) . Body Composition Body composition was estimated by using bioelectric impedance ( model TBF-300A [ Tanita Corp. , Arlington Heights , Illinois ] ) at approximately the same time of day ( afternoon or evening ) at each return visit . In a subset of 33 participants , the percentage of body fat as measured by bioelectric impedance had excellent correlation with the percentage as measured by dual-energy x-ray absorptiometry ( r = 0.93 [ 95 % CI , 0.87 to 0.97 ] ) . Vital Signs Blood pressure and pulse rate were measured in the nondominant arm by using an automated digital cuff ( model HEM-725C [ Omron Corp. , Vernon Hills , Illinois ] ) after the participant had been sitting for 3 minutes . Two measurements were taken at each visit and averaged for the analysis . Serum Lipids and Lipoproteins Serum specimens for lipid measurement were obtained in the morning after at least 8 hours of fasting at the screening visit and at 8 , 16 , and 24 weeks . Other Metabolic Effects Serum tests for sodium , potassium , chloride , urea nitrogen , creatinine , calcium , phosphorus , total protein , albumin , uric acid , total bilirubin , alanine aminotransferase , aspartate aminotransferase , alkaline phosphatase , thyroid-stimulating hormone , iron , hemoglobin , leukocyte count , and platelet count were obtained at the screening visit and at 8 , 16 , and 24 weeks . The glomerular filtration rate was estimated by using an equation that included age ; sex ; race ; and serum levels of albumin , creatinine , and urea nitrogen ( Modification of Diet in Renal Disease Study equation ) ( 16 ) . Adverse Effects At all return visits , participants completed an open-ended question naire on side effects . At the 20- and 24-week visits , participants completed a checklist of the side effects that were most often mentioned during the study . Statistical Analysis Analyses were performed by using S-PLUS software , version 6.1 ( Insightful Corp. , Seattle , Washington ) , or SAS software , version 8.02 ( SAS Institute , Inc. , Cary , North Carolina ) . For categorical outcomes , groups were compared by using the chi-square test or Fisher exact test , as appropriate . For all primary and secondary continuous outcomes , linear mixed-effects models ( PROC MIXED procedure in SAS software ) that included fixed and r and om effects were used to determine expected mean values at each time point and to test hypotheses of group differences . In most body weight and Background This study 's purpose investigated the impact of different macronutrient distributions and varying caloric intakes along with regular exercise for metabolic and physiological changes related to weight loss . Methods One hundred forty-one sedentary , obese women ( 38.7 ± 8.0 yrs , 163.3 ± 6.9 cm , 93.2 ± 16.5 kg , 35.0 ± 6.2 kg•m-2 , 44.8 ± 4.2 % fat ) were r and omized to either no diet + no exercise control group ( CON ) a no diet + exercise control ( ND ) , or one of four diet + exercise groups ( high-energy diet [ HED ] , very low carbohydrate , high protein diet [ VLCHP ] , low carbohydrate , moderate protein diet [ LCMP ] and high carbohydrate , low protein [ HCLP ] ) in addition to beginning a 3x•week-1 supervised resistance training program . After 0 , 1 , 10 and 14 weeks , all participants completed testing sessions which included anthropometric , body composition , energy expenditure , fasting blood sample s , aerobic and muscular fitness assessment s. Data were analyzed using repeated measures ANOVA with an alpha of 0.05 with LSD post-hoc analysis when appropriate . Results All dieting groups exhibited adequate compliance to their prescribed diet regimen as energy and macronutrient amounts and distributions were close to prescribed amounts . Those groups that followed a diet and exercise program reported significantly greater anthropometric ( waist circumference and body mass ) and body composition via DXA ( fat mass and % fat ) changes . Caloric restriction initially reduced energy expenditure , but successfully returned to baseline values after 10 weeks of dieting and exercising . Significant fitness improvements ( aerobic capacity and maximal strength ) occurred in all exercising groups . No significant changes occurred in lipid panel constituents , but serum insulin and HOMA-IR values decreased in the VLCHP group . Significant reductions in serum leptin occurred in all caloric restriction + exercise groups after 14 weeks , which were unchanged in other non-diet/non-exercise groups . Conclusions Overall and over the entire test period , all diet groups which restricted their caloric intake and exercised experienced similar responses to each other . Regular exercise and modest caloric restriction successfully promoted anthropometric and body composition improvements along with various markers of muscular fitness . Significant increases in relative energy expenditure and reductions in circulating leptin were found in response to all exercise and diet groups . Macronutrient distribution may impact circulating levels of insulin and overall ability to improve strength levels in obese women who follow regular exercise Objectives : The primary aim was to determine whether ready-to-eat cereal used as a portion-controlled , meal replacement promotes weight loss . Additional aims were to determine whether weight loss differed if the cereal was provided as a single br and or variety of br and s and whether this use of ready-to-eat cereal promotes continued weight loss following transition to a high-fiber , high-volume ( Volumetric ) diet . Methods : Body composition was measured and diet records , appetite question naires and activity logs were completed during baseline and end of intervention weeks 2 and 6 . Participants were assigned to one of four treatment groups . Group 1 ( 6 M , 22 F , mean age 43.0 ± 1.9 years , mean initial BMI 28.9 ± 0.4 kg/m2 ) consumed a serving of a single br and of ready-to-eat cereal with 2/3 C skim milk and a 100 Kcal portion of fruit for breakfast and as a replacement for either lunch or dinner for weeks 1 and 2 . No restrictions were placed on the non-cereal meal . They then followed the Volumetric diet for weeks 3 to 6 with a target energy restriction of 500 kcal/day . Group 2 ( 3 M , 25 F , mean age 40.9 ± 2.3 years , mean initial BMI 29.39 ± 0.6 kg/m2 ) followed the same protocol , but was permitted to select from a variety of ready-to-eat cereals during weeks 1 and 2 . Group 3 ( 7 M , 19 F , mean age 41.6 ± 2.4 years , mean initial BMI 29.3 ± 0.6 kg/m2 ) received no dietary instruction during the six-week study and Group 4 ( 9 M , 18 F , mean age 38.2 ± 2.8 years , mean initial BMI 29.3 ± 0.6 kg/m2 ) received no intervention prior to adoption of the Volumetric diet for weeks 3 to 6 . Results : The cereal interventions result ed in 640 ± 109 and 617 ± 105 kcal/day reductions of energy intake in Groups 1 and 2 , respectively , during the two-week cereal intervention . This led to comparable mean weight losses ( 1.91 ± 0.19 kg — Group 1 , 1.37 ± 0.15 kg — Group 2 ) that were significantly greater than that observed in Group 3 ( 0.08 ± 0.15 kg ) . The losses were primarily of fat mass . No significant changes of total body water were observed . Weight loss continued during the Volumetric diet in Groups 1 and 2 . The changes were comparable to those observed in Group 4 , and all were significantly greater than that of Group 3 . Self-reported hunger was slightly , but significantly higher than baseline in Groups 1 and 2 during the cereal intervention , but similar to baseline in Groups 1 , 2 and 3 during the Volumetric diet . Based on predicted weight loss , compliance with the Volumetric diet was similar and limited in all three intervention groups . Conclusions : Ready-to-eat cereals may be used to promote weight loss when consumed as a portion-controlled , meal replacement . Provision of a variety of br and s does not compromise efficacy . Weight losses may be maintained or increased after transition to the Volumetric diet . The later regimen effectively controls hunger and may lead to weight loss , but compliance is limited Background Obesity has reached epidemic proportions in the United States . It is implicated in the development of a variety of chronic disease states and is associated with increased levels of inflammation and oxidative stress . The objective of this study is to examine the effect of Medifast 's meal replacement program ( MD ) on body weight , body composition , and biomarkers of inflammation and oxidative stress among obese individuals following a period of weight loss and weight maintenance compared to a an isocaloric , food-based diet ( FB ) . Methods This 40-week r and omized , controlled clinical trial included 90 obese adults with a body mass index ( BMI ) between 30 and 50 kg/m2 , r and omly assigned to one of two weight loss programs for 16 weeks and then followed for a 24-week period of weight maintenance . The dietary interventions consisted of Medifast 's meal replacement program for weight loss and weight maintenance , or a self-selected , isocaloric , food-based meal plan . Results Weight loss at 16 weeks was significantly better in the Medifast group ( MD ) versus the food-based group ( FB ) ( 12.3 % vs. 6.9 % ) , and while significantly more weight was regained during weight maintenance on MD versus FB , overall greater weight loss was achieved on MD versus FB . Significantly more of the MD participants lost ≥ 5 % of their initial weight at week 16 ( 93 % vs. 55 % ) and week 40 ( 62 % vs. 30 % ) . There was no difference in satiety observed between the two groups during the weight loss phase . Significant improvements in body composition were also observed in MD participants compared to FB at week 16 and week 40 . At week 40 , both groups experienced improvements in biochemical outcomes and other clinical indicators . Conclusions Our data suggest that the meal replacement diet plan evaluated was an effective strategy for producing robust initial weight loss and for achieving improvements in a number of health-related parameters during weight maintenance , including inflammation and oxidative stress , two key factors more recently shown to underlie our most common chronic diseases . Trial Registration Clinical Trials.gov OBJECTIVE Studies suggest that high-dairy and high-fiber/low-glycemic index diets may facilitate weight loss , but data are conflicting . The effects on weight loss and body fat of a high-dairy diet and a diet high in dairy and fiber and low in glycemic index were compared with a st and ard diet . RESEARCH METHODS AND PROCEDURES Ninety obese subjects were recruited into a r and omized trial of three diets design ed to provide a calorie deficit of 500 calories/d over a 48-week period . The study compared a moderate ( not low)-calcium diet with a high-calcium diet . RESULTS Seventy-two subjects completed the study . Significant weight and fat loss occurred with all three diets . A diet with 1400 mg of calcium did not result in greater weight ( 11.8 + /- 6.1 kg ) or fat ( 9.0 + /- 6.0 kg ) loss than a diet with 800 mg of calcium ( 10.0 + /- 6.8 and 7.5 + /- 6.6 kg , respectively ) . A diet with 1400 mg of calcium , increased fiber content , and fewer high-glycemic index foods did not result in greater weight ( 10.6 + /- 6.8 kg ) or fat ( 8.5 + /- 7.8 kg ) loss than the st and ard diet with 800 mg of calcium . Lipid profile , high-sensitivity C-reactive protein , leptin , fasting glucose , and insulin improved significantly , but there were no significant differences between the experimental diets and the control diet . DISCUSSION We found no evidence that diets higher than 800 mg of calcium in dairy products or higher in fiber and lower in glycemic index enhance weight reduction beyond what is seen with calorie restriction alone OBJECTIVE : To compare the long-term compliance and effects of two low-fat diets differing in carbohydrate to protein ratio on body composition and biomarkers of cardiovascular disease risk in obese subjects with hyperinsulinemia . DESIGN : Outpatient , parallel , clinical intervention study of two groups of subjects r and omly assigned to either a st and ard protein ( SP ; 15 % protein , 55 % carbohydrate ) or high-protein ( HP ; 30 % protein , 40 % carbohydrate ) diet , during 12 weeks of energy restriction ( ∼6.5 MJ/day ) and 4 weeks of energy balance ( ∼8.3 MJ/day ) . Subsequently , subjects were asked to maintain the same dietary pattern for the succeeding 52 weeks with minimal professional support . SUBJECTS : A total of 58 obese , nondietetic subjects with hyperinsulinemia ( 13 males/45 females , mean age 50.2 y , mean body mass index ( BMI ) 34.0 kg/m2 , mean fasting insulin 17.8 mU/l ) participated in the study . MEASUREMENTS : Body composition , blood pressure , blood lipids , fasting glucose , insulin , CRP and sICAM-1 were measured at baseline and at weeks 16 and 68 . Urinary urea/creatinine ratio was measured at baseline , week 16 and at 3 monthly intervals thereafter . RESULTS : In total , 43 subjects completed the study with similar dropouts in each group ( P=0.76 ) . At week 68 , there was net weight loss ( SP −2.9±3.6 % , HP −4.1±5.8 % ; P<0.01 ) due entirely to fat loss ( P<0.001 ) with no diet effect . Both diets significantly increased HDL cholesterol concentrations ( P<0.001 ) and decreased fasting insulin , insulin resistance , sICAM-1 and CRP levels ( P<0.05 ) . Protein intake was significantly greater in HP during the initial 16 weeks ( P<0.001 ) , but decreased in HP and increased in SP during 52-week follow-up , with no difference between groups at week 68 , indicating poor long-term dietary adherence behaviour to both dietary patterns . CONCLUSION : Without active ongoing dietary advice , adherence to dietary intervention is poor . Nonetheless , both dietary patterns achieved net weight loss and improvements in cardiovascular risk factors BACKGROUND Humans are exposed to preformed N-nitroso compounds ( NOCs ) and endogenous NOCs . Several NOCs are potential human carcinogens , including N-nitrosodimethylamine ( NDMA ) , but evidence from population studies is inconsistent . OBJECTIVE We examined the relation between dietary NOCs ( NDMA ) , the endogenous NOC index , and dietary nitrite and cancer incidence in the European Prospect i ve Investigation into Cancer and Nutrition (EPIC)-Norfolk , United Kingdom , study . DESIGN This was a prospect i ve study of 23,363 men and women , aged 40 - 79 y , who were recruited in 1993 - 1997 and followed up to 2008 . The baseline diet was assessed with food-frequency question naires . RESULTS There were 3268 incident cancers after a mean follow-up of 11.4 y. Dietary NDMA intake was significantly associated with increased cancer risk in men and women [ hazard ratio ( HR ) : 1.14 ; 95 % CI : 1.03 , 1.27 ; P for trend = 0.03 ] and in men ( HR : 1.24 ; 95 % CI : 1.07 , 1.44 ; P for trend = 0.005 ) when the highest quartile was compared with the lowest quartile in age- and sex-adjusted analyses but not in multivariate analyses ( HR : 1.10 ; 95 % CI : 0.97 , 1.24 ; HR for men : 1.18 ; 95 % CI : 1.00 , 1.40 ; P for trend ≥ 0.05 ) . When continuously analyzed , NDMA was associated with increased risk of gastrointestinal cancers ( HR : 1.13 ; 95 % CI : 1.00 , 1.28 ) , specifically of rectal cancer ( HR : 1.46 ; 95 % CI : 1.16 , 1.84 ) per 1-SD increase after adjustment for age , sex , body mass index , cigarette smoking status , alcohol intake , energy intake , physical activity , education , and menopausal status ( in women ) . The endogenous NOC index and dietary nitrite were not significantly associated with cancer risk . There was a significant interaction between plasma vitamin C concentrations and dietary NDMA intake on cancer incidence ( P for interaction < 0.00001 ) . CONCLUSIONS Dietary NOC ( NDMA ) was associated with a higher gastrointestinal cancer incidence , specifically of rectal cancer . Plasma vitamin C may modify the relation between NDMA exposure and cancer risk Objective : High-carbohydrate (HC)–high-fibre diets are recommended for weight loss and for treating and preventing diseases such as diabetes and cardiovascular disease . We report a r and omised trial comparing high-fat ( HF ) and high-protein ( HP ) diets with the conventional approach . Research design and methods : A total of 93 overweight insulin-resistant women received advice following r and omisation to HF , HP or HC dietary regimes , to achieve weight loss followed by weight maintenance over 12 months . Weight , body composition and measures of carbohydrate and lipid metabolism were investigated . Results : Retention rates were 93 % for HP and 75 % for HC and HF . Features of the metabolic syndrome improved in all groups during the first 6 months , to a greater extent on HF and HP than an HC . During the second 6 months the HF group had increases in waist circumference ( mean difference 4.4 cm ( 95 % CI 3.0 , 5.8 ) ) , fat mass ( 2.3 kg ( 1.5 , 3.1 ) ) , triglycerides ( 0.28 mmol/l ( 0.09 , 0.46 ) ) and 2 h glucose ( 0.70 mmol/l ( 0.22 , 1.18 ) ) . Overall there was substantial sustained improvement in waist circumference , triglycerides and insulin in the HP group and sustained but more modest changes on HC . Dietary compliance at 12 months was poor in all groups . Conclusions : HP and HC approaches appear to be appropriate options for insulin-resistant individuals . When recommending HP diets appropriate composition of dietary fat must be ensured . HC diet recommendations must include advice regarding appropriate high-fibre , low glycaemic index foods BACKGROUND Limited evidence suggests that a higher ratio of protein to carbohydrate during weight loss has metabolic advantages . OBJECTIVE The objective was to evaluate the effects of a diet with a high ratio of protein to carbohydrate during weight loss on body composition , cardiovascular disease risk , nutritional status , and markers of bone turnover and renal function in overweight women . DESIGN The subjects were r and omly assigned to 1 of 2 isocaloric 5600-kJ dietary interventions for 12 wk according to a parallel design : a high-protein ( HP ) or a high-carbohydrate ( HC ) diet . RESULTS One hundred women with a mean ( + /-SD ) body mass index ( in kg/m(2 ) ) of 32 + /- 6 and age of 49 + /- 9 y completed the study . Weight loss was 7.3 + /- 0.3 kg with both diets . Subjects with high serum triacylglycerol ( > 1.5 mmol/L ) lost more fat mass with the HP than with the HC diet ( x + /- SEM : 6.4 + /- 0.7 and 3.4 + /- 0.7 kg , respectively ; P = 0.035 ) and had a greater decrease in triacylglycerol concentrations with the HP ( -0.59 + /- 0.19 mmol/L ) than with the HC ( -0.03 + /- 0.04 mmol/L ) diet ( P = 0.023 for diet x triacylglycerol interaction ) . Triacylglycerol concentrations decreased more with the HP ( 0.30 + /- 0.10 mmol/L ) than with the HC ( 0.10 + /- 0.06 mmol/L ) diet ( P = 0.007 ) . Fasting LDL-cholesterol , HDL-cholesterol , glucose , insulin , free fatty acid , and C-reactive protein concentrations decreased with weight loss . Serum vitamin B-12 increased 9 % with the HP diet and decreased 13 % with the HC diet ( P < 0.0001 between diets ) . Folate and vitamin B-6 increased with both diets ; homocysteine did not change significantly . Bone turnover markers increased 8 - 12 % and calcium excretion decreased by 0.8 mmol/d ( P < 0.01 ) . Creatinine clearance decreased from 82 + /- 3.3 to 75 + /- 3.0 mL/min ( P = 0.002 ) . CONCLUSION An energy-restricted , high-protein , low-fat diet provides nutritional and metabolic benefits that are equal to and sometimes greater than those observed with a high-carbohydrate diet BACKGROUND Lifestyle interventions produce short-term improvements in glycemia and cardiovascular disease ( CVD ) risk factors in individuals with type 2 diabetes mellitus , but no long-term data are available . We examined the effects of lifestyle intervention on changes in weight , fitness , and CVD risk factors during a 4-year study . METHODS The Look AHEAD ( Action for Health in Diabetes ) trial is a multicenter r and omized clinical trial comparing the effects of an intensive lifestyle intervention ( ILI ) and diabetes support and education ( DSE ; the control group ) on the incidence of major CVD events in 5145 overweight or obese individuals ( 59.5 % female ; mean age , 58.7 years ) with type 2 diabetes mellitus . More than 93 % of participants provided outcomes data at each annual assessment . RESULTS Averaged across 4 years , ILI participants had a greater percentage of weight loss than DSE participants ( -6.15 % vs -0.88 % ; P < .001 ) and greater improvements in treadmill fitness ( 12.74 % vs 1.96 % ; P < .001 ) , hemoglobin A(1c ) level ( -0.36 % vs -0.09 % ; P < .001 ) , systolic ( -5.33 vs -2.97 mm Hg ; P < .001 ) and diastolic ( -2.92 vs -2.48 mm Hg ; P = .01 ) blood pressure , and levels of high-density lipoprotein cholesterol ( 3.67 vs 1.97 mg/dL ; P < .001 ) and triglycerides ( -25.56 vs -19.75 mg/dL ; P < .001 ) . Reductions in low-density lipoprotein cholesterol levels were greater in DSE than ILI participants ( -11.27 vs -12.84 mg/dL ; P = .009 ) owing to greater use of medications to lower lipid levels in the DSE group . At 4 years , ILI participants maintained greater improvements than DSE participants in weight , fitness , hemoglobin A(1c ) levels , systolic blood pressure , and high-density lipoprotein cholesterol levels . CONCLUSIONS Intensive lifestyle intervention can produce sustained weight loss and improvements in fitness , glycemic control , and CVD risk factors in individuals with type 2 diabetes . Whether these differences in risk factors translate to reduction in CVD events will ultimately be addressed by the Look AHEAD trial . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00017953 CONTEXT The scarcity of data addressing the health effects of popular diets is an important public health concern , especially since patients and physicians are interested in using popular diets as individualized eating strategies for disease prevention . OBJECTIVE To assess adherence rates and the effectiveness of 4 popular diets ( Atkins , Zone , Weight Watchers , and Ornish ) for weight loss and cardiac risk factor reduction . DESIGN , SETTING , AND PARTICIPANTS A single-center r and omized trial at an academic medical center in Boston , Mass , of overweight or obese ( body mass index : mean , 35 ; range , 27 - 42 ) adults aged 22 to 72 years with known hypertension , dyslipidemia , or fasting hyperglycemia . Participants were enrolled starting July 18 , 2000 , and r and omized to 4 popular diet groups until January 24 , 2002 . INTERVENTION A total of 160 participants were r and omly assigned to either Atkins ( carbohydrate restriction , n=40 ) , Zone ( macronutrient balance , n=40 ) , Weight Watchers ( calorie restriction , n=40 ) , or Ornish ( fat restriction , n=40 ) diet groups . After 2 months of maximum effort , participants selected their own levels of dietary adherence . MAIN OUTCOME MEASURES One-year changes in baseline weight and cardiac risk factors , and self-selected dietary adherence rates per self-report . RESULTS Assuming no change from baseline for participants who discontinued the study , mean ( SD ) weight loss at 1 year was 2.1 ( 4.8 ) kg for Atkins ( 21 [ 53 % ] of 40 participants completed , P = .009 ) , 3.2 ( 6.0 ) kg for Zone ( 26 [ 65 % ] of 40 completed , P = .002 ) , 3.0 ( 4.9 ) kg for Weight Watchers ( 26 [ 65 % ] of 40 completed , P < .001 ) , and 3.3 ( 7.3 ) kg for Ornish ( 20 [ 50 % ] of 40 completed , P = .007 ) . Greater effects were observed in study completers . Each diet significantly reduced the low-density lipoprotein/high-density lipoprotein ( HDL ) cholesterol ratio by approximately 10 % ( all P<.05 ) , with no significant effects on blood pressure or glucose at 1 year . Amount of weight loss was associated with self-reported dietary adherence level ( r = 0.60 ; P<.001 ) but not with diet type ( r = 0.07 ; P = .40 ) . For each diet , decreasing levels of total/HDL cholesterol , C-reactive protein , and insulin were significantly associated with weight loss ( mean r = 0.36 , 0.37 , and 0.39 , respectively ) with no significant difference between diets ( P = .48 , P = .57 , P = .31 , respectively ) . CONCLUSIONS Each popular diet modestly reduced body weight and several cardiac risk factors at 1 year . Overall dietary adherence rates were low , although increased adherence was associated with greater weight loss and cardiac risk factor reductions for each diet group OBJECTIVE : To compare the long-term effects of three different programs including initial 6 weeks (V)LCD diets 420 kcal/d , 530 kcal/d , 880 kcal/d ) on sustained weight loss , attrition and obesity associated conventional cardio-vascular risk factors . DESIGN : Prospect i ve , r and omized clinical 52 weeks trial . Two weeks of a booster (V)LCD period after week 26 . SETTING : University outpatient obesity clinic . SUBJECTS : Ninety-three middle-aged obese patients ( 30 men ) , initial mean BMI 38.7 kg/m2 , age 20–65 y , from the waiting list . MAIN OUTCOME MEASURES : Weight loss pattern , attrition , reported side effects , blood pressure , blood glucose and serum lipid levels . Repeated frequent measurements up to week 26 , intermittently up to final measurements at week 52 . RESULTS : One year attrition ( 30–45 % ) , sustained weight loss ( 8–15 % of initial body weight ) and changes in obesity associated risk parameters were similar in all three group . Fewer adverse events were reported in the LCD group . CONCLUSION : The results compare favorably with most previous reports of similar design . VLCD ( 420 kcal or 530 kcal/d and LCD 880 kcal/d ) were equally effective in long term treatment of obesity . The tendency to less side effects with LCD suggests that such preparations deserve further attention BACKGROUND Failure to maintain weight losses in lifestyle change programs continues to be a major problem and warrants investigation of innovative approaches to weight control . OBJECTIVE The goal of this study was to compare two novel group interventions , both aim ed at improving weight loss maintenance , with a control group . METHODS AND PROCEDURES A total of 103 women lost weight on a meal replacement-supplemented diet and were then r and omized to one of three conditions for the 14-week maintenance phase : cognitive-behavioral treatment ( CBT ) ; CBT with an enhanced food monitoring accuracy ( EFMA ) program ; or these two interventions plus a reduced energy density eating ( REDE ) program . Assessment s were conducted periodically through an 18-month postintervention . Outcome measures included weight and self-reported dietary intake . Data were analyzed using completers only as well as baseline-carried-forward imputation . RESULTS Participants lost an average of 7.6 + /- 2.6 kg during the weight loss phase and 1.8 + /- 2.3 kg during the maintenance phase . Results do not suggest that the EFMA intervention was successful in improving food monitoring accuracy . The REDE group decreased the energy density ( ED ) of their diets more so than the other two groups . However , neither the REDE nor the EFMA condition showed any advantage in weight loss maintenance . All groups regained weight between 6- and 18-month follow-ups . DISCUSSION Although no incremental weight maintenance benefit was observed in the EFMA or EFMA + REDE groups , the improvement in the ED of the REDE group 's diet , if shown to be sustainable in future studies , could have weight maintenance benefits OBJECTIVE Low-carbohydrate diets have become a popular alternative to st and ard diets for weight loss . Our aim was to compare the cost-effectiveness of these two diets . RESEARCH METHODS AND PROCEDURES The patient population included 129 severely obese subjects ( BMI = 42.9 ) from a r and omized trial ; participants had a high prevalence of diabetes or metabolic syndrome . We compared within-trial costs , quality -adjusted life years ( QALYs ) , and the incremental cost-effectiveness ratio ( CER ) for the two study groups . We imputed missing values for QALYs . The CER was bootstrapped to derive 95 % confidence intervals and to define acceptability cut-offs . We took a societal perspective for our analysis . RESULTS Total costs during the one year of the trial were 6742 dollars + /- 6675 and 6249 dollars + /- 5100 for the low-carbohydrate and st and ard groups , respectively ( p = 0.78 ) . Participants experienced 0.64 + /- 0.02 and 0.61 + /- 0.02 QALYs during the one year of the study , respectively ( p = 0.17 for difference ) . The point estimate of the incremental CER was -1225 dollars/QALY ( i.e. , the low-carbohydrate diet dominated the st and ard diet ) . However , in the bootstrap analysis , the wide spread of CERs caused the 95 % confidence interval to be undefined . The probabilities that the low-carbohydrate diet was acceptable , using cut-offs of 50,000 dollars/QALY , 100,000 dollars/QALY , and 150,000 dollars/QALY , were 72.4 % 78.6 % , and 79.8 % , respectively . DISCUSSION The low-carbohydrate diet was not more cost-effective for weight loss than the st and ard diet in the patient population studied . Larger studies are needed to better assess the cost-effectiveness of dietary therapies for weight loss BACKGROUND Despite the popularity of the low-carbohydrate , high-protein , high-fat ( Atkins ) diet , no r and omized , controlled trials have evaluated its efficacy . METHODS We conducted a one-year , multicenter , controlled trial involving 63 obese men and women who were r and omly assigned to either a low-carbohydrate , high-protein , high-fat diet or a low-calorie , high-carbohydrate , low-fat ( conventional ) diet . Professional contact was minimal to replicate the approach used by most dieters . RESULTS Subjects on the low-carbohydrate diet had lost more weight than subjects on the conventional diet at 3 months ( mean [ + /-SD ] , -6.8+/-5.0 vs. -2.7+/-3.7 percent of body weight ; P=0.001 ) and 6 months ( -7.0+/-6.5 vs. -3.2+/-5.6 percent of body weight , P=0.02 ) , but the difference at 12 months was not significant ( -4.4+/-6.7 vs. -2.5+/-6.3 percent of body weight , P=0.26 ) . After three months , no significant differences were found between the groups in total or low-density lipoprotein cholesterol concentrations . The increase in high-density lipoprotein cholesterol concentrations and the decrease in triglyceride concentrations were greater among subjects on the low-carbohydrate diet than among those on the conventional diet throughout most of the study . Both diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load . CONCLUSIONS The low-carbohydrate diet produced a greater weight loss ( absolute difference , approximately 4 percent ) than did the conventional diet for the first six months , but the differences were not significant at one year . The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease . Adherence was poor and attrition was high in both groups . Longer and larger studies are required to determine the long-term safety and efficacy of low-carbohydrate , high-protein , high-fat diets Objective : To compare the effects of two energy-restricted healthy diets , one with a low GI and one with a high GI , on heart disease risk factors and weight loss in subjects at risk of heart disease . Design : A 12-week r and omized parallel study of low and high GI , healthy eating diets was carried out . Setting : The study was carried out at the Hammersmith Hospital . Subjects : Eighteen subjects were recruited by advertisement and r and omized to one of the two diets . Fourteen completed the study but one was excluded from the final analysis . Methods : At r and omization , subjects were advised to follow the intervention diet for 12 weeks . Before r and omization and on completion of the study , anthropometrics , fasting cholesterol and glucose blood tests and 24-h glucose measurements were taken using a continuous glucose monitoring system ( CGMS ) . Statistical analysis was carried out using non-parametric tests . Median ( IQR ) are presented . Results : A significantly different dietary GI was achieved in the low GI ( median : 51.3 ( IQR : 51.0–52.0 ) compared to the high GI ( 59.3 ( 59.2–64.0 ) ( P=0.032 ) group . By week 12 , both groups reduced their energy intake by : low GI group : −167 ( −312–−123 ) kcal/day ( P=0018 ) vs high GI group : –596 ( −625–−516 ) ( P=0.018 ) kcal/day , the difference between the groups being significant ( P=0.010 ) . However , only the low GI group lost weight ( −4.0 ( −4.4–−2.4 ) kg ( P=0.018 ) whereas the high GI group did not significantly change in weight ( −1.5 ( −3.6–0.8 ) kg ( P=0.463 ) . By week 12 , the low GI group also had a significantly lower 24-h area under the curve ( AUC ) ( 7556 ( 7315–8434 ) vs 8841 ( 8424–8846 ) mmol-h/l ( P=0.045 ) and overnight AUC ( 2429 ( 2423–2714 ) vs 3000 ( 2805–3072 ) mmol-h/l ( P=0.006 ) glucose as measured by CGMS . There were no differences in the other heart disease risk factors assessed . Conclusions : This pilot study provides some evidence that consuming a low GI diet in addition to weight loss and healthy eating may reduce cardiovascular risk . Other potential benefits of GI might have been masked by weight loss in the low GI group . Larger-scale studies need to follow . Sponsorship : The study was funded by the British Heart Foundation Seventy-six obese women with a mean age of 42.1 years and weight of 106.0 kg were r and omly assigned to one of three treatments : ( a ) very low calorie diet alone ; ( b ) behavior therapy alone ; or their combination ( i.e. combined treatment ) . Weight losses for the three conditions at the end of treatment were 13.1 , 13.0 , and 16.8 kg , respectively , with losses for combined treatment significantly greater than those for the two other conditions . Weight losses 1 year after treatment were 4.7 , 6.6 , and 10.6 kg , respectively . A significantly greater percentage of subjects in the behavior therapy alone ( 36 percent ) and combined treatment conditions ( 32 percent ) maintained their full end-of-treatment weight losses than in the very low calorie diet alone condition ( 5 percent ) . Five years after treatment , a majority of subjects in all three conditions had returned to their pretreatment weight , and 55 percent of the total sample had received additional weight reduction therapy . The short and long term effects of treatment are discussed in terms of their implication s for practice and research Diets with increased protein and reduced carbohydrates ( PRO ) are effective for weight loss , but the long-term effect on maintenance is unknown . This study compared changes in body weight and composition and blood lipids after short-term weight loss ( 4 mo ) followed by weight maintenance ( 8 mo ) using moderate PRO or conventional high-carbohydrate ( CHO ) diets . Participants ( age = 45.4 + /- 1.2 y ; BMI = 32.6 + /- 0.8 kg/m(2 ) ; n = 130 ) were r and omized to 2 energy-restricted diets ( -500 kcal/d or -2093 kJ/d ) : PRO with 1.6 g x kg(-1 ) x d(-1 ) protein and < 170 g/d carbohydrates or CHO with 0.8 g x kg(-1 ) x d(-1 ) protein , > 220 g/d carbohydrates . At 4 mo , the PRO group had lost 22 % more fat mass ( FM ) ( -5.6 + /- 0.4 kg ) than the CHO group ( -4.6 + /- 0.3 kg ) but weight loss did not differ between groups ( -8.2 + /- 0.5 kg vs. -7.0 + /- 0.5 kg ; P = 0.10 ) . At 12 mo , the PRO group had more participants complete the study ( 64 vs. 45 % , P < 0.05 ) with greater improvement in body composition ; however , weight loss did not differ between groups ( -10.4 + /- 1.2 kg vs. -8.4 + /- 0.9 kg ; P = 0.18 ) . Using a compliance criterion of participants attaining > 10 % weight loss , the PRO group had more participants ( 31 vs. 21 % ) lose more weight ( -16.5 + /- 1.5 vs. -12.3 + /- 0.9 kg ; P < 0.01 ) and FM ( -11.7 + /- 1.0 vs. -7.9 + /- 0.7 kg ; P < 0.01 ) than the CHO group . The CHO diet reduced serum cholesterol and LDL cholesterol compared with PRO ( P < 0.01 ) at 4 mo , but the effect did not remain at 12 mo . PRO had sustained favorable effects on serum triacylglycerol ( TAG ) , HDL cholesterol ( HDL-C ) , and TAG : HDL-C compared with CHO at 4 and 12 mo ( P < 0.01 ) . The PRO diet was more effective for FM loss and body composition improvement during initial weight loss and long-term maintenance and produced sustained reductions in TAG and increases in HDL-C compared with the CHO diet Background While high protein diets have been shown to improve satiety and retention of lean body mass ( LBM ) , this study was design ed to determine effects of a protein-enriched meal replacement ( MR ) on weight loss and LBM retention by comparison to an isocaloric carbohydrate-enriched MR within customized diet plans utilizing MR to achieve high protein or st and ard protein intakes . Methods Single blind , placebo-controlled , r and omized outpatient weight loss trial in 100 obese men and women comparing two isocaloric meal plans utilizing a st and ard MR to which was added supplementary protein or carbohydrate powder . MR was used twice daily ( one meal , one snack ) . One additional meal was included in the meal plan design ed to achieve individualized protein intakes of either 1 ) 2.2 g protein/kg of LBM per day [ high protein diet ( HP ) ] or 2 ) 1.1 g protein/kg LBM/day st and ard protein diet ( SP ) . LBM was determined using bioelectrical impedance analysis ( BIA ) . Body weight , body composition , and lipid profiles were measured at baseline and 12 weeks . Results Eighty-five subjects completed the study . Both HP and SP MR were well tolerated , with no adverse effects . There were no differences in weight loss at 12 weeks ( -4.19 ± 0.5 kg for HP group and -3.72 ± 0.7 kg for SP group , p > 0.1 ) . Subjects in the HP group lost significantly more fat weight than the SP group ( HP = -1.65 ± 0.63 kg ; SP = -0.64 ± 0.79 kg , P = 0.05 ) as estimated by BIA . There were no significant differences in lipids nor fasting blood glucose between groups , but within the HP group a significant decrease in cholesterol and LDL cholesterol was noted at 12 weeks . This was not seen in the SP group . Conclusion Higher protein MR within a higher protein diet result ed in similar overall weight loss as the st and ard protein MR plan over 12 weeks . However , there was significantly more fat loss in the HP group but no significant difference in lean body mass . In this trial , subject compliance with both the st and ard and protein-enriched MR strategy for weight loss may have obscured any effect of increased protein on weight loss demonstrated in prior weight loss studies using whole food diets Background We aim ed to investigate if overweight and obese adults " close " to Mediterranean diet present better insulin , lipids profile and better pressure levels , compared to individuals close to a more Westernized diet . Methods The ATTICA study is a population -based cohort that has r and omly enrolled 3042 adult men and women , stratified by age – gender , from the greater area of Athens , during 2001–2002 . Of them , in this work were have studied 1762 participants with excess body weight , meaning overweight ( BMI : 25–29.9 kg/m2 ) and obese ( BMI > 30 kg/m2 ) . 1064 were men and 698 women ( 20–89 years old ) . Adherence to Mediterranean diet was assessed through a diet-score that was based on a vali date d food-frequency question naire . Blood pressure was measured and also fasting glucose , insulin and blood lipids . Insulin sensitivity was also assessed by the homeostasis model assessment ( HOMA ) approach ( glucose × insulin/22.5 ) . Results Individuals with excess bodyweight in the highest tertile of diet score , were more insulin sensitive than those in the lowest tertile ( 11.4 % lower HOMA , p = 0.06 ) , had 13 % lower levels of total cholesterol ( p = 0.001 ) and 3 mmHg decrease of systolic blood pressure levels ( p < 0.001 ) , when adjusted for age , sex and BMI . Multivariate analysis after taking into account several confounders demonstrated that insulin sensitivity , total cholesterol and systolic blood pressure were independently but only modestly correlated with Mediterranean diet in people with excess bodyweight . Conclusion Adherence to Mediterranean diet is modeslty associated with a better insulin sensitivity , lower levels of total cholesterol and lower levels of systolic blood pressure in overweight and obese subjects . This may suggest that compared to general population , the beneficial effect of this diet in cardiovascular system of excess body weight people is limited Some weight loss diets promote protein intake ; however , the association of protein with disease is unclear . In 1986 , 29,017 postmenopausal Iowa women without cancer , coronary heart disease ( CHD ) , or diabetes were followed prospect ively for 15 years for cancer incidence and mortality from CHD , cancer , and all causes . Mailed question naires assessed dietary , lifestyle , and medical information . Nutrient density models estimated risk ratios from a simulated substitution of total and type of dietary protein for carbohydrate and of vegetable for animal protein . The authors identified 4,843 new cancers , 739 CHD deaths , 1,676 cancer deaths , and 3,978 total deaths . Among women in the highest intake quintile , CHD mortality decreased by 30 % from an isoenergetic substitution of vegetable protein for carbohydrate ( 95 % confidence interval ( CI ) : 0.49 , 0.99 ) and of vegetable for animal protein ( 95 % CI : 0.51 , 0.98 ) , following multivariable adjustment . Although no association was observed with any outcome when animal protein was substituted for carbohydrate , CHD mortality was associated with red meats ( risk ratio = 1.44 , 95 % CI : 1.06 , 1.94 ) and dairy products ( risk ratio = 1.41 , 95 % CI : 1.07 , 1.86 ) when substituted for servings per 1,000 kcal ( 4.2 MJ ) of carbohydrate foods . Long-term adherence to high-protein diets , without discrimination toward protein source , may have potentially adverse health consequences BACKGROUND : We have previously reported that a fat-reduced high-protein diet had more favourable effects on body weight loss over 6 months than a medium-protein diet . OBJECTIVE : To extend this observation by a further 6–12 months less stringent intervention and a 24 months follow-up . DESIGN : A r and omised 6 months strictly controlled dietary intervention followed by 6–12 months dietary counselling period , and a subsequent 24 months follow-up , comparing an ad libitum , fat-reduced diet ( 30 % of energy ) either high in protein ( 25 % of energy , HP ) or medium in protein ( 12 % of energy , MP).SUBJECTS : A total of 50 overweight and obese subjects ( age : 19–55 y ; BMI : 26–34 kg/m2 ) . MEASUREMENTS : Change in body weight , body composition and blood parameters . RESULTS : After 6 months , the HP group ( n=23 ) achieved a greater weight loss than the MP group ( n=23 ) ( 9.4 vs 5.9 kg ) ( P<0.01 ) . After 12 months , 8 % had dropped out in the HP vs 28 % in the MP group ( P<0.07 ) . After 12 months , the weight loss was not significantly greater among the subjects in the HP group ( 6.2 and 4.3 kg ) , but they had a 10 % greater reduction in intra-abdominal adipose tissue and more in the HP group ( 17 % ) lost > 10 kg than in the MP ( P<0.09 ) . At 24 months , both groups tended to maintain their 12 months weight loss , but more than 50 % were lost to follow-up . CONCLUSION : A fat-reduced diet high in protein seems to enhance weight loss and provide a better long-term maintenance of reduced intra-abdominal fat stores OBJECTIVES . To compare weight loss on a balanced hypocaloric diet to that of a Very Low Calorie Diet ( VLCD ) after two months of treatment and to further compare 26 months of weight maintenance and safety with or without VLCD assistance in obese patients . DESIGN . Prospect i ve , r and omized , controlled intervention trial , initially with two and later with three parallel groups . SETTING . Swedish University out-patient obesity clinic . SUBJECTS . Eighty-one obese patients of both gender with a BMI ≥30 kg/m2 from the waiting list participated in a structured weight reduction+weight maintenance programme . INTERVENTION . Twenty-seven patients ( group A ) were r and omized to a balanced diet of 6720 kJ/d ( 1600 kcal/d ) during the whole treatment period . The other patients ( n=54 ) were r and omized to VLCD ( Nutrilett ® ) 1764 kJ/d ( 420 kcal/d ) diet during the first two months . The VLCD treated patients were rer and omized after the initial treatment to the well balanced hypocaloric diet ( 6720 kJ/d ) with ( group C ) or without ( group B ) 1 MJ of VLCD to be taken during the evening . MAIN OUTCOME MEASURES . During the first two-month period , the mean body weight loss in the VLCD group was 18.9±7.1 kg compared to 7.2±4.8 kg in the diet treated group , with a similar relative fat loss assessed by bioimpedance of 68 % and 76 % respectively . The maintained weight loss in all groups after 28 months of treatment was 10.9±10.2 kg in the 52 % who completed the programme . Weight losses and drop-out rates were similar in all three groups . CONCLUSIONS . Twenty-four months weight maintenance and drop out rates are independent of whether the initial treatment commences with VLCD or a hypocaloric diet . One MJ nutrition powder taken freely does not affect 24 months weight maintenance on a hypocaloric ( 6.7 MJ/d ) diet BACKGROUND Effective primary care practice ( PCP ) treatments are needed for extreme obesity . The Louisiana Obese Subjects Study ( LOSS ) tested whether , with brief training , PCPs could effectively implement weight loss for individuals with a body mass index ( BMI ) ( calculated as weight in kilograms divided by height in meters squared ) of 40 to 60 . METHODS The LOSS , a 2-year ( July 5 , 2005 , through January 30 , 2008 ) r and omized , controlled , " pragmatic clinical trial " trained 7 PCPs and 1 research clinic in obesity management . Primary outcome measure was year-2 percentage change from baseline weight . Volunteers ( 597 ) were screened and r and omized to intensive medical intervention ( IMI ) ( n = 200 ) or usual care condition ( UCC ) ( n = 190 ) . The UCC group had instruction in an Internet weight management program . The IMI group recommendations included a 900-kcal liquid diet for 12 weeks or less , group behavioral counseling , structured diet , and choice of pharmacotherapy ( sibutramine hydrochloride , orlistat , or diethylpropion hydrochloride ) during months 3 to 7 and continued use of medications and maintenance strategies for months 8 to 24 . RESULTS The mean age of participants was 47 years ; 83 % were women , and 75 % were white . Retention rates were 51 % for the IMI group and 46 % for the UCC group ( P = .30 ) . After 2 years , the results were as follows : ( 1 ) among 390 r and omized participants , 31 % in the IMI group achieved a 5 % or more weight loss and 7 % achieved a 20 % weight loss or more , compared with 9 % and 1 % of those in the UCC group . ( 2 ) The mean + /- SEM baseline observation carried forward analysis showed a weight loss of -4.9 % + /- 0.8 % in IMI and -0.2 + /- 0.3 % in UCC . ( 3 ) Last observation carried forward analysis showed a weight loss of -8.3 % + /- 0.79 % for IMI , whereas UCC was -0.0 % + /- 0.4 % . ( 4 ) A total of 101 IMI completers lost -9.7 % + /- 1.3 % ( -12.7 + /- 1.7 kg ) , whereas 89 UCC completers lost -0.4 % + /- 0.7 % ( -0.5 + /- 0.9 kg ) ; ( P < .001 for all group differences ) . Many metabolic parameters improved . CONCLUSION Primary care practice s can initiate effective medical management for extreme obesity ; future efforts must target improving retention and weight loss maintenance . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00115063 We tested the hypothesis that the use of a very-low-calorie diet ( VLCD ) in combination with behavior modification would promote long-term glycemic control in obese type 2 diabetic subjects . Thirty-six diabetic subjects were r and omly assigned to a st and ard behavior therapy program or to a behavior therapy program that included an 8-week period of VLCD . The behavior therapy group consumed a balanced diet of 4200 to 6300 J/d throughout the 20-week program . The VLCD group consumed a balanced diet of 4200 to 6300 J for weeks 1 to 4 , followed by a VLCD ( 1680 J/d of lean meat , fish , and fowl ) for weeks 5 to 12 . The VLCD group then gradually reintroduced other foods during weeks 13 to 16 and consumed a balanced diet of 4200 to 6300 J/d for weeks 17 to 20 . Thirty-three of the 36 subjects completed the 20-week program and the 1-year follow-up . Use of the VLCD produced greater decreases in fasting glucose at the end of the 20-week program and at 1-year follow-up and greater long-term reductions in HbA1 . The VLCD group also had greater weight losses at week 20 , but weight losses from pretreatment to 1-year follow-up were similar in the two treatment groups . The improved glycemic control with the VLCD appeared to be due to increased insulin secretion , but further research is needed to confirm this Objective : To investigate whether a diet with a reduced glycaemic index ( GI ) has effects on appetite , energy intake , body weight and composition in overweight and obese female subjects . Design : R and omized crossover intervention study including two consecutive 12-week periods . Lower or higher GI versions of key carbohydrate-rich foods ( breads , breakfast cereals , rice and pasta/potatoes ) were provided to subjects to be incorporated into habitual diets in ad libitum quantities . Foods intended as equivalents to each other were balanced in macronutrient composition , fibre content and energy density . Subjects : Nineteen overweight and obese women , weight-stable , with moderate hyperinsulinaemia ( age : 34–65 years , body mass index : 25–47 kg m−2 , fasting insulin : 49–156 pmol l−1 ) . Measurements : Dietary intake , body weight and composition after each 12-week intervention . Subjectively rated appetite and short-term ad libitum energy intake at a snack and lunch meal following fixed lower and higher GI test breakfasts ( GI 52 vs 64 ) in a laboratory setting . Results : Free-living diets differed in GI by 8.4 units ( 55.5 vs 63.9 ) , with key foods providing 48 % of carbohydrate intake during both periods . There were no differences in energy intake , body weight or body composition between treatments . On laboratory investigation days , there were no differences in subjective ratings of hunger or fullness , or in energy intake at the snack or lunch meal . Conclusion : This study provides no evidence to support an effect of a reduced GI diet on satiety , energy intake or body weight in overweight/obese women . Cl aims that the GI of the diet per se may have specific effects on body weight may therefore be misleading We examined the effect of dietary energy density change on body weight in participants of a r and omized trial . Intervention participants markedly increased fruit and vegetable intake while reducing energy intake from fat . Participants were 2,718 breast cancer survivors , aged 26–74 yr , with baseline mean body mass index of 27.3 kg/mm 2 ( SD = 6.3 ) . We assessed dietary intake by sets of four 24-h dietary recalls and vali date d with plasma carotenoid concentrations . Weight and height were measured at baseline , 1 yr , and 4 yr . Dietary energy density was calculated using food but excluding beverages . Intervention participants significantly reduced dietary energy density compared to controls and maintained it over 4 yr — both in cross-sectional ( P m < 0.0001 ) and longitudinal ( Group m × Time interaction , P m < 0.0001 ) analyses . Total energy intake or physical activity did not vary between groups . The intervention group had a small but significant weight loss at 1 yr ( Group m × Time interaction , P m < 0.0001 ) , but no between-group weight difference was observed at 4 yr . Our study showed that reducing dietary energy density did not result in a reduction in total energy intake and suggests that this strategy alone is not sufficient to promote long-term weight loss in a free-living population Chronic insulin resistance contributes to sub clinical inflammation , thrombosis/impaired fibrinolysis , and dyslipidemia . The effect of dietary carbohydrate , specifically of glycemic index ( GI ) and glycemic load ( GL ) , on established and emerging coronary heart disease risk factors has not been eluci date d fully . We conducted a r and omized crossover feeding study of matched diets differing only in GI and GL in 24 overweight or obese but otherwise healthy men to investigate the effects on insulin sensitivity , inflammation , thrombosis/fibrinolysis , lipoproteins/lipids , and body composition . All meals for the high- and low-GI/GL diets were prepared in a metabolic kitchen . Each participant consumed both diets in r and om order for 4 weeks each , with a 4-week washout period in between . Each participant underwent a frequently sample d intravenous glucose tolerance test for assessment of insulin sensitivity ; blood sampling for the measurement of inflammatory markers , coagulation factors , and lipoproteins/lipids ; and dual-energy x-ray absorptiometry for assessment of body composition at the beginning and end of each dietary period . There were no statistically significant differences in glucose metabolism factors , inflammatory markers , or coagulation factors after 4 weeks on the high- and low-GI/GL diets . The high-GI/GL diet result ed in a slightly greater reduction in fat mass and a slightly greater increase in lean mass compared with the low-GI/GL diet . The high-GI/GL diet result ed in significant , but unexpected , reductions in total and low-density lipoprotein cholesterol , whereas high-density lipoprotein cholesterol concentration was significantly reduced on the high-GI/GL diet compared with the low-GI/GL diet . Overall , high- and low-GI/GL diets of 4 weeks ' duration had no consistent effects on coronary heart disease risk factors in this group of overweight/obese men OBJECTIVE The purpose of this study was to evaluate the effects of a combination weight loss program using intermittent low-calorie diets , energy-controlled meal replacement products , and sibutramine on weight loss , diabetes control , and cardiovascular risk factors in overweight or obese subjects with type 2 diabetes . RESEARCH DESIGN AND METHODS Overweight or obese individuals with type 2 diabetes treated with diet or oral medication were r and omly assigned to either a st and ard therapy or combination therapy group . Both groups received a st and ardized program to facilitate weight loss . The combination therapy group also received 10 - 15 mg sibutramine daily , low-calorie diets using meal replacement products for 1 week every 2 months , and between low-calorie diet weeks , once daily use of meal replacement product and snack bars to replace one usual meal and snack . Primary outcome measures were changes in body weight , glycemic control , plasma lipids , blood pressure , pulse , and body composition at 1 year . RESULTS At 1 year , combination therapy , compared with st and ard therapy , result ed in significantly more weight loss ( -7.3 + /- 1.3 kg vs. -0.8 + /- 0.9 kg , P < 0.001 ) and reduction in HbA(1c ) ( -0.6 + /- 0.3 vs. 0.0 + /- 0.2 % , P = 0.05 ) . Combination therapy result ed in reduced requirement for diabetes medications and decreased fat mass and lean body mass . A 5-kg decrease in weight at 1 year was associated with a decrease of 0.4 % in HbA(1c ) ( P = 0.006 ) . Changes in fasting glucose , lipids , pulse , and blood pressure did not differ between groups . CONCLUSIONS This combination weight loss program result ed in greater weight loss and improved diabetes control compared with a st and ard weight loss program in overweight or obese subjects with type 2 diabetes OBJECTIVES We studied the effect of the Mediterranean diet on plasma levels of C-reactive protein ( CRP ) , white blood cell counts , interleukin (IL)-6 , tumor necrosis factor (TNF)-alpha , amyloid A , fibrinogen , and homocysteine . BACKGROUND To the best of our knowledge , the mechanism(s ) by which the Mediterranean diet reduces cardiovascular risk are not well understood . METHODS During the 2001 to 2002 period , we r and omly enrolled 1,514 men ( 18 to 87 years old ) and 1,528 women ( 18 to 89 years old ) from the Attica area of Greece ( of these , 5 % of men and 3 % of women were excluded because of a history of cardiovascular disease ) . Among several factors , adherence to the Mediterranean diet was assessed by a diet score that incorporated the inherent characteristics of this diet . Higher values of the score meant closer adherence to the Mediterranean diet . RESULTS Participants who were in the highest tertile of the diet score had , on average , 20 % lower CRP levels ( p = 0.015 ) , 17 % lower IL-6 levels ( p = 0.025 ) , 15 % lower homocysteine levels ( p = 0.031 ) , 14 % lower white blood cell counts ( p = 0.001 ) , and 6 % lower fibrinogen levels ( p = 0.025 ) , as compared with those in the lowest tertile . The findings remained significant even after various adjustments were made . Borderline associations were found regarding TNF-alpha ( p = 0.076 ) , amyloid A levels ( p = 0.19 ) , and diet score . CONCLUSIONS Adherence to the traditional Mediterranean diet was associated with a reduction in the concentrations of inflammation and coagulation markers . This may partly explain the beneficial actions of this diet on the cardiovascular system A frequently cited concern of very-low-carbohydrate diets is the potential for increased risk of renal disease associated with a higher protein intake . However , to date , no well-controlled r and omized studies have evaluated the long-term effects of very-low-carbohydrate diets on renal function . To study this issue , renal function was assessed in 68 men and women with abdominal obesity ( age 51.5+/-7.7 years , body mass index [ calculated as kg/m(2 ) ] 33.6+/-4.0 ) without preexisting renal dysfunction who were r and omized to consume either an energy-restricted ( approximately 1,433 to 1,672 kcal/day ) , planned isocaloric very-low-carbohydrate ( 4 % total energy as carbohydrate [ 14 g ] , 35 % protein [ 124 g ] , 61 % fat [ 99 g ] ) , or high-carbohydrate diet ( 46 % total energy as carbohydrate [ 162 g ] , 24 % protein [ 85 g ] , 30 % fat [ 49 g ] ) for 1 year . Body weight , serum creatinine , estimated glomerular filtration rate and urinary albumin excretion were assessed before and after 1 year ( April 2006-July 2007 ) . Repeated measures analysis of variance was conducted . Weight loss was similar in both groups ( very-low-carbohydrate : -14.5+/-9.7 kg , high-carbohydrate : -11.6+/-7.3 kg ; P=0.16 ) . By 1 year , there were no changes in either group in serum creatinine levels ( very-low-carbohydrate : 72.4+/-15.1 to 71.3+/-13.8 mumol/L , high-carbohydrate : 78.0+/-16.0 to 77.2+/-13.2 mumol/L ; P=0.93 time x diet effect ) or estimated glomerular filtration rate ( very-low-carbohydrate : 90.0+/-17.0 to 91.2+/-17.8 mL/min/1.73 m(2 ) , high-carbohydrate : 83.8+/-13.8 to 83.6+/-11.8 mL/min/1.73 m(2 ) ; P=0.53 time x diet effect ) . All but one participant was classified as having normoalbuminuria at baseline , and for these participants , urinary albumin excretion values remained in the normoalbuminuria range at 1 year . One participant in high-carbohydrate had microalbuminuria ( 41.8 microg/min ) at baseline , which decreased to a value of 3.1 microg/min ( classified as normoalbuminuria ) at 1 year . This study provides preliminary evidence that long-term weight loss with a very-low-carbohydrate diet does not adversely affect renal function compared with a high-carbohydrate diet in obese individuals with normal renal function BACKGROUND Portion size is an important determinant of energy intake . To our knowledge , no r and omized controlled trial has evaluated the efficacy of portion control tools to induce weight loss . In patients with type 2 diabetes mellitus , weight reduction improves glycemic control . METHODS We r and omly assigned 130 obese patients with type 2 diabetes mellitus ( including 55 patients taking insulin ) to the daily use of a commercially available portion control plate for 6 months ( intervention group ) vs to usual care in the form of dietary teaching ( usual care control group ) . RESULTS Follow-up was 93.8 % . Patients in the intervention group lost significantly more weight than control subjects ( mean+/-SD , 1.8%+/-3.9 % vs 0.1%+/-3.0 % , P=.006 ) . Compared with controls , more patients in the intervention group required a decrease in their diabetes medications at 6 months ( 26.2 % vs 10.8 % , P=.04 ) . CONCLUSIONS Compared with usual care , the portion control tool studied was effective in inducing weight loss . The portion control plate also enabled patients with diabetes mellitus to decrease their hypoglycemic medications without sacrificing glycemic control . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00254124 OBJECTIVE To assess the long-term effects of a prepackaged , nutritionally complete , prepared meal plan compared with a usual-care diet ( UCD ) on weight loss and cardiovascular risk factors in overweight and obese persons . DESIGN In this r and omized multicenter study , 302 persons with hypertension and dyslipidemia ( n = 183 ) or with type 2 diabetes mellitus ( n = 119 ) were r and omized to the nutrient-fortified prepared meal plan ( approximately 22 % energy from fat , 58 % from carbohydrate , and 20 % from protein ) or to a macronutrient-equivalent UCD . MAIN OUTCOME MEASURES The primary outcome measure was weight change . Secondary measures were changes in blood pressure or plasma lipid , lipoprotein , glucose , or glycosylated hemoglobin levels ; quality of life ; nutrient intake ; and dietary compliance . RESULTS After 1 year , weight change in the hypertension/dyslipidemia group was -5.8+/-6.8 kg with the prepared meal plan vs -1.7+/-6.5 kg with the UCD plan ( P<.001 ) ; for the type 2 diabetes mellitus group , the change was -3.0+/-5.4 kg with the prepared meal plan vs -1.0+/-3.8 kg with the UCD plan ( P<.001 ) ( data given as mean + /- SD ) . In both groups , both interventions improved blood pressure , total and low-density lipoprotein cholesterol levels , glycosylated hemoglobin level , and quality of life ( P<.02 ) ; in the diabetic group , the glucose level was reduced ( P<.001 ) . Compared with those in the UCD group , participants with hypertension/dyslipidemia in the prepared meal plan group showed greater improvements in total ( P<.01 ) and high-density lipoprotein ( P<.03 ) cholesterol levels , systolic blood pressure ( P<.03 ) , and glucose level ( P<.03 ) ; in participants with type 2 diabetes mellitus , there were greater improvements in glucose ( P = .046 ) and glycosylated hemoglobin ( P<.02 ) levels . The prepared meal plan group also showed greater improvements in quality of life ( P<.05 ) and compliance ( P<.001 ) than the UCD group . CONCLUSIONS Long-term dietary interventions induced significant weight loss and improved cardiovascular risk in high-risk patients . The prepared meal plan simultaneously provided the simplicity and nutrient composition necessary to maintain long-term compliance and to reduce cardiovascular risk This study examined the relation between method of weight loss and long-term maintenance among successful weight losers enrolled in a weight-loss maintenance trial . Participants were 186 adults ( mean age = 51.6 + /- 10.7 years , mean BMI = 28.6 + /- 4.7 kg/m(2 ) ) enrolled in the STOP Regain trial who had lost at least 10 % of their body weight in the past 2 years using a very low-calorie diet ( VLCD ; n = 24 ) , commercial program ( n = 95 ) , or self-guided approach ( n = 67 ) . Participants were r and omized to a weight-maintenance intervention delivered face to face or over the internet or to a newsletter control condition , and followed for 18 months . At study entry , individuals who had used a VLCD had achieved a weight loss of 24 % of their maximum weight within the past 2 years compared to 17 % achieved by those who had used a commercial program or self-guided approach ( P < 0.001 ) . However , individuals who had used a VLCD regained significantly more weight than the other two groups and by 6 months , there were no significant differences in overall percent weight loss ( i.e. , initial weight loss and maintenance ) between VLCD , commercial , and self-guided methods . In contrast , individuals who had used a self-guided approach maintained their weight losses from baseline through 18 months . The large initial weight losses achieved by individuals who had used a VLCD were not maintained over time , whereas individuals who had used a self-guided approach maintained their initial weight losses with the greatest success . The generalizability of these findings is limited by the sizeable weight losses achieved by study participants BACKGROUND The rapid emergence of coronary artery disease ( CAD ) in south Asian people is not explained by conventional risk factors . In view of cardioprotective effects of a Mediterranean style diet rich in alpha-linolenic acid , we assessed the benefits of this diet for patients at high risk of CAD . METHODS We did a r and omised , single-blind trial in 1000 patients with angina pectoris , myocardial infa rct ion , or surrogate risk factors for CAD . 499 patients were allocated to a diet rich in whole grains , fruits , vegetables , walnuts , and almonds . 501 controls consumed a local diet similar to the step I National Cholesterol Education Program ( NCEP ) prudent diet . FINDINGS The intervention group consumed more fruits , vegetables , legumes , walnuts , and almonds than did controls ( 573 g [ SD 127 ] vs 231 g [ 19 ] per day p<0.001 ) . The intervention group had an increased intake of whole grains and mustard or soy bean oil . The mean intake of alpha-linolenic acid was two-fold greater in the intervention group ( 1.8 g [ SD 0.4 ] vs 0.8 g [ 0.2 ] per day , p<0.001 ) . Total cardiac end points were significantly fewer in the intervention group than the controls ( 39 vs 76 events , p<0.001 ) . Sudden cardiac deaths were also reduced ( 6 vs 16 , p=0.015 ) , as were non-fatal myocardial infa rct ions ( 21 vs 43 , p<0.001 ) . We noted a significant reduction in serum cholesterol concentration and other risk factors in both groups , but especially in the intervention diet group . In the treatment group , patients with pre-existing CAD had significantly greater benefits compared with such patients in the control group . INTERPRETATION An Indo-Mediterranean diet that is rich in alpha-linolenic acid might be more effective in primary and secondary prevention of CAD than the conventional step I NCEP prudent diet Untested alternative weight loss diets , such as very low carbohydrate diets , have unsubstantiated efficacy and the potential to adversely affect cardiovascular risk factors . Therefore , we design ed a r and omized , controlled trial to determine the effects of a very low carbohydrate diet on body composition and cardiovascular risk factors . Subjects were r and omized to 6 months of either an ad libitum very low carbohydrate diet or a calorie-restricted diet with 30 % of the calories as fat . Anthropometric and metabolic measures were assessed at baseline , 3 months , and 6 months . Fifty-three healthy , obese female volunteers ( mean body mass index , 33.6 + /- 0.3 kg/m(2 ) ) were r and omized ; 42 ( 79 % ) completed the trial . Women on both diets reduced calorie consumption by comparable amounts at 3 and 6 months . The very low carbohydrate diet group lost more weight ( 8.5 + /- 1.0 vs. 3.9 + /- 1.0 kg ; P < 0.001 ) and more body fat ( 4.8 + /- 0.67 vs. 2.0 + /- 0.75 kg ; P < 0.01 ) than the low fat diet group . Mean levels of blood pressure , lipids , fasting glucose , and insulin were within normal ranges in both groups at baseline . Although all of these parameters improved over the course of the study , there were no differences observed between the two diet groups at 3 or 6 months . beta- Hydroxybutyrate increased significantly in the very low carbohydrate group at 3 months ( P = 0.001 ) . Based on these data , a very low carbohydrate diet is more effective than a low fat diet for short-term weight loss and , over 6 months , is not associated with deleterious effects on important cardiovascular risk factors in healthy women BACKGROUND Adipocytokines are associated with insulin resistance and cardiovascular disease and can be modified with weight loss . While we previously demonstrated weight loss and a reduction in leptin in obese adults who followed a low-carbohydrate diet for 6 months , the long-term effects of this diet on adipocytokines are unknown . METHODS 132 obese adults with a body mass index of > or = 35 kg/m2 were r and omized to receive one year of dietary counseling to follow either a low-carbohydrate diet < 30 g/day ( LC ) or a caloric-restricted diet ( reduced by 500 calories/day with < 30 % of calories from fat ) ( LF ) . Weight , leptin , adiponectin , TNF-alpha , CRP , and insulin were measured at 0 , 6 , and 36 months ( 24 months post-counseling ) . Follow-up data at was collected for 53 participants who returned at 36 months . RESULTS Mean weight change from baseline was not different between the groups at 36 months . Between 6 and 36 months weight was unchanged for LF , while LC appeared to regain weight [ + 4.84 + /- 35.6 kg ( + 3.0 % ) ] . This difference , however , was not significant ( p = 0.08 ) . Leptin was unchanged in LF at both 6 and 36 months . In LC leptin decreased by 8.49 + /- 6.4 ng/mL or 22.7 % at 6 months ( p < 0.001 ) and increased by 10.68 + /- 25.2 ng/mL or 41.9 % between 6 and 36 months ( p = 0.02 ) . There were no differences in insulin , adiponectin , TNF-alpha , or CRP between the groups . CONCLUSIONS Favorable changes in leptin that accompany weight loss are not sustained in individuals who followed a low-carbohydrate diet for one year . A low-carbohydrate diet had no significant effect on insulin , adiponectin , TNF-alpha , or CRP compared to a low-fat diet at 36 months Abstract Objective To compare the effectiveness of four commercial weight loss diets available to adults in the United Kingdom . Design Six month multicentre r and omised unblinded controlled trial . Setting Community based sample of otherwise healthy overweight and obese adults . Interventions Dr Atkins ' new diet revolution , Slim-Fast plan , Weight Watchers pure points programme , and Rosemary Conley 's eat yourself slim diet and fitness plan . Main outcome measures Weight and body fat changes over six months . Results All diets result ed in significant loss of body fat and weight over six months . Groups did not differ significantly but loss of body fat and weight was greater in all groups compared with the control group . In an intention to treat analysis , average weight loss was 5.9 kg and average fat loss was 4.4 kg over six months . The Atkins diet result ed in significantly higher weight loss during the first four weeks , but by the end was no more or less effective than the other diets . Conclusions Clinical ly useful weight loss and fat loss can be achieved in adults who are motivated to follow commercial diets for a substantial period . Given the limited re sources for weight management in the NHS , healthcare practitioners should discuss with their patients programmes known to be effective . Trial registration Clinical trials NCT00327821 [ Clinical Trials.gov ] OBJECTIVE The long-term health consequences of diets used for weight control are not established . We have evaluated the association of the frequently recommended low carbohydrate diets - usually characterized by concomitant increase in protein intake - with long-term mortality . DESIGN The Women 's Lifestyle and Health cohort study initiated in Sweden during 1991 - 1992 , with a 12-year almost complete follow up . SETTING The Uppsala Health Care Region . SUBJECTS 42,237 women , 30 - 49 years old at baseline , volunteers from a r and om sample , who completed an extensive question naire and were traced through linkages to national registries until 2003 . MAIN OUTCOME MEASURES We evaluated the association of mortality with : decreasing carbohydrate intake ( in deciles ) ; increasing protein intake ( in deciles ) and an additive combination of these variables ( low carbohydrate-high protein score from 2 to 20 ) , in Cox models controlling for energy intake , saturated fat intake and several nondietary covariates . RESULTS Decreasing carbohydrate or increasing protein intake by one decile were associated with increase in total mortality by 6 % ( 95 % CI : 0 - 12 % ) and 2 % ( 95 % CI : -1 to 5 % ) , respectively . For cardiovascular mortality , amongst women 40 - 49 years old at enrolment , the corresponding increases were , respectively , 13 % ( 95 % CI : -4 to 32 % ) and 16 % ( 95 % CI : 5 - 29 % ) , with the additive score being even more predictive . CONCLUSIONS A diet characterized by low carbohydrate and high protein intake was associated with increased total and particularly cardiovascular mortality amongst women . Vigilance with respect to long-term adherence to such weight control regimes is advisable OBJECTIVE Although weight management is an important component in the treatment of type 2 diabetes , there has been concern about the use of liquid meal replacements ( MRs ) in treating obese patients with type 2 diabetes because of the sugar content of the MRs . The goal of this study was to evaluate the safety and feasibility of using MRs for weight loss in obese patients with type 2 diabetes . RESEARCH METHODS AND PROCEDURES Seventy-five subjects with type 2 diabetes , treated only with oral agents , were recruited for this 12-week clinical study . Subjects were r and omized into three groups using either a MR containing lactose , fructose , and sucrose , a MR in which fructose and sucrose were replaced with oligosaccharides ( sugar-free Slim-Fast ) , or an exchange diet plan ( EDP ) using the proportion of macronutrients recommended by the American Diabetes Association . RESULTS Fifty-seven patients ( 41 MR and 16 EDP ) finished the study . None developed serious adverse effects , including major hypoglycemic reactions . Weight losses in the MR 1 and MR 2 groups were comparable ( 6.4 % and 6.7 % , respectively ) and greater than the weight loss in the EDP group ( 4.9 % ) . Fasting glucose level was significantly reduced in the MR group compared with the EDP group ( p = 0.012 ) . There was a significant reduction in the MR group in total cholesterol and low-density lipoprotein cholesterol that was not seen in the EDP group . DISCUSSION We have shown that liquid MRs are a safe and effective weight loss tool for obese subjects with type 2 diabetes , and can result in improvements in body weight , glucose , insulin , hemoglobin A1c and lipid levels To determine the effect of a 6-month very low carbohydrate diet program on body weight and other metabolic parameters . Fifty-one overweight or obese healthy volunteers who wanted to lose weight were placed on a very low carbohydrate diet ( < 25 g/d ) , with no limit on caloric intake . They also received nutritional supplementation and recommendations about exercise , and attended group meetings at a research clinic . The outcomes were body weight , body mass index , percentage of body fat ( estimated by skinfold thickness ) , serum chemistry and lipid values , 24-hour urine measurements , and subjective adverse effects . Forty-one ( 80 % ) of the 51 subjects attended visits through 6 months . In these subjects , the mean ( + /- SD ) body weight decreased 10.3 % + /- 5.9 % ( P < 0.001 ) from baseline to 6 months ( body weight reduction of 9.0 + /- 5.3 kg and body mass index reduction of 3.2 + /- 1.9 kg/m(2 ) ) . The mean percentage of body weight that was fat decreased 2.9 % + /- 3.2 % from baseline to 6 months ( P < 0.001 ) . The mean serum bicarbonate level decreased 2 + /- 2.4 mmol/L ( P < 0.001 ) and blood urea nitrogen level increased 2 + /- 4 mg/dL ( P < 0.001 ) . Serum total cholesterol level decreased 11 + /- 26 mg/dL ( P = 0.006 ) , low-density lipoprotein cholesterol level decreased 10 + /- 25 mg/dL ( P = 0.01 ) , triglyceride level decreased 56 + /- 45 mg/dL ( P < 0.001 ) , high-density lipoprotein ( HDL ) cholesterol level increased 10 + /- 8 mg/dL ( P < 0.001 ) , and the cholesterol/HDL cholesterol ratio decreased 0.9 + /- 0.6 units ( P < 0.001 ) . There were no serious adverse effects , but the possibility of adverse effects in the 10 subjects who did not adhere to the program can not be eliminated . A very low carbohydrate diet program led to sustained weight loss during a 6-month period . Further controlled research is warranted BACKGROUND For many people , maintenance of weight loss is elusive . Whereas high-protein ( HP ) diets have been found to be superior to high-carbohydrate ( HC ) diets for weight loss in the short term , their benefits long term are unclear , particularly for weight maintenance . Furthermore , the literature lacks consensus on the long-term effects of an HP diet on cardiovascular disease risk factors . OBJECTIVE The objective was to investigate whether macronutrient dietary composition plays a role in weight maintenance and in improvement of cardiovascular disease risk factors . DESIGN The study comprised 2 phases . Phase 1 featured a very-low-energy diet for 3 mo . In phase 2 , the subjects were r and omly assigned to an HP or an HC diet for 12 mo . The diets were isocaloric , tightly controlled , and individually prescribed for weight maintenance . The subjects were overweight or obese but otherwise healthy men and women . RESULTS The subjects lost an average of 16.5 kg during phase 1 and maintained a mean ( + /-SEM ) weight loss of 14.5 + /- 1.2 kg ( P < 0.001 ) during phase 2 ; no significant differences between groups were observed . By the end of the study , reductions in systolic blood pressure were 14.3 + /- 2.4 mm Hg for the HP group and 7.7 + /- 2.2 mm Hg for the HC group ( P < 0.045 ) . Forty-seven percent of the 180 subjects who began the study completed both phases . CONCLUSIONS The results indicate that the protein or carbohydrate content of the diet has no effect on successful weight-loss maintenance . A general linear model analysis indicated that dietary treatment ( HP or HC ) was a significant factor in systolic blood pressure change and in favor of the HP diet . This trial was registered at www . clinical trials.gov as NCT 00625236 BACKGROUND Trials comparing the effectiveness and safety of weight-loss diets are frequently limited by short follow-up times and high dropout rates . METHODS In this 2-year trial , we r and omly assigned 322 moderately obese subjects ( mean age , 52 years ; mean body-mass index [ the weight in kilograms divided by the square of the height in meters ] , 31 ; male sex , 86 % ) to one of three diets : low-fat , restricted-calorie ; Mediterranean , restricted-calorie ; or low-carbohydrate , non-restricted-calorie . RESULTS The rate of adherence to a study diet was 95.4 % at 1 year and 84.6 % at 2 years . The Mediterranean-diet group consumed the largest amounts of dietary fiber and had the highest ratio of monounsaturated to saturated fat ( P<0.05 for all comparisons among treatment groups ) . The low-carbohydrate group consumed the smallest amount of carbohydrates and the largest amounts of fat , protein , and cholesterol and had the highest percentage of participants with detectable urinary ketones ( P<0.05 for all comparisons among treatment groups ) . The mean weight loss was 2.9 kg for the low-fat group , 4.4 kg for the Mediterranean-diet group , and 4.7 kg for the low-carbohydrate group ( P<0.001 for the interaction between diet group and time ) ; among the 272 participants who completed the intervention , the mean weight losses were 3.3 kg , 4.6 kg , and 5.5 kg , respectively . The relative reduction in the ratio of total cholesterol to high-density lipoprotein cholesterol was 20 % in the low-carbohydrate group and 12 % in the low-fat group ( P=0.01 ) . Among the 36 subjects with diabetes , changes in fasting plasma glucose and insulin levels were more favorable among those assigned to the Mediterranean diet than among those assigned to the low-fat diet ( P<0.001 for the interaction among diabetes and Mediterranean diet and time with respect to fasting glucose levels ) . CONCLUSIONS Mediterranean and low-carbohydrate diets may be effective alternatives to low-fat diets . The more favorable effects on lipids ( with the low-carbohydrate diet ) and on glycemic control ( with the Mediterranean diet ) suggest that personal preferences and metabolic considerations might inform individualized tailoring of dietary interventions . ( Clinical Trials.gov number , NCT00160108 . CONTEXT : Long-term success in weight loss with dietary treatment has been elusive . OBJECTIVE : To evaluate a diet moderate in fat based on the Mediterranean diet compared to a st and ard low-fat diet for weight loss when both were controlled for energy . DESIGN : A r and omized , prospect i ve 18 month trial in a free-living population . PATIENTS : A total of 101 overweight men and women ( 26.5–46 kg/m2).INTERVENTION : ( 1 ) Moderate-fat diet ( 35 % of energy ) ; ( 2 ) low-fat diet ( 20 % of energy).MAIN OUTCOME MEASUREMENTS : Change in body weight . RESULTS : After 18 months , 31/50 subjects in the moderate-fat group , and 30/51 in the low fat group were available for measurements . In the moderate-fat group , there were mean decreases in body weight of 4.1 kg , body mass index of 1.6 kg/m2 , and waist circumference of 6.9 cm , compared to increases in the low-fat group of 2.9 kg , 1.4 kg/m2 and 2.6 cm , respectively ; P≤0.001 between the groups . The difference in weight change between the groups was 7.0 kg . ( 95 % CI 5.3 , 8.7 ) . Only 20 % ( 10/51 ) of those in the low-fat group were actively participating in the weight loss program after 18 months compared to 54 % ( 27/50 ) in the moderate-fat group , ( P<0.002 ) . The moderate-fat diet group was continued for an additional year . The mean weight loss after 30 months compared to baseline was 3.5 kg ( n=19 , P=0.03 ) . CONCLUSIONS : A moderate-fat , Mediterranean-style diet , controlled in energy , offers an alternative to a low-fat diet with superior long-term participation and adherence , with consequent improvements in weight loss Objective : To examine changes in plasma lipids and lipoproteins after 51 months of reduced energy intake and sustained weight loss . Methods : One-hundred patients were r and omized to one of two dietary interventions for 3 months ( weight loss period ) . Groups A and B received an energy-restricted diet plan of 5.2–6.3 MJ/day but group B was further instructed to replace two of three meals with a nutrient-fortified liquid meal replacement ( MR ) . Upon completion of the weight loss period , all patients were given the same instructions regarding energy intake and were advised to use one MR daily . Body weight and 7 day food diaries were measured monthly or bimonthly and blood lipids at baseline , 3 , 9 and 51 months . Results : Of the original 100 patients 75 had completed 4 y. Of those 75 , 73 had complete lipid records . Baseline body weights of Groups A and B were 90.7±14.0 and 91.6±9.8 kg , respectively . The percentage change in total cholesterol ( % ΔTC ) decreased in a linear fashion with increasing weight loss , when all data was combined , but did not approach statistical significance ( P≤0.26 , r=0.02 ) . Further regression analysis found a significant negative linear relationship ( P≤0.0001 , r=0.69 ) between initial total cholesterol ( TC ) concentrations and % ΔTC . Hence , data from 27 of the 73 completers who exhibited an elevated serum total cholesterol ( ≥6.2 mmol/l ) were isolated and analyzed further . Baseline TC was 6.75±0.64 , 5.85±0.63 at 9 months ( P<0.05 ) and 5.76±0.52 mmol/l at 51 months ( P<0.05 ) . Similar values for VLDL-cholesterol were 1.33±0.80 , 0.74±0.24 and 0.66±0.21 mmol/l by 51 months ( P<0.05 ) . Weight decreased by 5.2±5.1 , 7.6±4.9 and 6.7±4.6 % at 3 , 9 and 51 months , respectively . Conclusion : Continuous energy restriction associated with a clinical ly meaningful weight loss significantly improved the lipid profile of high-risk patients . Similar weight and diet changes occurring in patients with normal plasma cholesterol were either increased or without affect The purpose of the present study was to examine the relationship between patterns of meal replacement ( MR ) adherence and changes in outcomes during a behaviorally-oriented weight loss program . Data from the present study are based on sixty female participants ( age : 29 - 62 years , BMI : 27.99 - 37.50 kg/m(2 ) ) . Participants were r and omized into either a control or experimental condition , which tested the use of MRs during weight loss maintenance . Outcome measures included body weight , depression , physical activity , cognitive restraint , disinhibition , hunger , and binge eating collected at four assessment points . Within the experimental condition , we further examined adherence to MRs and its relationship with the outcome measures . We found evidence of differences at baseline on some measures ( e.g. , weight , physical activity and depression ) while on others ( cognitive restraint , disinhibition , and hunger ) , differences that emerged over the course of treatment . Further research is necessary to determine if there are measures associated with successful MR use that can be detected at baseline and if MR adherence itself leads to changes in eating behavior The purpose of this study was to determine the effects of dietary protein and eating frequency on perceived appetite and satiety during weight loss . A total of 27 overweight/obese men ( age 47 ± 3 years ; BMI 31.5 ± 0.7 kg/m(2 ) ) were r and omized to groups that consumed an energy-restriction diet ( i.e. , 750 kcal/day below daily energy need ) as either higher protein ( HP , 25 % of energy as protein , n = 14 ) or normal protein ( NP , 14 % of energy as protein , n = 13 ) for 12 weeks . Beginning on week 7 , the participants consumed their respective diets as either 3 eating occasions/day ( 3-EO ; every 5 h ) or 6 eating occasions/day ( 6-EO ; every 2 h ) , in r and omized order , for 3 consecutive days . Indexes of appetite and satiety were assessed every waking hour on the third day of each pattern . Daily hunger , desire to eat , and preoccupation with thoughts of food were not different between groups . The HP group experienced greater fullness throughout the day vs. NP ( 511 ± 56 vs. 243 ± 54 mm · 15 h ; P < 0.005 ) . When compared to NP , the HP group experienced lower late-night desire to eat ( 13 ± 4 vs. 27 ± 4 mm , P < 0.01 ) and preoccupation with thoughts of food ( 8 ± 4 vs. 21 ± 4 mm ; P < 0.01 ) . Within groups , the 3 vs. 6-EO patterns did not influence daily hunger , fullness , desire to eat , or preoccupation with thoughts of food . The 3-EO pattern led to greater evening and late-night fullness vs. 6-EO but only within the HP group ( P < 0.005 ) . Collectively , these data support the consumption of HP intake , but not greater eating frequency , for improved appetite control and satiety in overweight/obese men during energy restriction-induced weight loss OBJECTIVES To evaluate in a prospect i ve , r and omized clinical trial ( RCT ) , symptom response among obese knee osteoarthritis ( OA ) patients following a feasible , intensive weight-loss program for 16 weeks . METHODS Eligible patients were obese [ body mass index ( BMI ) > 30 kg/m(2 ) ] ; > 50 years old , with primary knee OA . Participants were r and omized to either a very-low-energy diet ( VLED ) or a low-energy diet ( LED ) ( 415 kcal/day and 810 kcal/day , respectively ) , using commercially available formula foods - only for the first 8 weeks , managed by dieticians . The 8 weeks were followed by an additional 8-week period of a hypo-energetic diet consisting of normal food plus meal replacements ( 1200 kcal/day ) . The primary endpoint was the number of patients responding according to the Outcome Measures in Rheumatology Clinical Trials and Osteoarthritis Research Society International ( OMERACT-OARSI ) responder criterion . The statistical analysis was based on a non-responder intention-to-treat ( ITT ) population ( baseline observation carried forward ) . RESULTS One hundred and ninety two patients ( 155 ( 80.7 % ) females ) with a mean age 62.5 years [ st and ard deviation ( SD ) 6.4 ; range 50 - 78 years ] ; average BMI 37.3 ( SD 4.8 ) were included . At 16 weeks , similar proportions of the VLED and LED groups , 59 ( 61.5 % ) , and 63 ( 65.6 % ) patients , respectively , met the OMERACT-OARSI responder criteria , with no statistical significant difference between the groups ( P=0.55 ) . Combining the groups the pooled estimate was 64 % meeting the responder criteria [ 95 % confidence interval ( CI ) 57 % , 70 % ] . There was an overall reduction in pain , corresponding to an average pain reduction on the visual analogue scale ( VAS ) of 11.1 ( 95%CI 13.6 , 8.5 ) in the combined groups . At week 16 weight loss in the combined groups was 12.8 kg ( 95%CI : 11.84 - 13.66 ; P<0.001 ) . 71 % lost > or = 10 % body weight in both diet groups , with a pooled estimate of 74 % ( 95%CI : 68 - 80 % ) . CONCLUSION No clinical ly significant differences were found between the 415 kcal/day and 810 kcal/day diets . A 16-week formula-diet weight-loss program result ed in a fast and effective weight loss with very few adverse events result ing in a highly significant improvement in symptoms in overweight patients with knee OA BACKGROUND & AIMS Low glycemic index ( GI ) based diets could influence the accompanying physiological adaptations to energy restriction in the treatment of obesity . It was aim ed to investigate the effects of two energy-restricted diets with different food distribution and GI values on weight loss and energy metabolism in the nutritional treatment of obesity . SUBJECTS AND METHODS Participants ( n=32 ; BMI : 32.5+/-4.3 kg/m(2 ) ) were r and omly assigned to follow two energy-restricted diets with higher-GI or lower-GI for 8 weeks . The energy restriction was -30 % in relation to energy expenditure . Anthropometry , energy expenditure and mitochondrial oxidation were assessed at baseline and at the endpoint of the intervention . Body weight was also measured one year after the treatment . The work was approved by the ethical committees of the University of Navarra ( 54/2006 ) . RESULTS Volunteers consuming the lower-GI diet showed a significantly higher weight loss than their counterparts ( -5.3+/-2.6 % vs -7.5+/-2.9 % ; p=0.032 ) , although the decrease in resting energy expenditure ( REE ) was similar between groups ( p=0.783 ) . Mitochondrial oxidation was significantly affected by the type of diet ( p=0.001 ) , being activated after the lower-GI treatment ( p=0.022 ) . Interestingly , one year after the nutritional intervention weight regain was only statistically significant in the higher-GI group ( p=0.033 ) . CONCLUSIONS Lower-GI energy-restricted diets achieved through a specific differential food selection can improve the energy adaptations during obesity treatment , favouring weight loss and probably weight maintenance compared with higher-GI hypocaloric diets Background : Dietary adherence has been implicated as an important factor in the success of dieting strategies ; however , studies assessing and investigating its association with weight loss success are scarce . Objective : We aim ed to document the level of dietary adherence using measured diet data and to examine its association with weight loss success . Design : Secondary analysis was performed using data from 181 free-living overweight/obese women ( mean±s.d . age=43±5 years , body mass index=31±4 kg m−2 ) participating in a 1-year r and omized clinical trial ( the A TO Z study ) comparing popular weight loss diets ( Atkins , Zone and Ornish ) . Participants ' dietary adherence was assessed as the difference between their respective assigned diet 's recommended macronutrient goals and their self-reported intake . Association between dietary adherence and 12-month weight change was computed using Spearman 's correlations . Differences in baseline characteristics and macronutrient intake between the most and least adherent tertiles for diet groups were compared using t-tests . Results : Within each diet group , adherence score was significantly correlated with 12-month weight change ( Atkins , rs=0.42 , P=0.0003 ; Zone , rs=0.34 , P=0.009 and Ornish , rs=0.38 , P=0.004 ) . Twelve-month weight change in the most vs least adherent tertiles , respectively , was −8.3±5.6 vs −1.9±5.8 kg , P=0.0006 ( Atkins ) ; −3.7±6.3 vs −0.4±6.8 kg , P=0.12 ( Zone ) and −6.5±6.8 vs −1.7±7.9 kg , P=0.06 ( Ornish ) . Conclusions : Regardless of assigned diet groups , 12-month weight change was greater in the most adherent compared to the least adherent tertiles . These results suggest that strategies to increase adherence may deserve more emphasis than the specific macronutrient composition of the weight loss diet itself in supporting successful weight loss OBJECTIVE To examine changes in biomarkers of disease risk after 51 months of reduced energy intake and sustained weight loss . RESEARCH METHODS AND PROCEDURES This study was conducted as a prospect i ve , r and omized , two-arm , parallel intervention for 12 weeks followed by a prospect i ve , single-arm , 4-year trial in a university-based hospital clinic . One hundred patients were r and omly assigned to one of two dietary interventions for 3 months . Group A was prescribed an energy-restricted diet of 1200 to 1500 kcal/d , and group B was prescribed an isocaloric diet , whereby two of three meals were replaced with nutrient-fortified liquid meal replacements . After 3 months , the patients were prescribed the same caloric reduction and used once-daily replacements for the succeeding 4 years . Body weight and blood pressure were checked monthly . Biomarkers of disease risk were measured after 3 , 9 , 15 , 27 , and 51 months . RESULTS During the 3-month weight-loss period , body weight was reduced by 1.5 + /- 0.4 % and 7.8 + /- 0.5 % ( mean + /- SEM ) for groups A and B , respectively . After 4 years , 75 % of the patients were evaluated . Total mean weight loss was 3.3 + /- 0.8 % and 8.4 + /- 0.8 % for groups A and B , respectively . Both groups of patients showed significant improvement in glucose , insulin , triacylglycerol , and systolic blood pressure . Cholesterol concentrations were reduced in patients with high initial cholesterol levels and maintenance of a 7 % weight loss . DISCUSSION Providing a structured meal plan with liquid meal replacements is an effective treatment for obese subjects . Long-term maintenance of weight loss with meal replacements improves biomarkers of disease risk PURPOSE To evaluate a year-long behavioral weight control program , used with and without an intermittent very-low-calorie diet ( VLCD ) in the treatment of type II diabetes mellitus . PATIENTS AND METHODS Subjects ( n = 93 ) were r and omly assigned to 50-week treatment programs that used either a balanced low-calorie diet ( LCD ) of 1,000 to 1,000 kilocalories ( kcal ) per day throughout or included 2 12-week periods of a VLCD of 400 to 500 kcal per day alternating with the balanced LCD . Weight , glycemic control , blood pressure , and lipids were assessed at baseline , at the end of the year-long treatment , and at 2-year follow-up . RESULTS Subjects in the VLCD program lost significantly more weight than did LCD subjects at the end of the 50-week program ( 14.2 kg versus 10.5 kg ; P = 0.057 ) and remained off diabetes medication longer ( P < 0.05 ) . These benefits of the VLCD were due primarily to the first 12 weeks of the diet ; the second diet maintained , but did not increase , these effects . Subjects in both groups experienced marked improvements in glycemic control and cardiovascular risk factors over the year-long program , but attendance declined in the latter weeks of treatment and weight was regained . There was also marked recidivism in both groups in the year following treatment . CONCLUSIONS The intermittent VLCD improved weight loss and glycemic control , but these effects were quite modest and do not appear to justify the clinical use of an intermittent VLCD . Moreover , lengthening treatment to a full year did not prevent relapse . Thus , further research is needed to develop a successful approach to long-term weight control Objective : We have evaluated the effects on mortality of habitual low carbohydrate – high-protein diets that are thought to contribute to weight control . Design : Cohort investigation . Setting : Adult Greek population .Subjects methods : Follow-up was performed from 1993 to 2003 in the context of the Greek component of the European Prospect i ve Investigation into Cancer and nutrition . Participants were 22 944 healthy adults , whose diet was assessed through a vali date d question naire . Participants were distributed by increasing deciles according to protein intake or carbohydrate intake , as well as by an additive score generated by increasing decile intake of protein and decreasing decile intake of carbohydrates . Proportional hazards regression was used to assess the relation between high protein , high carbohydrate and the low carbohydrate – high protein score on the one h and and mortality on the other . Results : During 113 230 persons years of follow-up , there were 455 deaths . In models with energy adjustment , higher intake of carbohydrates was associated with significant reduction of total mortality , whereas higher intake of protein was associated with nonsignificant increase of total mortality ( per decile , mortality ratios 0.94 with 95 % CI 0.89 –0.99 , and 1.02 with 95 % CI 0.98 –1.07 respectively ) . Even more predictive of higher mortality were high values of the additive low carbohydrate – high protein score ( per 5 units , mortality ratio 1.22 with 95 % CI 1.09 –to 1.36 ) . Positive associations of this score were noted with respect to both cardiovascular and cancer mortality . Conclusion : Prolonged consumption of diets low in carbohydrates and high in protein is associated with an increase in total mortality OBJECTIVE To assess changes in body composition with weight loss in obese subjects r and omized to a laparoscopic adjustable gastric b and surgical program or a medical program using a very-low-energy diet and orlistat . RESEARCH METHODS AND PROCEDURES Using body composition measurements by DXA , neutron activation for total body nitrogen , and whole body gamma counting for total body potassium , we studied changes in fat mass , fat distribution , fat-free mass , total bone mineral content , total body protein , and body cell mass at 6 ( n = 61 paired ) and 24 months ( n = 53 paired ) after r and omization . RESULTS At 24 months , the surgical group had lost significantly more weight ( surgical , 20.3 + /- 6.5 kg ; medical , 5.9 + /- 8.0 kg ) . There was favorable fat-free mass to fat mass loss ratios for both groups ( surgical , 1:5.5 ; medical , 1:5.9 ) . Changes in total body nitrogen or potassium were favorable in each group . A small reduction in mean bone mineral content occurred throughout the study but was not associated with extent of weight loss or treatment group . At 6 months , weight loss for both groups was similar ( surgical , 14.1 + /- 4.5 kg ; medical , 13.3 + /- 7.3 kg ) . The medical program subjects lost less fat-free mass and skeletal muscle and had increased total body protein . The proportion of body fat to limb fat remained remarkably constant throughout the study . DISCUSSION Weight loss programs used in this study induced fat loss without significant deleterious effects on the components of fat-free mass BACKGROUND Despite the popularity of low-glycemic index ( GI ) and high-protein diets , to our knowledge no r and omized , controlled trials have systematic ally compared their relative effects on weight loss and cardiovascular risk . METHODS A total of 129 overweight or obese young adults ( body mass index , > or = 25 [ calculated as weight in kilograms divided by the square of height in meters ] ) were assigned to 1 of 4 reduced-fat , high-fiber diets for 12 weeks . Diets 1 and 2 were high carbohydrate ( 55 % of total energy intake ) , with high and low GIs , respectively ; diets 3 and 4 were high protein ( 25 % of total energy intake ) , with high and low GIs , respectively . The glycemic load was highest in diet 1 and lowest in diet 4 . Changes in weight , body composition , and blood chemistry profile were studied . RESULTS While all groups lost a similar mean + /- SE percentage of weight ( diet 1 , -4.2 % + /- 0.6 % ; diet 2 , -5.5 % + /- 0.5 % ; diet 3 , -6.2 % + /- 0.4 % ; and diet 4 , -4.8 % + /- 0.7 % ; P = .09 ) , the proportion of subjects in each group who lost 5 % or more of body weight varied significantly by diet ( diet 1 , 31 % ; diet 2 , 56 % ; diet 3 , 66 % ; and diet 4 , 33 % ; P = .01 ) . Women on diets 2 and 3 lost approximately 80 % more fat mass ( -4.5 + /- 0.5 [ mean + /- SE ] kg and -4.6 + /- 0.5 kg ) than those on diet 1 ( -2.5 + /- 0.5 kg ; P = .007 ) . Mean + /- SE low-density-lipoprotein cholesterol levels declined significantly in the diet 2 group ( -6.6 + /- 3.9 mg/dL [ -0.17 + /- 0.10 mmol/L ] ) but increased in the diet 3 group ( + 10.0 + /- 3.9 mg/dL [ + 0.26 + /- 0.10 mmol/L ] ; P = .02 ) . Goals for energy distribution were not achieved exactly : both carbohydrate groups ate less fat , and the diet 2 group ate more fiber . CONCLUSION Both high-protein and low-GI regimens increase body fat loss , but cardiovascular risk reduction is optimized by a high-carbohydrate , low-GI diet OBJECTIVE To evaluate whether a 5-week low-glycemic index ( LGI ) diet versus a high-glycemic index ( HGI ) diet can modify glucose and lipid metabolism as well as total fat mass in nondiabetic men . RESEARCH DESIGN AND METHODS In this study , 11 healthy men were r and omly allocated to 5 weeks of an LGI or HGI diet separated by a 5-week washout interval in a crossover design . RESULTS The LGI diet result ed in lower postpr and ial plasma glucose and insulin profiles and areas under the curve ( AUCs ) than the HGI diet . A 5-week period of the LGI diet lowered plasma triacylglycerol excursion after lunch ( AUC , P < 0.05 LGI vs. HGI ) . These modifications were associated with a decrease in the total fat mass by approximately 700 g ( P < 0.05 ) and a tendency to increase lean body mass ( P < 0.07 ) without any change in body weight . This decrease in fat mass was accompanied by a decrease in leptin , lipoprotein lipase , and hormone-sensitive lipase RNAm quantities in the subcutaneous abdominal adipose tissue ( P < 0.05 ) . CONCLUSIONS We concluded that 5 weeks of an LGI diet ameliorates some plasma lipid parameters , decreases total fat mass , and tends to increase lean body mass without changing body weight . These changes were accompanied by a decrease in the expression of some genes implicated in lipid metabolism . Such a diet could be of benefit to healthy , slightly overweight subjects and might play a role in the prevention of metabolic diseases and their cardiovascular complications OBJECTIVE To determine the efficacy of a weight-loss diet using packaged portion-controlled entrees compared with a self-selected diet based on the U.S. Department of Agriculture Food Guide Pyramid ( FGP ) ( United States Department of Agriculture , Center for Nutrition Policy and Promotion , Washington , DC ; 1996 ) . RESEARCH METHODS AND PROCEDURES Sixty healthy women ( BMI 26 to 40 kg/m(2 ) ; 24 to 60 years old ) were r and omized into two intervention groups for an 8-week parallel arm study . The portion-controlled group consumed two frozen entrees daily , plus additional food servings from the FGP . The self-selected diet group consumed a recommended number of servings from the FGP . Diets were design ed to be the same in composition ( 55 % carbohydrate , 25 % protein , 20 % fat ) and energy level ( 1365 kcal ) . Each group met weekly to monitor compliance and take measures . Outcomes included weight , body composition by DXA , hip and waist circumference , blood pressure , fasting blood lipids , glucose , insulin , and C-reactive protein . Significant differences were assessed using repeated measures ANOVA . RESULTS The portion-controlled group ( n = 26 ) experienced greater decreases in weight ( 5.6 + /- 2.2 kg or 6.5 % vs. 3.6 + /- 2.5 kg or 4.2 % ) , fat mass ( 3.6 + /- 1.8 vs. 2.3 + /- 1.4 kg ) , total cholesterol ( 24.4 + /- 21.5 mg/dL or 12.4 % vs. 13.0 + /- 13.9 mg/dL or 6.7 % ) , and fasting insulin ( -1.8 + /- 3.7 vs.+0.3 + /- 3.8 micro U/mL ) than the self-selected diet group ( n = 27 ) ( p < 0.05 ) . DISCUSSION Consumption of portion-controlled entrees result ed in greater losses of weight and fat , thereby reducing cardiovascular disease risk . Accurate portion control is an important factor in weight loss success , and use of packaged entrees is an effective method of achieving this Background : Wholegrain intake is inversely related to weight gain over time , but little information is available on the role of pulses in weight control . Objective : To compare weight loss , metabolic outcomes , and nutrient intakes in obese people assigned to a diet rich in pulses and wholegrains or a control diet . Methods : R and omized controlled study of 18 months with 113 volunteers ( body mass index [ BMI ] ≥ 28 kg/m2 ) . Diets were based on guidelines published by the National Heart Foundation of New Zeal and . The intervention group was advised to consume 2 serves of pulses and 4 serves of wholegrain foods per day as substitutions for more refined carbohydrates . Results : Fiber intakes were higher , intakes of several vitamins and minerals were better maintained , and dietary glycemic index was lower in the intervention compared with the control group . Mean ( st and ard error [ SE ] ) weight loss at 6 months was 6.0 ( 0.7 ) kg and 6.3 ( 0.6 ) kg in the control and intervention groups , respectively , and was not different between groups ( p > 0.05 ) . Blood pressure , triglycerides , and glycemic load were lowered in both groups compared with baseline . Waist circumference was decreased at 18 months in the intervention compared with the control group ( −2.8 cm ; 95 % confidence interval [ CI ] : −0.4 , −5.1 ) . Conclusions : Incorporation of pulses and wholegrain foods into a weight loss program result ed in a greater reduction in waist circumference compared with the group consuming a control diet , although no difference in weight loss was noted between groups . Retention of several nutrients was better with the pulse and wholegrain diet The authors posed 2 questions in this r and omized study of maintenance procedures in which participants were followed for 15 months after completion of a very-low-calorie diet : Would stimulus narrowing during the re introduction of solid food , achieved by the use of prepackaged foods , improve weight losses and the maintenance of those losses as compared with the use of regular food ? Would re introduction of foods dependent on progress in losing or maintaining weight be superior to re introduction on a time-dependent basis ? Neither the stimulus narrowing condition nor the re introduction procedure enhanced either maximum weight loss or maintenance of those losses . The stimulus narrowing condition appeared to be poorly tolerated ; compliance and attendance were poorer in this condition than in the regular food condition Background / objectives : Weight loss in obesity can reduce morbidity and mortality and benefits persist as long as weight loss is maintained . Weight maintenance is difficult in the long term and new strategies need to be developed to achieve this goal . We aim ed to evaluate the efficacy of substituting a low-calorie diet formula for a meal in a weight loss program during the maintenance phase . Methods : R and omized paralleled clinical trial including 62 adult patients with at least a 5 % weight loss with diet alone for 6 months , r and omized to two groups : daily replacement of one meal with a low-calorie diet formula , or dieting alone for another 6 months ( weight maintenance phase ) . Results : Weight maintenance or further weight loss occurred in 83.9 % of patients in the intervention group , whereas only in 58.1 % in the control group ( P=0.025 ) . As a whole , patients in the intervention group lost a further 3.2±3.7 % of initial weight compared with a 1.3±3.6 % in the control group ( P=0.030 ) . Body fat mass diminished in both groups , with no differences between them ( 1.6±3.5 vs 1.0±9.3 kg , respectively , P=0.239 ) , and the same happened with free fat mass ( 0.9±3.3 vs 0.4±6.7 kg , respectively , P=0.471 ) . A multivariate logistic regression analysis ( R 2=0.114 , P=0.023 ) retained only the intervention as a predictor of the achievement of weight maintenance with an odds ratio ( 95 % confidence interval ) of 3.756 ( 1.138–12.391 ) . Conclusions : Substitution of a low-calorie diet formula for a meal is an effective measure for weight loss maintenance compared with dieting alone This study compared the weight losses of 49 obese women r and omly assigned to a 52-week behavioral program combined with either moderate or severe caloric restriction . Subjects in the balanced deficit diet ( BDD ) condition were prescribed a 1,200-kcal/day diet throughout treatment , and those in the very-low-calorie diet ( VLCD ) condition were given a 420-kcal/day liquid diet for 16 weeks and a 1,200-kcal/day diet thereafter . The VLCD subjects lost significantly more weight than the BDD subjects at all periods through Week 26 , at which time mean losses were 21.45 and 11.86 kg , respectively . VLCD subjects , however , regained weight during the next 26 weeks of weekly therapy and during a 26-week weight maintenance program that provided biweekly meetings . Mean weight losses at the end of the maintenance program were 10.94 and 12.18 kg , respectively . Reports of binge eating declined in both groups , and no relationship was observed between binge eating and weight loss or attrition BACKGROUND Lifestyle changes involving diet , behavior , and physical activity are the cornerstone of successful weight control . Incorporating meal replacements ( 1 - 2 per day ) into traditional lifestyle interventions may offer an additional strategy for overweight patients in the primary care setting . METHODS One hundred thirteen overweight premenopausal women ( mean + /- SD age , 40.4 + /- 5.5 years ; weight , 82 + /- 10 kg ; and body mass index , 30 + /- 3 kg/m(2 ) ) participated in a 1-year weight-reduction study consisting of 26 sessions . The women were r and omly assigned to 3 different traditional lifestyle-based groups : ( 1 ) dietitian-led group intervention ( 1 hour per session ) , ( 2 ) dietitian-led group intervention incorporating meal replacements ( 1 hour per session ) , or ( 3 ) primary care office intervention incorporating meal replacements with individual physician and nurse visits ( 10 - 15 minutes per visit ) . RESULTS For the 74 subjects ( 65 % ) completing 1 year , the primary care office intervention using meal replacements was as effective as the traditional dietitian-led group intervention not using meal replacements ( mean + /- SD weight loss , 4.3 % + /- 6.5 % vs 4.1 % + /- 6.4 % , respectively ) . Comparison of the dietitian-led groups showed that women using meal replacements maintained a significantly greater weight loss ( 9.1 % + /- 8.9 % vs 4.1 % + /- 6.4 % ) ( P = .03 ) . Analysis across groups showed that weight loss of 5 % to 10 % was associated with significant ( P = .01 ) reduction in percentage of body fat , body mass index , waist circumference , resting energy expenditure , insulin level , total cholesterol level , and low-density lipoprotein cholesterol level . Weight loss of 10 % or greater was associated with additional significant ( P = .05 ) improvements in blood pressure and triglyceride level . CONCLUSIONS A traditional lifestyle intervention using meal replacements can be effective for weight control and reduction in risk of chronic disease in the physician 's office setting as well as in the dietitian-led group setting Evidence suggests that a low-glycemic index ( LGI ) diet has a satiating effect and thus may enhance weight maintenance following weight loss . This study was conducted at Hammersmith Hospital , London , UK , and assessed the effect of altering diet GI on weight-loss maintenance . It consisted of a weight-loss phase and a 4-month r and omized weight maintenance phase . Subjects were seen monthly to assess dietary compliance and anthropometrics . Appetite was assessed bimonthly by visual analogue scales while meal challenge postpr and ial insulin and glucose concentrations were assessed before and after the intervention . Following a median weight loss of 6.1 ( interquartile range : 5.2 - 7.1 ) % body weight , subjects were r and omized to a high-glycemic index ( HGI ) ( n = 19 ) or LGI ( n = 23 ) diet . Dietary composition differed only in GI ( HGI group : 63.7 + /- 9.4 ; LGI group : 49.7 + /- 5.7 , P < 0.001 ) and glycemic load ( HGI group : 136.8 + /- 56.3 ; LGI group : 89.7 + /- 27.5 , P < 0.001 ) . Groups did not differ in body weight ( weight change over 4 months , HGI group : 0.3 + /- 1.9 kg ; LGI group : -0.7 + /- 2.9 kg , P = 0.3 ) or other anthropometric measurements . This pilot study suggests that in the setting of healthy eating , changing the diet GI does not appear to significantly affect weight maintenance Objectives : Soy protein intake has favorable effects on body weight and fat distribution in experimental animals but these effects have not been demonstrated in humans . To compare effects of soy- vs. milk-based meal replacements ( MR ) we assessed weight loss and serum lipoproteins changes for obese subjects who consumed low-energy diets ( LED ) including either milk-based or soy-based MR . Methods : Overweight or obese women and men ( body mass indices 27–40 kg/m2 ) were r and omly assigned to LED providing 1200 kcal/day , with consumption of five soy-based or two milk-based liquid MR for a 12-week weight loss trial . Serum lipoprotein measurements were obtained at baseline , 6 and 12 weeks . Results : For soy and milk MR groups , subject numbers were , respectively , 51 and 39 r and omized and 30 and 22 completers . MR use averaged : soy , 3.7/day ; and milk , 1.9/day . Weight losses for completers at 12 weeks were : soy MR , 9.0 % of initial body weight ( 95 % confidence intervals , 7.3–10.6 % ) ; and milk MR , 7.9 % ( 5.8–8.8 % ) with no significant differences . Reductions from baseline in serum cholesterol and LDL-cholesterol values , respectively , at six weeks were significantly greater ( P < 0.015 ) with soy MR ( 15.2 % and 17.4 % ) than with milk MR ( 7.9 % and 7.7 % ) . Soy MR use was associated with significant reductions in serum triglycerides at 6 and 12 weeks while milk MR use was not . Conclusions : Soy MR use , as part of a low-energy diet , was associated with slightly but not significantly greater weight loss over a 12-week period than milk MR use . These observations confirm previous studies documenting the effectiveness of MR use for weight loss BACKGROUND The incidence of type 2 diabetes increases markedly for obese children after puberty . However , the effect of dietary composition on body weight and diabetes risk factors has not been studied in adolescents . OBJECTIVE To compare the effects of an ad libitum , reduced-glycemic load ( GL ) diet with those of an energy-restricted , reduced-fat diet in obese adolescents . DESIGN R and omized control trial consisting of a 6-month intervention and a 6-month follow-up . MAIN OUTCOME MEASURES Body composition ( body mass index [ BMI ; calculated as weight in kilograms divided by the square of height in meters ] and fat mass ) and insulin resistance ( homeostasis model assessment ) were measured at 0 , 6 , and 12 months . Seven-day food diaries were used as a process measure . SUBJECTS Sixteen obese adolescents aged 13 to 21 years . Intervention Experimental ( reduced-GL ) treatment emphasized selection of foods characterized by a low to moderate glycemic index , with 45 % to 50 % of energy from carbohydrates and 30 % to 35 % from fat . In contrast , conventional ( reduced-fat ) treatment emphasized selection of low-fat products , with 55 % to 60 % of energy from carbohydrates and 25 % to 30 % from fat . RESULTS Fourteen subjects completed the study ( 7 per group ) . The GL decreased significantly in the experimental group , and dietary fat decreased significantly in the conventional group ( P<.05 for both ) . At 12 months , mean + /- SEM BMI ( -1.3 + /- 0.7 vs 0.7 + /- 0.5 ; P = .02 ) and fat mass ( -3.0 + /- 1.6 vs 1.8 + /- 1.0 kg ; P = .01 ) had decreased more in the experimental compared with the conventional group , differences that were material ly unchanged in an intention-to-treat model ( n = 16 ) ( BMI , P = .02 ; fat mass , P = .01 ) . Insulin resistance as measured by means of homeostasis model assessment increased less in the experimental group during the intervention period ( -0.4 + /- 0.9 vs 2.6 + /- 1.2 ; P = .02 ) . In post hoc analyses , GL was a significant predictor of treatment response among both groups ( R2 = 0.51 ; P = .006 ) , whereas dietary fat was not ( R2 = 0.14 ; P = .22 ) . CONCLUSIONS An ad libitum reduced-GL diet appears to be a promising alternative to a conventional diet in obese adolescents . Large-scale r and omized controlled trials are needed to further evaluate the effectiveness of reduced-GL and -glycemic index diets in the treatment of obesity and prevention of type 2 diabetes This report provides a further analysis of the first year weight losses in the Look AHEAD ( Action for Health in Diabetes ) study and identifies factors associated with success . Participants were a total of 5,145 men and women with type 2 diabetes who were recruited at 16 sites and r and omly assigned to an intensive lifestyle intervention ( ILI ) or a control condition , Diabetes Support and Education ( DSE ) . During year 1 , participants in ILI received comprehensive diet and physical activity counseling in a total of 42 group and individual sessions , compared with three educational sessions for DSE participants . As reported previously , at the end of the year , ILI participants lost 8.6 % of initial weight , compared to 0.7 % for DSE ( P < 0.001 ) . Within the ILI group , all racial/ethnic groups achieved clinical ly significant weight losses ( > 5.5 % ) , although there were significant differences among groups . For the year , ILI participants attended an average of 35.4 treatment sessions and reported exercising a mean of 136.6 min/week and consuming a total of 360.9 meal replacement products . Greater self-reported physical activity was the strongest correlate of weight loss , followed by treatment attendance and consumption of meal replacements . The use of orlistat , during the second half of the year , increased weight loss only marginally in those ILI participants who had lost < 5 % of initial weight during the first 6 months and chose to take the medication thereafter as a toolbox option . The lifestyle intervention was clinical ly effective in all subsets of an ethnically and demographically diverse population Aims /hypothesisThe aim of this study was to investigate the association of dietary macronutrient composition and energy density with the change in body weight and waist circumference and diabetes incidence in the Finnish Diabetes Prevention Study .Subjects and methods Overweight , middle-aged men ( n=172 ) and women ( n=350 ) with impaired glucose tolerance were r and omised to receive either ‘ st and ard care ’ ( control ) or intensive dietary and exercise counselling . Baseline and annual examinations included assessment of dietary intake with 3-day food records and diabetes status by repeated 75-g OGTTs . For these analyses the treatment groups were combined and only subjects with follow-up data ( n=500 ) were included . Results Individuals with low fat ( < median ) and high fibre ( > median ) intakes lost more weight compared with those consuming a high-fat ( > median ) , low-fibre ( < median ) diet ( 3.1 vs 0.7 kg after 3 years ) . In separate models , hazard ratios for diabetes incidence during a mean follow-up of 4.1 years were ( highest compared with lowest quartile ) 0.38 ( 95 % CI 0.19–0.77 ) for fibre intake , 2.14 ( 95 % CI 1.16–3.92 ) for fat intake , and 1.73 ( 95 % CI 0.89–3.38 ) for saturated-fat intake , after adjustment for sex , intervention assignment , weight and weight change , physical activity , baseline 2-h plasma glucose and intake of the nutrient being investigated . Compared with the low-fat/high-fibre category , hazard ratios were 1.98 ( 95 % CI 0.98–4.02 ) , 2.68 ( 95 % CI 1.40–5.10 ) , and 1.89 ( 95 % CI 1.09–3.30 ) for low-fat/low-fibre , high-fat/high-fibre , and high-fat/low-fibre , respectively . Conclusions /interpretationDietary fat and fibre intake are significant predictors of sustained weight reduction and progression to type 2 diabetes in high-risk subjects , even after adjustment for other risk factors HYPOTHESIS Modest , preoperative weight loss will improve perioperative outcomes among high-risk , morbidly obese patients undergoing Roux-en-Y gastric bypass . DESIGN A prospect i ve , longitudinal assessment of characteristics and outcomes of gastric bypass patients . SETTING All patients undergoing open or laparoscopic Roux-en-Y gastric bypass surgery for morbid obesity or its comorbid medical problems at Geisinger Medical Center in Danville , Pennsylvania , during a 3-year period from May 31 , 2002 , to February 24 , 2006 , were included in this analysis . Patients were required to participate in a st and ardized multidisciplinary preoperative program that encompasses medical , psychological , nutritional , and surgical interventions and education . In addition , patients were encouraged to achieve a 10 % loss of excess body weight prior to surgical intervention . RESULTS Of the 884 subjects , 425 ( 48 % ) lost more than 10 % of their excess body weight prior to the operation . After surgery ( mean follow-up , 12 months ) , this group was more likely to achieve 70 % loss of excess body weight ( P < .001 ) . Those who lost more than 5 % of excess body weight prior to surgery were statistically less likely to have a length of stay of greater than 4 days ( P = .03 ) . CONCLUSIONS This study shows that high-risk morbidly obese c and i date s for bariatric surgery who are able to achieve a loss of 5 % to 10 % excess body weight prior to surgery have a higher probability of a shorter length of hospital stay and more rapid postoperative weight loss OBJECTIVE To compare the effects of an energy reduced very low carbohydrate , high saturated fat diet ( LC ) and an isocaloric high carbohydrate , low fat diet ( LF ) on endothelial function after 12 months . DESIGN AND SUBJECTS Forty-nine overweight or obese patients ( age 50.0 + /- 1.1 years , BMI 33.7 + /- 0.6 kg m(-2 ) ) were r and omized to either an energy restricted ( approximately 6 - 7 MJ ) , planned isocaloric LC or LF for 52 weeks . Body weight , endothelium-derived factors , flow-mediated dilatation ( FMD ) , adiponectin , augmentation index ( AIx ) and pulse wave velocity ( PWV ) were assessed . All data are mean + /- SEM . RESULTS Weight loss was similar in both groups ( LC -14.9 + /- 2.1 kg , LF -11.5 + /- 1.5 kg ; P = 0.20 ) . There was a significant time x diet effect for FMD ( P = 0.045 ) ; FMD decreased in LC ( 5.7 + /- 0.7 % to 3.7 + /- 0.5 % ) but remained unchanged in LF ( 5.9 + /- 0.5 % to 5.5 + /- 0.7 % ) . PWV improved in both groups ( LC -1.4 + /- 0.6 m s(-1 ) , LF -1.5 + /- 0.6 m s(-1 ) ; P = 0.001 for time ) with no diet effect ( P = 0.80 ) . AIx and VCAM-1 did not change in either group . Adiponectin , eSelectin , tPA and PAI-1 improved similarly in both groups ( P < 0.01 for time ) . CONCLUSION Both LC and LF hypoenergetic diets achieved similar reductions in body weight and were associated with improvements in PWV and a number of endothelium-derived factors . However , the LC diet impaired FMD suggesting chronic consumption of a LC diet may have detrimental effects on endothelial function OBJECTIVE Providing overweight patients with the food they should eat has been shown to significantly improve weight loss in a behavioral treatment program . The objective of this study was to examine the contribution of three components of food provision to these positive effects : the specific meal plans indicating what foods should be eaten at each meal ; the food itself ; and the fact that the food was provided free . SUBJECTS 163 overweight women . DESIGN R and omized , controlled study with subjects assigned to one of four conditions : ( 1 ) a st and ard behavioral treatment program ( SBT ) with weekly meetings for six months ; ( 2 ) SBT plus structured meal plans and grocery lists ; ( 3 ) SBT plus meal plans plus food provision , with subjects sharing the cost ; or ( 4 ) SBT plus meal plans plus free food provision . RESULTS Subjects in Group 1 lost significantly less weight than subjects in Groups 2 - 4 at the end of the six month program ( -8.0 kg vs -12.0 , -11.7 and -11.4 kg respectively ) and at follow-up one year later ( -3.3 kg vs -6.9 , -7.5 and -6.6 kg respectively ) . No significant differences were seen in weight loss between Groups 2 - 4 , suggesting that the component of food provision that is responsible for its success is the provision of highly structured meal plans and grocery lists . Subjects receiving meal plans were more likely to exhibit an eating pattern of three meals/day , had more definite plans regarding what to eat and reported more favorable changes in foods stored in their homes and in perceived barriers to weight loss . CONCLUSIONS Providing structured meal plans and grocery lists improves outcome in a behavioral weight control program ; no further benefit is seen by actually giving food to patients OBJECTIVE To evaluate the efficacy and safety of a carbohydrate restricted versus a low fat diet on weight loss , metabolic markers , body composition , and cardiac function tests in severely obese adolescents . STUDY DESIGN Subjects were r and omly assigned to 1 of 2 diets : a high protein , low carbohydrate ( 20 g/d ) diet ( high protein , low carbohydrate , HPLC ) or low fat ( 30 % of calories ) regimen for 13 weeks ; close monitoring was maintained to evaluate safety . After the intervention , no clinical contact was made until follow-up measurements were obtained at 24 and 36 weeks from baseline . The primary outcome was change in body mass index Z-score for age and sex ( BMI -Z ) at 13 , 24 , and 36 weeks . RESULTS Forty-six subjects ( 24 HPLC , 22 in low fat ) initiated and 33 subjects completed the intervention ; follow-up data were available on approximately half of the subjects . Significant reduction in ( BMI -Z ) was achieved in both groups during intervention and was significantly greater for the HPLC group ( P = .03 ) . Both groups maintained significant BMI -Z reduction at follow-up ; changes were not significantly different between groups . Loss of lean body mass was not spared in the HPLC group . No serious adverse effects were observed related to metabolic profiles , cardiac function , or subjective complaints . CONCLUSIONS The HPLC diet is a safe and effective option for medically supervised weight loss in severely obese adolescents Objective : To assess the efficacy and safety of a low calorie soy-based meal replacement program for the treatment of obesity . Design : A 12-week prospect i ve r and omized controlled clinical trial . Setting : Outpatient weight control research unit . Subjects : One hundred obese ( 28 < BMI ≤41 kg/m2 ) volunteers between the ages of 35 and 65 y. Seventy-four participants completed the trial . Interventions : Participants were r and omized to either the meal replacement treatment group ( n=50 ; 240 g/day , 1200 kcal/day ) or control group ( n=50 ) . Both groups at baseline received a single dietary counseling session and a pamphlet describing weight loss practice s . Main outcome measures : Weight , body fat , serum lipid concentrations . Results : By intent-to-treat analysis , the treatment group lost significantly more weight than the control group ( 7.00 vs 2.90 kg ; P<0.001 ) and had a greater change in total ( 22.5 vs 6.8 mg/dl ; P=0.013 ) and LDL cholesterol ( 21.2 vs 7.1 mg/dl ; P<0.009 ) . Among completers only , the treatment group again lost more weight ( 7.1 kg ; n=37 vs 2.9 kg ; n=37 ; P=0.0001 ) and had a greater reduction in total cholesterol ( 26.1 mg/dl ; n=37 vs 6.7 mg/dl ; P=0.0012 ) and a greater change in LDL cholesterol ( 21.6 vs 5.5 mg/dl ; P=0.0025 ) . ( For any given degree of weight loss , the reduction in LDL cholesterol was significantly greater in the treatment group . ) Treatment was well tolerated and no serious side effects were detected . Conclusions : Use of this soy-based meal replacement formula was effective in lowering body weight , fat mass and in reducing LDL cholesterol beyond what could be expected given the weight lost . Sponsorship : This research was funded by Nutripharma . Dr Allison is a member of the United Soybean Board 's Scientific Advisory Panel and Chair of the Research Grants Committee OBJECTIVE Weight loss and consumption of viscous fibers both lower low-density lipoprotein ( LDL ) cholesterol levels . We evaluated whether or not a whole-grain , ready-to-eat ( RTE ) oat cereal containing viscous fiber , as part of a dietary program for weight loss , lowers LDL cholesterol levels and improves other cardiovascular disease risk markers more than a dietary program alone . DESIGN R and omized , parallel-arm , controlled trial . SUBJECTS/ SETTING Free-living , overweight and obese adults ( N=204 , body mass index 25 to 45 ) with baseline LDL cholesterol levels 130 to 200 mg/dL ( 3.4 to 5.2 mmol/L ) were r and omized ; 144 were included in the main analysis of participants who completed the trial without significant protocol violations . INTERVENTION Two portions per day of whole-grain RTE oat cereal ( 3 g/day oat b-glucan ) or energy-matched low-fiber foods ( control ) , as part of a reduced energy ( approximately 500 kcal/day deficit ) dietary program that encouraged limiting consumption of foods high in energy and fat , portion control , and regular physical activity . MAIN OUTCOME MEASURES Fasting lipoprotein levels , waist circumference , triceps skinfold thickness , and body weight were measured at baseline and weeks 4 , 8 , 10 , and 12 . RESULTS LDL cholesterol level was reduced significantly more with whole-grain RTE oat cereal vs control ( -8.7+/-1.0 vs -4.3+/-1.1 % , P=0.005 ) . Total cholesterol ( -5.4+/-0.8 vs -2.9+/-0.9 % , P=0.038 ) and non-high-density lipoprotein-cholesterol ( -6.3+/-1.0 vs -3.3+/-1.1 % , P=0.046 ) were also lowered significantly more with whole-grain RTE oat cereal , whereas high-density lipoprotein and triglyceride responses did not differ between groups . Weight loss was not different between groups ( -2.2+/-0.3 vs -1.7+/-0.3 kg , P=0.325 ) , but waist circumference decreased more ( -3.3+/-0.4 vs -1.9+/-0.4 cm , P=0.012 ) with whole-grain RTE oat cereal . Larger reductions in LDL , total , and non-high-density lipoprotein cholesterol levels and waist circumference were evident as early as week 4 in the whole-grain RTE oat cereal group . CONCLUSIONS Consumption of a whole-grain RTE oat cereal as part of a dietary program for weight loss had favorable effects on fasting lipid levels and waist circumference Background Safe and effective weight control strategies are needed to stem the current obesity epidemic . The objective of this one-year study was to document and compare the macronutrient and micronutrient levels in the foods chosen by women following two different weight reduction interventions . Methods Ninety-six generally healthy overweight or obese women ( ages 25–50 years ; BMI 25–35 kg/m2 ) were r and omized into a Traditional Food group ( TFG ) or a Meal Replacement Group ( MRG ) incorporating 1–2 meal replacement drinks or bars per day . Both groups had an energy-restricted goal of 5400 kJ/day . Dietary intake data was obtained using 3-Day Food records kept by the subjects at baseline , 6 months and one-year . For more uniform comparisons between groups , each diet intervention consisted of 18 small group sessions led by the same Registered Dietitian . Results Weight loss for the 73 % ( n = 70 ) completing this one-year study was not significantly different between the groups , but was significantly different ( p ≤ .05 ) within each group with a mean ( ± st and ard deviation ) weight loss of -6.1 ± 6.7 kg ( TFG , n = 35 ) vs -5.0 ± 4.9 kg ( MRG , n = 35 ) . Both groups had macronutrient ( Carbohydrate : Protein : Fat ) ratios that were within the ranges recommended ( 50:19:31 , TFG vs 55:16:29 , MRG ) . Their reported reduced energy intake was similar ( 5729 ± 1424 kJ , TFG vs 5993 ± 2016 kJ , MRG ) . There was an improved dietary intake pattern in both groups as indicated by decreased intake of saturated fat ( ≤ 10 % ) , cholesterol ( < 200 mg/day ) , and sodium ( < 2400 mg/day ) , with increased total servings/day of fruits and vegetables ( 4.0 ± 2.2 , TFG vs 4.6 ± 3.2 , MRG ) . However , the TFG had a significantly lower dietary intake of several vitamins and minerals compared to the MRG and was at greater risk for inadequate intake . Conclusion In this one-year university-based intervention , both dietitian-led groups successfully lost weight while improving overall dietary adequacy . The group incorporating fortified meal replacements tended to have a more adequate essential nutrient intake compared to the group following a more traditional food group diet . This study supports the need to incorporate fortified foods and /or dietary supplements while following an energy-restricted diet for weight loss PURPOSE The purpose of this study is to compare the efficacy of a portion-controlled meal replacement diet ( PCD ) to a st and ard diet ( SD ) based on recommendations by the American Diabetes Association in achieving and maintaining weight loss among obese participants with type 2 diabetes . METHODS This study is a university-based , controlled clinical trial . Participants were 119 men and women with diabetes with a body mass index between 25 and 40 kg/m(2 ) , assigned r and omly to one of two 34-week , 75 % of predicted energy need diets ( portion controlled or st and ard , self-selected , food based ) and then followed by 1-year maintenance . RESULTS Using intention-to-treat analyses , weight loss at 34 weeks and weight maintenance at 86 weeks was significantly better on PCD versus SD . Approximately 40 % of the PCD participants lost > or = 5 % of their initial weight compared with 12 % of those on the SD . Significant improvements in biochemical and metabolic measures were observed at 34 weeks in both groups . The retention rate and self-reported ease of adherence in the PCD group were significantly higher throughout the study . CONCLUSIONS A diet using portion-controlled meal replacements yielded significantly greater initial weight loss and less regain after 1 year of maintenance than a st and ard , self-selected , food-based diet . As PCDs may help obese patients with type 2 diabetes adhere to a weight control program , diabetes educators may consider recommending them as part of a comprehensive approach to weight control BACKGROUND Data on the long-term association between low-carbohydrate diets and mortality are sparse . OBJECTIVE To examine the association of low-carbohydrate diets with mortality during 26 years of follow-up in women and 20 years in men . DESIGN Prospect i ve cohort study of women and men who were followed from 1980 ( women ) or 1986 ( men ) until 2006 . Low-carbohydrate diets , either animal-based ( emphasizing animal sources of fat and protein ) or vegetable-based ( emphasizing vegetable sources of fat and protein ) , were computed from several vali date d food-frequency question naires assessed during follow-up . SETTING Nurses ' Health Study and Health Professionals ' Follow-up Study . PARTICIPANTS 85 168 women ( aged 34 to 59 years at baseline ) and 44 548 men ( aged 40 to 75 years at baseline ) without heart disease , cancer , or diabetes . MEASUREMENTS Investigators documented 12 555 deaths ( 2458 cardiovascular-related and 5780 cancer-related ) in women and 8678 deaths ( 2746 cardiovascular-related and 2960 cancer-related ) in men . RESULTS The overall low-carbohydrate score was associated with a modest increase in overall mortality in a pooled analysis ( hazard ratio [ HR ] comparing extreme deciles , 1.12 [ 95 % CI , 1.01 to 1.24 ] ; P for trend = 0.136 ) . The animal low-carbohydrate score was associated with higher all-cause mortality ( pooled HR comparing extreme deciles , 1.23 [ CI , 1.11 to 1.37 ] ; P for trend = 0.051 ) , cardiovascular mortality ( corresponding HR , 1.14 [ CI , 1.01 to 1.29 ] ; P for trend = 0.029 ) , and cancer mortality ( corresponding HR , 1.28 [ CI , 1.02 to 1.60 ] ; P for trend = 0.089 ) . In contrast , a higher vegetable low-carbohydrate score was associated with lower all-cause mortality ( HR , 0.80 [ CI , 0.75 to 0.85 ] ; P for trend < /= 0.001 ) and cardiovascular mortality ( HR , 0.77 [ CI , 0.68 to 0.87 ] ; P for trend < 0.001 ) . LIMITATIONS Diet and lifestyle characteristics were assessed with some degree of error . Sensitivity analyses indicated that results were probably not substantively affected by residual confounding or an unmeasured confounder . Participants were not a representative sample of the U.S. population . CONCLUSION A low-carbohydrate diet based on animal sources was associated with higher all-cause mortality in both men and women , whereas a vegetable-based low-carbohydrate diet was associated with lower all-cause and cardiovascular disease mortality rates . PRIMARY FUNDING SOURCE National Institutes of Health |
13,692 | 14,974,005 | REVIEW ER 'S CONCLUSIONS There is evidence that occupational therapy has a positive effect on functional ability in patients with rheumatoid arthritis | BACKGROUND For persons with rheumatoid arthritis ( RA ) the physical , personal , familial , social and vocational consequences are extensive .
Occupational therapy ( OT ) , with the aim to facilitate task performance and to decrease the consequences of rheumatoid arthritis for daily life activities , is considered to be a cornerstone in the management of rheumatoid arthritis .
Till now the efficacy of occupational therapy for patients with rheumatoid arthritis on functional performance and social participation has not been systematic ally review ed .
OBJECTIVES To determine whether OT interventions ( classified as comprehensive therapy , training of motor function , training of skills , instruction on joint protection and energy conservation , counseling , instruction about assistive devices and provision of splints ) for rheumatoid arthritis patients improve outcome on functional ability , social participation and /or health related quality of life . | One hundred and thirty-two patients discharged from a rheumatology unit were r and omly allocated to general practitioner care , attendance at hospital outpatient clinics , or follow-up by a senior occupational therapist attached to the hospital treatment team . At the end of 1 and 2 years a number of clinical and functional tests were applied , and information was gathered about the provision and use of aids and the provision of domestic support . In addition the st and ard of overall care was judged by an independent assessor . Although no significant intergroup differences in disease activity or function emerged , it is clear that patients prefer continuing contact with the hospital team , and this may lead to differences appearing in the future . The financial advantages of therapist follow-up are discussed A h and exerciser with an electronic counter and a visual display was used to measure compliance objective ly , to investigate the effects of visual feedback on compliance , and to assess the impact of exercise on seven mild and five moderate rheumatoid arthritis patients . A multiple time-series design varying the onset of the visual display was utilized . Compliance was assessed weekly over the 7 weeks of the study . Pretest and posttest measures of various indicators of h and functioning were taken by an occupational therapist . Visual display of the number of exercises completed decreased the number of noncompliant patients from six to two , with the maximum degree of noncompliance reduced from 44 to 5 % . Thus the use of visual display is effective in producing compliance to exercise regimens . In light of the small sample size , however , no definitive conclusions can be drawn regarding the effects of exercise on h and functioning OBJECTIVE To investigate the immediate and short-term effects of 3 commercial wrist orthoses on grip strength and function . METHODS Thirty-six patients with definite rheumatoid arthritis participated in the r and omized , controlled , cross-over design study of 3 commercial wrist extensor orthoses . Dominant-h and dynamometric grip strength was assessed at both initial and followup sessions while splinted and nonsplinted . Functional impact was assessed using a written question naire . RESULTS All 3 commercial orthoses reduced grip strength when first donned . After a 1-week adjustment period , one orthosis , the Smith and Nephew Roylan D-Ring ( Roylan ) , afforded splinted grip strength equal to that of the nonsplinted grip strength . The other 2 orthoses continued to reduce grip strength , and afforded splinted grip strength significantly below that of the Roylan . The Roylan was deemed comfortable by more subjects than the other orthoses . CONCLUSIONS The belief that commercial orthotic use increases grip strength , either immediately or after 1 week , is not supported by this study 's data . Different styles of commercial wrist orthoses appear to have differing influence on splinted grip strength OBJECTIVES This study compared soft versus hard resting h and splints on pain and h and function in 39 persons with rheumatoid arthritis . Splint preference was also evaluated to determine its effects on splint wear compliance . METHOD A repeated measures research design was used to compare the two experimental conditions , wearing a soft splint versus a hard splint on the dominant h and for 28 days at night only , and an unsplinted control period of 28 days . RESULTS Arthritis pain was considerably less during both splinted periods when compared with the pretest . Subjects identified fewer joints as being painful during the soft splint condition than during the unsplinted condition . There were no significant differences among conditions on h and function measures . Splint preference was 57 % for the soft splint , 33 % for the hard splint , and 10 % for no splint . Splint wear compliance was significantly better with the soft splint ( 82 % ) than with the hard splint ( 67 % ) . CONCLUSION The findings indicate that resting h and splints are effective for pain relief and that persons with rheumatoid arthritis are more likely to prefer and comply with soft splint use for this purpose . Individualized splint prescription that focuses on client comfort and preference may enhance splint wear compliance Objective : To evaluate the long-term effects of joint protection on health status of people with early rheumatoid arthritis ( RA ) . Design : A four-year follow-up of a r and omized , controlled , assessor-blinded trial was conducted . Setting : Two rheumatology outpatient departments . Participants : People with rheumatoid arthritis less than five years since diagnosis . Interventions : Two 8-hour interventions were originally compared : a st and ard arthritis education programme , including 21/2 hours of joint protection based on typical UK occupational therapy practice ( plus 51/2 hours on RA , exercise , pain management , diet and foot care ) ; and a joint protection programme , using educational-behavioural training . Main measures : Adherence to joint protection , pain , h and pain on activity , Arthritis Impact Measurement Scales 2 and Arthritis Self-efficacy were recorded at 0 and 4 years . Results : Sixty-five people attended the joint protection and 62 the st and ard programmes . Groups at entry were similar in age ( 51 years ; 49 years ) , disease duration ( 21 months : 17.5 months ) and use of nonsteroidal anti-inflammatory and disease-modifying drugs . At four years , the joint protection group continued to have significantly better : joint protection adherence ( p=0.001 ) ; early morning stiffness ( p=0.01 ) ; AIMS 2 activities of daily living ( ADL ) scores ( p=0.04 ) compared with the st and ard group . The joint protection group also had significantly fewer h and deformities : metacarpophalangeal ( MCP ) ( p=0.02 ) and wrist joints ( p=0.04 ) . Conclusion : Attending an educational = behavioural joint protection programme significantly improves joint protection adherence and maintains functional ability long term . This approach is more effective than st and ard methods of training and should be more widely adopted OBJECTIVE Five styles of commercial static wrist extensor orthoses were compared to determine whether any style , or styles , afforded better power grip strength or finger dexterity . Because wrist extensor orthoses are intended for use during functional tasks , their influence on h and function is of great importance . METHOD Twenty-three right-h and -dominant women without upper extremity dysfunction participated in this crossover study . Dominant-h and finger dexterity and power grip strength were evaluated while wearing each of five commercial orthoses-Kendall-Futuro # 33 ( Futuro ) , AliMed Freedom Long ( AliMed Long ) , AliMed Freedom Short ( AliMed Short ) , Smith & Nephew Rolyan D-Ring ( Rolyan ) , and LMB Wrist Rest (LMB)-- and while using the dominant h and without an orthosis ( free h and ) . Finger dexterity was assessed with the unimanual subtest of the Purdue Pegboard . Grip strength was assessed with a Jamar hydraulic dynamometer . RESULTS Four of the study orthoses ( Futuro , AliMed Short , Rolyan , and LMB ) afforded finger dexterity that did not differ significantly from that of the free h and . The AliMed Long orthosis slowed finger speed when compared with the speeds afforded by both the LMB orthosis and the free h and . The Rolyan orthosis permitted a power grip strength that was not significantly different from the free h and . The other four commercial orthoses reduced grip strength when compared with the strength observed when wearing a Rolyan orthosis and when gripping with a free h and . CONCLUSION The five styles of commercial orthoses affect power grip and finger dexterity differently . When power grip or finger dexterity are priorities , differences among the orthoses furnish grounds for initial suggestions , although medical needs and patient preference should be the overriding factors in the final selection of an orthosis Summary Seven patients with definite RA and bilateral ulnar deviation of Fearnley grade I were included in a study of the usefulness of noctural resting splints . Each patient used the splint on average 17 months on one h and , r and omly chosen , with the free h and as control . Joint mobility , grip strength , pain and radiographic findings were recorded at start and finish of the study . Splint treatment influenced grip strength positively , and most patients stated pain relief during the night . However , all but one patient showed progression of ulnar deviation in both h and s , and there was no significant difference in progression between treated and nontreated h and s. This study thus supported the use of resting splints at night for pain relief but not for prevention of ulnar deviation Consecutive new attendees at a rheumatology clinic were r and omly allocated to one of three groups . All groups received routine care , but one received no other intervention , one an educational booklet on arthritis and one the booklet plus instruction from a health professional . Prior to intervention , all groups had similar knowledge . Nottingham Health Profile ( NHP ) and Health Assessment Question naire ( HAQ ) score . After 6 weeks , the knowledge score was significantly increased in both groups given the booklet , but not in the control group . The group instructed by a health professional showed no greater increase than the group given the booklet alone . Increased knowledge was not associated with improved clinical status and no group showed a significant change in NHP or HAQ scores . Nearly all patients said they found the booklet useful The effect of active h and exercise and warm wax treatment was evaluated in 52 rheumatoid arthritis patients r and omized into four groups : ( 1 ) both exercise and wax bath , ( 2 ) exercise only , ( 3 ) wax bath only , and ( 4 ) controls . Treatment was given three times a week for 4 weeks . Deficits in flexion and extension in digits II-V bilaterally , grip function , grip strength , pain , and stiffness were measured before and after the treatment period . The control group was measured at corresponding times . Wax bath treatment followed by active h and exercise result ed in significant improvements of range of motion ( ROM ) and grip function . Active h and exercise alone reduced stiffness and pain with nonresisted motion and increased ROM . Wax bath alone had no significant effect OBJECTIVE To study differing home h and exercise interventions to determine effects on grip strength , and secondarily any immediate or short term effects on range of motion , pain , deformities , h and disease activity , and dexterity . METHODS R and omized controlled trial of 12 weeks of home h and exercise performed for 10 - 20 min twice daily . Study exercise interventions were range of motion exercises , balanced resistive exercises , and range of motion plus balanced resistive exercises . RESULTS Aside from transient , mild to moderate discomfort , exercises were well tolerated . Range of motion exercises were associated with improved right h and joint count . Range of motion plus balanced resistive exercises were associated with increased left h and dexterity . Home h and exercise ( exercise groups combined ) significantly increased left grip strength . CONCLUSIONS Temporary use of home h and exercise has acceptable side effects and is an effective means of increasing grip strength Preliminary work regarding the development and pilot study of an individualized instructional program for rheumatoid arthritis clients is presented . The effect of the individualized instructional program was tested with 31 out patients . Using analysis of covariance , the experimental group subjects scored significantly higher on the knowledge post-test when compared to scores of control group subjects ( P = 0.0045 ) . Analysis of variance for repeated measures revealed no significant difference in performance of tasks for the control group and experimental group ( P = 0.08 ) . In a follow-up study , the effect of the self-instructional program , practice time , and contracting were explored for their effect on adherence to self-care activities . Experimental groups ( n = 42 ) scored significantly better than the control group ( n = 11 ) on the knowledge post-test ( P < 0.01 ) , performance of joint protection practice s ( P = 0.01 ) , range of motion exercises ( P = 0.01 ) , and adherence to joint protection practice s at home ( P < 0.01 ) . Groups did not differ on adherence to range of motion exercises at home ( P = 0.83 ) Most systematic review s rely substantially on the assessment of the method ological quality of the individual trials . The aim of this study was to obtain consensus among experts about a set of generic core items for quality assessment of r and omized clinical trials ( RCTs ) . The invited participants were experts in the field of quality assessment of RCTs . The initial item pool contained all items from existing criteria lists . Subsequently , we reduced the number of items by using the Delphi consensus technique . Each Delphi round comprised a question naire , an analysis , and a feedback report . The feedback report included staff team decisions made on the basis of the analysis and their justification . A total of 33 international experts agreed to participate , of whom 21 completed all question naires . The initial item pool of 206 items was reduced to 9 items in three Delphi rounds . The final criteria list ( the Delphi list ) was satisfactory to all participants . It is a starting point on the way to a minimum reference st and ard for RCTs on many different research topics . This list is not intended to replace , but rather to be used alongside , existing criteria lists In order to examine the effectiveness of cognitive behavioral therapy for patients with rheumatoid arthritis ( RA ) three patients groups were studied : a cognitive behavioral therapy group ( CBT ) , an occupational therapy group ( OT ) , and a waiting-list control group . The CBT received a comprehensive , 10-session treatment package that taught progressive relaxation , rational thinking and the differential use of pain coping strategies . CBT result ed in minor changes in pain coping behavior at posttreatment , while CBT and OT showed an increase of knowledge of RA . No therapeutic effects with regard to health status were demonstrated at posttreatment and at 6 months follow-up . Clinical and laboratory measures of disease activity revealed progressive deterioration of the patients during the course of the study . It is suggested that the ineffectiveness of CBT might be due to the progressive course of RA in the patients studied , as well as to the rather small changes in coping behavior We report a prospect i ve , r and omized pilot study comparing a new workbook-based program , design ed to teach patients with rheumatoid arthritis ( RA ) energy conservation behaviors , with st and ard occupational therapy ( OT ) . Sixteen patients took part in the new program and nine received the st and ard therapy . Data on the number of tender or swollen joints , grip strength , walk time , activities of daily living , psychologic adjustment to illness , and daily activity log , were measured before and three months after intervention . Eleven percent of those who received st and ard therapy and 50 % of those who received the workbook increased their amount of physically active time ( p = .10 ) . Twenty-two percent of the control group and 50 % of those in the workbook group achieved a better balance of rest and physical activity ( p = .07 ) . We conclude that the adoption of energy conservation behaviors is different in the two groups . This initial study suggests that interrupting physical activity with rest periods may result in increased physical activity in patients with RA OBJECTIVE To examine the efficacy of wrist orthoses on pain , motion , and function of the wrist . METHODS Consecutive patients were r and omized to a treatment group using wrist orthoses or to a control group using no wrist orthoses , in a prospect i ve , controlled , 6-month study . RESULTS Changes in wrist joint variables and general disease activity variables were not statistically different between the orthosis group ( n = 36 ) and the control group ( n = 33 ) . Patients in the orthosis group had 25 % and 12 % improvements in grip strength and pinch grip and 50 % reduction in pain while using the wrist orthosis . CONCLUSION Use of wrist orthoses improves function and reduces pain , but has no effects after 6 months , compared to a control group , on measures of local or general disease activity Forty-four female patients with sero-positive active RA participated in a 48-month trial to assess the effect of simple h and exercises . Twenty-two patients in the test group were given a daily exercise regime of six exercises . The control group were not given any exercises . At the end of 48 months there was a statistically significant improvement in grip strength ( P < 0.0001 ) and pincer grip strength ( P < 0.0005 ) in the test group . There was a significant deterioration in the control group ( P < 0.0000 ) . A simple exercise programme is beneficial for the rheumatoid h and as far as grip and pincer grip strength are concerned OBJECTIVE To compare the short-term utility and clinical effectiveness of the commercial-made Futuro wrist orthosis with a newly developed , custom-made ThermoLyn wrist orthosis . METHODS Using a r and omized cross-over trial , 10 patients with rheumatoid arthritis used each of the two orthoses for two weeks . Outcome measures were patients ' judgments with respect to different statements about utility and clinical assessment s including pain and swelling of the wrist and finger joints , range of motion of the wrist , and grip strength . At the end of the study the patients were asked which of the two orthoses they preferred and why . RESULTS Patients tended to favor the Futuro wrist orthosis with respect to pain relief and to h and ling the orthosis . The visual analog scale score of the appearance of the ThermoLyn wrist orthosis was a little higher than that of the Futuro wrist orthosis , but the difference was not statistically significant . Clinical parameters such as pain in the wrist , swelling of the wrist and finger joints , and movements of the wrist showed that the Futuro orthosis tended to be more effective than the ThermoLyn orthosis . None of the differences reached statistical significance . At the end of the study , 5 patients preferred the Futuro and 5 patients the ThermoLyn wrist orthosis . Arguments in favor of the ThermoLyn orthosis were better hygiene , stability , and no need to remove the orthosis during dirty and wet conditions . Arguments in favor of the Futuro orthosis were greater suppleness and freedom of movement . CONCLUSIONS The ready-made fabric Futuro wrist orthosis appears to be as good as the more expensive individually made synthetic ThermoLyn wrist orthosis with respect to short-term utility and clinical effectiveness . The conditions under which the orthosis will be worn will help to decide which orthosis is the best for the patient . In the event that the patient wants to use the orthosis in wet and dirty conditions , the ThermoLyn wrist orthosis is a good alternative to the Futuro wrist orthosis OBJECTIVE To determine the effect of a wrist orthosis on work performance , h and dexterity , and pain during task performance , 40 individuals with rheumatoid arthritis were studied using a 2 period , crossover design . METHODS Each patient was fitted with a Futuro wrist orthosis . Dexterity was measured with and without the orthosis using the Jebsen H and Function Test . Work performance was assessed using 2 tasks ( one simulating the use of shears , the other the use of a screwdriver ) on a work simulator . All tasks were performed both with and without the orthosis , with the order of orthosis versus no orthosis r and omly assigned . Pain before and after performing tasks was assessed using a 10 cm horizontal visual analog scale . RESULTS While on the screwdriver task work performance was less with the orthosis ( p = 0.0002 ) ; on the shears task there was no significant difference in work performance with and without the orthosis . The average pain after performing both tasks was significantly less with the orthosis on . A 2 factor analysis of variance model with repeated measures suggested that taking into account the reduced work performance during splint wear , pain was still significantly reduced with splint wear . The average time to complete all 7 tasks on the Jebsen H and Function Test was longer when the subjects wore the splint compared to when they did not ( 62.0 vs 57.6 s , respectively ; p = 0.0086 ) . CONCLUSION The results suggest that the effect of splint wear on work performance is highly task specific , and thus the ergonomic dem and s of the individual 's daily life must be considered if a splint is to provide maximal effectiveness This study examined the efficacy of an exercise and relaxation program for adults with rheumatoid arthritis . The program integrates principles of occupational therapy and T'ai-Chi Ch'uan and was expected to be more effective than traditional exercise and rest regimens because of its expressive and pleasurable elements . There were significant differences between 17 experimental and 16 control subjects on two categories of dependent variables after the former group 's participation in the experimental program . These dependent variables were range of motion measures and subject self-reports of frequency , enjoyment , and benefits of home exercise and rest routines . Pretest , posttest , and 4-month follow-up data were analyzed . Program participants showed significantly greater upper extremity range of motion 4 months after completing the program although the reported frequency of exercise and rest was greater in the control group . Postprogram reports of enjoyment were significantly higher for experimental than for control subjects . If these initial results are confirmed in further studies , the efficacy of the use of purpose ful activity for exercise and rest will be supported . This study also supports the integration of Eastern and Western frames of reference in the treatment of patients with chronic illness This paper presents the design and evaluation of an occupational therapy program developed at the National Institutes of Health for teaching energy conservation and joint protection to adults with rheumatoid arthritis . An existing model for educational diagnosis in health education was used to identify program , behavioral , and educational objectives for the new program . The use of this model result ed in measurable objectives , which were used as outcome measures in the r and omized research evaluation of the new program . The dependent variables measured were activity-of-daily-living status , psychosocial adjustment to illness , knowledge , disease activity , pain , and fatigue . None were significantly different after the intervention . The independent variables measured included components of balancing rest and physical activity . After 3 months , a greater percentage of the subjects receiving the workbook-based occupational therapy program than those receiving traditional occupational therapy demonstrated an application of the behaviors the intervention was design ed to change Because there is little information about the efficacy of home occupational therapy , we decided to assess the effects of a home service on patients with rheumatoid arthritis . 105 patients aged 18 - 70 years , on stable medical therapy , were r and omised to receive a 6-week comprehensive programme of occupational therapy ( experimental group , 53 patients ) or to receive no such treatment ( control group , 52 ) . At 6 weeks , control patients received the experimental regimen , and experimental patients were continued on treatment as needed up to 12 weeks . Outcomes were measured at baseline , 6 , and 12 weeks with a global functional capacity score ( functional score ) . At 6 weeks the functional score for the experimental group was significantly higher than that for the control group ( mean difference = 8.1 , 95 % Cl 1.7 to 15.8 , p = 0.012 ) . Control patients at 12 weeks showed a similar improvement to experimental patients at 6 weeks , and between 6 and 12 weeks the experimental patients were stable . Occupational therapy leads to a statistically significant and clinical ly important improvement in function in patients with rheumatoid arthritis OBJECTIVE To investigate the effect of 3 commercial wrist orthoses on finger dexterity and h and function of patients with rheumatoid arthritis ( RA ) . METHODS Forty-two patients with definite RA participated in the cross-over study comparing 3 styles of commercial wrist orthoses . Finger dexterity and h and function of the dominant h and were assessed while splinted and unsplinted , at the initial session and after 1 week of intermittent orthosis use . Finger dexterity was assessed using two subtests from the Purdue Pegboard Test ( Purdue ) and h and function was assessed using the Jebsen-Taylor H and Function Test ( Jebsen-Taylor ) . RESULTS Both finger dexterity and h and function were reduced by splinting ; men and women were affected similarly . There was no difference in finger dexterity or h and function afforded by the 3 orthoses . Results on both the Purdue and Jebsen-Taylor tests showed a significant learning effect across time . CONCLUSIONS The 3 commercial wrist orthoses studied reduce dexterity similarly and significantly . When commercial wrist orthoses are to be used during tasks that require maximum dexterity , this reduction should be weighed against the known benefits of splinting This study examined the effects of an occupational therapist 's approach during the initial splinting session on the subsequent use of resting h and splints by patients with rheumatoid arthritis . Forty subjects were r and omly assigned either to a st and ard treatment ( control ) group or to a compliance-enhancement ( experimental ) group , for whom the use of learning principles , sharing of expectations , use of a positive affective tone and behaviors by the therapist , and the assumption of responsibility by the patient were emphasized . During the 28-day period after splinting , patients in the experimental and control groups wore their splints an average of 23.3 and 18.1 days , respectively ( p = 0.056 ) . Nine subjects in the experimental group , but only four in the control group used their splints every day ( p = 0.035 ) . Knowledge of splint use correlated with actual use , regardless of the group assignment ( p = 0.035 ) . Change in the amount of wrist and h and pain was not significant in either group ; however , the experimental group experienced a decrease in the duration of morning stiffness ( p = 0.013 ) . This intervention provides health professionals with a pragmatic and effective method to enhance compliance OBJECTIVE To describe patients ' functional uses of 3 commercial wrist orthoses , to describe patients ' preference patterns for the orthoses , and to clarify orthotic attributes that are viewed positively and negatively . METHODS Using a cross-over design , 42 patients with definite rheumatoid arthritis used each of 3 commercial orthoses for one week . There was a one-week wash-out between each week of use . At the end of the study , private semi-structured interviews were conducted with each participant . Data from close-ended questions were tabulated . Open-ended data were analyzed using qualitative methods . RESULTS Patients reported that the 3 commercial wrist orthoses reduced wrist pain similarly , but that comfort and a sense of security during functional tasks were only found if the orthoses were comfortable and well-fitting . Most subjects preferred the padded , short forearm orthosis , though a small number found it uncomfortably warm , and many complained that it was difficult to use when wearing long-sleeved garments . Common complaints about the two elastic orthoses included chafing at the thumb webspace and chafing at the proximal closures . Longer forearm length was often perceived as providing unnecessarily high levels of wrist support . CONCLUSIONS No single orthosis suited all subjects . Satisfaction with an orthosis appears to be based not only on its therapeutic effect , but also the comfort and ease of its use . To maximize patient satisfaction and improve the likelihood of appropriate fit and comfort , several styles of commercial orthoses should be available . The current trend toward restricted clinic stocks appears contrary to both therapeutic goals and patient satisfaction A r and omized , controlled trial was conducted to determine efficacy of the Isotoner and the Futuro compression gloves in 39 patients with h and synovitis secondary to rheumatoid arthritis . After 7 days of nighttime treatment , both br and s of gloves were found to decrease subjective symptoms of pain and stiffness ( p < 0.05 ) . In addition , swelling of the proximal interphalangeal joints decreased , while range of motion , rate of finger motion , and grip strength all increased ( p < 0.05 ) . Compression gloves should be used with caution in patients with bilateral carpal tunnel syndrome , because 12 of 13 such patients experienced worsening of their symptoms following one nighttime wearing of compression gloves . While both gloves were found to be efficacious in improving the signs and symptoms of h and synovitis , neither glove was found to be superior to the other . Patient preferences related to glove composition and fit may ultimately determine which glove to prescribe |
13,693 | 29,991,644 | Conclusions : Our meta- analysis of clinical trials and prospect i ve cohort studies demonstrates that MVM supplementation does not improve cardiovascular outcomes in the general population | Background : Multiple studies have attempted to identify the association between multivitamin/mineral ( MVM ) supplementation and cardiovascular disease ( CVD ) outcomes , but the benefits remain controversial .
We performed a systematic review and meta- analysis of the associations between MVM supplementation and various CVD outcomes , including coronary heart disease ( CHD ) and stroke . | Prognosis studies are investigations of future events or the evaluation of associations between risk factors and health outcomes in population s of patients ( 1 ) . The results of such studies improve our underst and ing of the clinical course of a disease and assist clinicians in making informed decisions about how best to manage patients . Prognostic research also informs the design of intervention studies by helping define subgroups of patients who may benefit from a new treatment and by providing necessary information about the natural history of a disorder ( 2 ) . There has recently been a rapid increase in the use of systematic review methods to synthesize the evidence on research questions related to prognosis . It is essential that investigators conducting systematic review s thoroughly appraise the method ologic quality of included studies to be confident that a study 's design , conduct , analysis , and interpretation have adequately reduced the opportunity for bias ( 3 , 4 ) . Caution is warranted , however , because inclusion of method ologically weak studies can threaten the internal validity of a systematic review ( 4 ) . This follows abundant empirical evidence that inadequate attention to biases can cause invalid results and inferences ( 5 - 9 ) . However , there is limited consensus on how to appraise the quality of prognosis studies ( 1 ) . A useful framework to assess bias in such studies follows the basic principles of epidemiologic research ( 10 , 11 ) . We focus on 6 areas of potential bias : study participation , study attrition , prognostic factor measurement , confounding measurement and account , outcome measurement , and analysis . The main objectives of our review of review s are to describe methods used to assess the quality of prognosis studies and to describe how well current practice s assess potential biases . Our secondary objective is to develop recommendations to guide future quality appraisal , both within single studies of prognostic factors and within systematic review s of the evidence . We hope this work facilitates future discussion and research on biases in prognosis studies and systematic review s. Methods Literature Search and Study Selection We identified systematic review s of prognosis studies by search ing MEDLINE ( 1966 to October 2005 ) using the search strategy recommended by McKibbon and colleagues ( 12 ) . This strategy combines broad search terms for systematic review s ( systematic review .mp ; meta- analysis .mp ) and a sensitive search strategy for prognosis studies ( cohort , incidence , mortality , follow-up studies , prognos * , predict * , or course ) . We also search ed the reference lists of included review s and method ologic papers to identify other relevant publications . We restricted our search to English- language publications . One review er conducted the search and selected the studies . Systematic review s , defined as review s of published studies with a comprehensive search and systematic selection , were included if they assessed the method ologic quality of the included studies by using 1 or more explicit criteria . We excluded studies if they were meta-analyses of independent patient data only , if their primary goal was to investigate the effectiveness of an intervention or specific diagnostic or screening tests , or if they included studies that were not done on humans . Data Extraction and Synthesis Individual items included in the quality assessment of the systematic review s were recorded as they were reported in the publication ( that is , the information that would be available to readers and future review ers ) . We review ed journal Web sites and contacted the authors of the systematic review s for additional information when authors made such an offer in their original papers . When review s assessed different study design s by using different sets of quality items , we extracted only those items used to assess cohort studies . We constructed a comprehensive list of distinct items that the review s used to assess the quality of their included studies . The full text of each review was screened . All items used by the review authors to assess the quality of studies were extracted into a computerized spreadsheet by 1 review er . Two experienced review ers , a clinical epidemiologist and an epidemiologist , independently synthesized the quality items extracted from the prognosis review s to determine how well the systematic review s assessed potential biases . We did this in 3 steps : 1 ) identified distinct concepts or domains addressed by the quality items ; 2 ) grouped each extracted quality item into the appropriate domain or domains ; and 3 ) identified the domains necessary to assess potential biases in prognosis studies . We then used this information to assess how well the review s ' quality assessment included items from the domains necessary to assess potential biases . After completing each of the first 3 steps , the review ers met to attempt to reach a consensus . The consensus process involved each review er presenting his or her observations and results , followed by discussion and debate . A third review er was available in cases of persistent disagreement or uncertainty . In the first step , all domains addressed by the quality items were identified . The first review er iteratively and progressively defined the domains as items were extracted from the included review s. The second review er defined domains from a r and om list of all extracted quality items . Limited guidance was provided to the review ers so that their assessment s and definitions of domains would be independent . The review ers agreed on a final set of domains that adequately and completely defined all of the extracted items . In the second step , review ers independently grouped each extracted item into the appropriate domains . Review ers considered each extracted item by asking , What is each particular quality item addressing ? or What are the review 's authors getting at with the particular quality assessment item ? . Items were grouped into the domain or domains that best represented the concepts being addressed . For example , the extracted items at least 80 % of the group originally identified was located for follow-up and follow-up was sufficiently complete or does n't jeopardize validity were each independently classified by both review ers as assessing the domain completeness of follow-up adequate , whereas the extracted item quantification and description of all subjects lost to follow-up was classified as assessing the domain completeness of follow-up described . In the third step , we identified the domains necessary to assess potential biases . Each review er considered the ability of the identified domains to adequately address , at least in part , 1 of the following 6 potential biases : 1 ) study participation , 2 ) study attrition , 3 ) prognostic factor measurement , 4 ) confounding measurement and account , 5 ) outcome measurement , and 6 ) analysis . Domains were considered to adequately address part of the framework if information garnered from that domain would inform the assessment of potential bias . For example , both review ers judged that the identified domain study population represents source population or population of interest assessed potential bias in a prognosis study , whereas the domain research question definition did not , although the latter is an important consideration in assessing the inclusion of studies in a systematic review . Finally , on the basis of our previous ratings , we looked at whether each review included items from the domains necessary to assess the 6 potential biases . We calculated the frequency of systematic review s by assessing each potential bias and the number of review s that adequately assessed bias overall . From this systematic synthesis , we developed recommendations for improving quality appraisal in future systematic review s of prognosis studies . We used Microsoft Access and Excel 2002 ( Microsoft Corp. , Redmond , Washington ) for data management and SAS for Windows , version 9.1 ( SAS Institute , Inc. , Cary , North Carolina ) for descriptive statistics . Role of the Funding Sources The funding sources , the Canadian Institutes of Health Research , the Canadian Chiropractic Research Foundation , the Ontario Chiropractic Association , and the Ontario Ministry of Health and Long Term Care , did not have a role in the collection , analysis , or interpretation of the data or in the decision to su bmi t the manuscript for publication . Results We identified 1384 potentially relevant articles . Figure 1 shows a flow chart of studies that were included and excluded . Figure 2 shows the number of review s identified by year of publication . We excluded 131 systematic review s of prognosis studies that did not seem to include any quality assessment of the included studies ; this represented 44 % of prognosis review s. We included 163 review s of prognosis studies in our analysis ( 13 - 175 ) . The most common topics were cancer ( 15 % ) , musculoskeletal disorders and rheumatology ( 13 % ) , cardiovascular ( 10 % ) , neurology ( 10 % ) , and obstetrics ( 10 % ) . Other review s included a wide range of health and health care topics . Sixty-three percent of the review s investigated the association between a specific prognostic factor and a particular outcome ; the remainder investigated multiple prognostic factors or models . The number of primary studies included in each systematic review ranged from 3 to 167 ( median , 18 [ interquartile range , 12 to 31 ] ) . A complete description of the included review s is available from the authors on request . Figure 1 . Flow diagram of inclusion and exclusion criteria of systematic review s. Figure 2 . Number of systematic review s of prognosis studies identified over time . Quality Items One hundred fifty-three review s provided adequate detail to allow extraction of quality items . Eight hundred eighty-two distinct quality items were extracted from the review s. Most review s developed their own set of quality items , with only a few applying criteria from previous review s. Most quality items BACKGROUND Disodium ethylenediaminetetraacetic acid ( EDTA ) reduced adverse cardiac outcomes in a factorial trial also testing oral vitamins . This report describes the intent-to-treat comparison of the 4 factorial groups overall and in patients with diabetes . METHODS This was a double-blind , placebo-controlled , 2 × 2 factorial multicenter r and omized trial of 1,708 post-myocardial infa rct ion ( MI ) patients ≥50 years of age and with creatinine ≤2.0 mg/dL r and omized to receive 40 EDTA chelation or placebo infusions plus 6 caplets daily of a 28-component multivitamin-multimineral mixture or placebo . The primary end point was a composite of total mortality , MI , stroke , coronary revascularization , or hospitalization for angina . RESULTS Median age was 65 years , 18 % were female , 94 % were Caucasian , 37 % were diabetic , 83 % had prior coronary revascularization , and 73 % were on statins . Five-year Kaplan-Meier estimates for the primary end point was 31.9 % in the chelation + high-dose vitamin group , 33.7 % in the chelation + placebo vitamin group , 36.6 % in the placebo infusion + active vitamin group , and 40.2 % in the placebo infusions + placebo vitamin group . The reduction in primary end point by double active treatment compared with double placebo was significant ( hazard ratio 0.74 , 95 % CI 0.57 - 0.95 , P = .016 ) . In patients with diabetes , the primary end point reduction of double active compared with double placebo was more pronounced ( hazard ratio 0.49 , 95 % CI 0.33 - 0.75 , P < .001 ) . CONCLUSIONS In stable post-MI patients on evidence -based medical therapy , the combination of oral high-dose vitamins and chelation therapy compared with double placebo reduced clinical ly important cardiovascular events to an extent that was both statistically significant and of potential clinical relevance BACKGROUND Although multivitamins are widely used , there are limited prospect i ve studies investigating their association with both long- and short-term risk of cardiovascular disease ( CVD ) . OBJECTIVE The objective was to investigate how multivitamin use is associated with the long- and short-term risk of CVD . DESIGN A prospect i ve cohort study was conducted of 37,193 women from the Women 's Health Study aged ≥45 y and free of CVD and cancer at baseline who were followed for an average of 16.2 y. At baseline , women self-reported a wide range of lifestyle , clinical , and dietary factors . Women were categorized into 1 ) no current use and 2 ) current use of multivitamins . Duration and up date d measures over the course of the follow-up to address short-term effects were also considered . Women were followed for major CVD events , including myocardial infa rct ion ( MI ) , stroke , and CVD death . RESULTS During the follow-up , 1493 incident cases of CVD [ defined as myocardial infa rct ion ( MI ) , stroke , and CVD death ] occurred . In multivariable analyses , multivitamin use compared with no use was not associated with major CVD events ( HR : 1.01 ; 95 % CI : 0.89 , 1.15 ) , MI ( HR : 1.04 ; 95 % CI : 0.84 , 1.27 ) , stroke ( HR : 0.99 ; 95 % CI : 0.83 , 1.18 ) , or CVD death ( HR : 1.10 ; 95 % CI : 0.84 , 1.45 ) . A nonsignificant inverse association was observed between baseline multivitamin use and major CVD events among women aged ≥70 y ( P-interaction = 0.04 ) and those consuming <3 servings/d of fruit and vegetables ( P-interaction = 0.01 ) . When updating information on multivitamin use during the course of follow-up , no associations were observed for major CVD events ( HR : 0.91 ; 95 % CI : 0.82 , 1.02 ) , MI ( HR : 0.89 ; 95 % CI : 0.74 , 1.06 ) , stroke ( HR : 0.91 ; 95 % CI : 0.78 , 1.06 ) , and CVD death ( HR : 0.91 ; 95 % CI : 0.71 , 1.16 ) . CONCLUSIONS In this study of middle-aged and elderly women , neither baseline nor time-varying multivitamin use was associated with the long-term risk of major CVD events , MI , stroke , cardiac revascularizations , or CVD death . Additional studies are needed to clarify the role of multivitamins on CVD Purpose To prospect ively evaluate the association of vitamin/mineral supplementation with cancer , cardiovascular , and all-cause mortality . Methods In the Heidelberg cohort of the European Prospect i ve Investigation into Cancer and Nutrition ( EPIC-Heidelberg ) , which was recruited in 1994–1998 , 23,943 participants without pre-existing cancer and myocardial infa rct ion/stroke at baseline were included in the analyses . Vitamin/mineral supplementation was assessed at baseline and during follow-up . Cox regression models were used to estimate hazard ratios ( HRs ) and 95 % confidence intervals ( CIs ) . Results After an average follow-up time of 11 years , 1,101 deaths were documented ( cancer deaths = 513 and cardiovascular deaths = 264 ) . After adjustment for potential confounders , neither any vitamin/mineral supplementation nor multivitamin supplementation at baseline was statistically significantly associated with cancer , cardiovascular , or all-cause mortality . However , baseline users of antioxidant vitamin supplements had a significantly reduced risk of cancer mortality ( HR : 0.52 ; 95 % CI : 0.28 , 0.97 ) and all-cause mortality ( HR : 0.58 ; 95 % CI : 0.38 , 0.88 ) . In comparison with never users , baseline non-users who started taking vitamin/mineral supplements during follow-up had significantly increased risks of cancer mortality ( HR : 1.74 ; 95 % CI : 1.09 , 2.77 ) and all-cause mortality ( HR : 1.58 ; 95 % CI : 1.17 , 2.14 ) . Conclusions Based on limited numbers of users and cases , this cohort study suggests that supplementation of antioxidant vitamins might possibly reduce cancer and all-cause mortality . The significantly increased risks of cancer and all-cause mortality among baseline non-users who started taking supplements during follow-up may suggest a “ sick-user effect , ” which research ers should be cautious of in future observational studies Background Recent r and omized data suggest that calcium supplements may be associated with increased risk of cardiovascular disease ( CVD ) events . Using a longitudinal cohort study , we assessed the association between calcium intake , from both foods and supplements , and atherosclerosis , as measured by coronary artery calcification ( CAC ) . Methods and Results We studied 5448 adults free of clinical ly diagnosed CVD ( 52 % female ; aged 45–84 years ) from the Multi‐Ethnic Study of Atherosclerosis . Baseline total calcium intake was assessed from diet ( using a food frequency question naire ) and calcium supplements ( by a medication inventory ) and categorized into quintiles . Baseline CAC was measured by computed tomography , and CAC measurements were repeated in 2742 participants ≈10 years later . At baseline , mean calcium intakes across quintiles were 313.3 , 540.3 , 783.0 , 1168.9 , and 2157.4 mg/day . Women had higher calcium intakes than men . After adjustment for potential confounders , among 1567 participants without baseline CAC , the relative risk ( RR ) of developing incident CAC over 10 years , by quintile 1 to 5 of calcium intake , were 1 ( reference ) , 0.95 ( 0.79–1.14 ) , 1.02 ( 0.85–1.23 ) , 0.86 ( 0.69–1.05 ) , and 0.73 ( 0.57–0.93 ) . After accounting for total calcium intake , calcium supplement use was associated with increased risk for incident CAC ( RR=1.22 [ 1.07–1.39 ] ) . No relation was found between baseline calcium intake and 10‐year changes in log‐transformed CAC among those participants with baseline CAC > 0 . Conclusions High total calcium intake was associated with a decreased risk of incident atherosclerosis over long‐term follow‐up , particularly if achieved without supplement use . However , calcium supplement use may increase the risk for incident CAC Importance Cohort studies have reported increased incidence of cardiovascular disease ( CVD ) among individuals with low vitamin D status . To date , r and omized clinical trials of vitamin D supplementation have not found an effect , possibly because of using too low a dose of vitamin D. Objective To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population . Design , Setting , and Participants The Vitamin D Assessment Study is a r and omized , double-blind , placebo-controlled trial that recruited participants mostly from family practice s in Auckl and , New Zeal and , from April 5 , 2011 , through November 6 , 2012 , with follow-up until July 2015 . Participants were community-resident adults aged 50 to 84 years . Of 47 905 adults invited from family practice s and 163 from community groups , 5110 participants were r and omized to receive vitamin D3 ( n = 2558 ) or placebo ( n = 2552 ) . Two participants retracted consent , and all others ( n = 5108 ) were included in the primary analysis . Interventions Oral vitamin D3 in an initial dose of 200 000 IU , followed a month later by monthly doses of 100 000 IU , or placebo for a median of 3.3 years ( range , 2.5 - 4.2 years ) . Main Outcomes and Measures The primary outcome was the number of participants with incident CVD and death , including a prespecified subgroup analysis in participants with vitamin D deficiency ( baseline deseasonalized 25-hydroxyvitamin D [ 25(OH)D ] levels < 20 ng/mL ) . Secondary outcomes were myocardial infa rct ion , angina , heart failure , hypertension , arrhythmias , arteriosclerosis , stroke , and venous thrombosis . Results Of the 5108 participants included in the analysis , the mean ( SD ) age was 65.9 ( 8.3 ) years , 2969 ( 58.1 % ) were male , and 4253 ( 83.3 % ) were of European or other ethnicity , with the remainder being Polynesian or South Asian . Mean ( SD ) baseline deseasonalized 25(OH)D concentration was 26.5 ( 9.0 ) ng/mL , with 1270 participants ( 24.9 % ) being vitamin D deficient . In a r and om sample of 438 participants , the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group . The primary outcome of CVD occurred in 303 participants ( 11.8 % ) in the vitamin D group and 293 participants ( 11.5 % ) in the placebo group , yielding an adjusted hazard ratio of 1.02 ( 95 % CI , 0.87 - 1.20 ) . Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes . Conclusions and Relevance Monthly high-dose vitamin D supplementation does not prevent CVD . This result does not support the use of monthly vitamin D supplementation for this purpose . The effects of daily or weekly dosing require further study . Trial Registration clinical trials.gov Identifier : CONTEXT Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine . OBJECTIVE To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas . DESIGN , SETTING , AND PARTICIPANTS A double-blind , placebo-controlled , 2-factor , phase 3 , r and omized clinical trial conducted at 9 clinical centers between July 6 , 1994 , and October 1 , 2004 . Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma . INTERVENTION Participants were r and omly assigned in a 1:1 ratio to receive 1 mg/d of folic acid ( n = 516 ) or placebo ( n = 505 ) , and were separately r and omized to receive aspirin ( 81 or 325 mg/d ) or placebo . Follow-up consisted of 2 colonoscopic surveillance cycles ( the first interval was at 3 years and the second at 3 or 5 years later ) . MAIN OUTCOME MEASURES The primary outcome measure was occurrence of at least 1 colorectal adenoma . Secondary outcomes were the occurrence of advanced lesions ( > or = 25 % villous features , high- grade dysplasia , size > or = 1 cm , or invasive cancer ) and adenoma multiplicity ( 0 , 1 - 2 , or > or =3 adenomas ) . RESULTS During the first 3 years , 987 participants ( 96.7 % ) underwent colonoscopic follow-up , and the incidence of at least 1 colorectal adenoma was 44.1 % for folic acid ( n = 221 ) and 42.4 % for placebo ( n = 206 ) ( unadjusted risk ratio [ RR ] , 1.04 ; 95 % confidence interval [ CI ] , 0.90 - 1.20 ; P = .58 ) . Incidence of at least 1 advanced lesion was 11.4 % for folic acid ( n = 57 ) and 8.6 % for placebo ( n = 42 ) ( unadjusted RR , 1.32 ; 95 % CI , 0.90 - 1.92 ; P = .15 ) . A total of 607 participants ( 59.5 % ) underwent a second follow-up , and the incidence of at least 1 colorectal adenoma was 41.9 % for folic acid ( n = 127 ) and 37.2 % for placebo ( n = 113 ) ( unadjusted RR , 1.13 ; 95 % CI , 0.93 - 1.37 ; P = .23 ) ; and incidence of at least 1 advanced lesion was 11.6 % for folic acid ( n = 35 ) and 6.9 % for placebo ( n = 21 ) ( unadjusted RR , 1.67 ; 95 % CI , 1.00 - 2.80 ; P = .05 ) . Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers . There was no significant effect modification by sex , age , smoking , alcohol use , body mass index , baseline plasma folate , or aspirin allocation . CONCLUSIONS Folic acid at 1 mg/d does not reduce colorectal adenoma risk . Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00272324 OBJECTIVE To investigate the effect of supplementation with multivitamin and mineral on blood pressure and C-reactive protein ( CRP ) in obese women with increased cardiovascular disease risk as having hypertension , hyperglycemia or hyperlipemia . SUBJECTS AND METHODS 128 obese Chinese women aged 18 - 55 years with increased cardiovascular disease risk participated in a 26-week r and omized , double-blind , placebo-controlled trial . Subjects were r and omized to four groups , and received either one tablet of high-dose multivitamin and mineral supplement ( MMS ) , or one tablet of low-dose MMS ( Low MMS ) , or calcium 162 mg ( Calcium ) or identical placebo ( Placebo ) daily during the study . Diastolic blood pressure ( DBP ) , systolic blood pressure ( SBP ) and serum concentrations of CRP were measured at baseline and end-trial . RESULTS At baseline , the subjects had an average age of 42.0+/-7.1 years and BMI of 30.9+/-2.8 kg/m2 . There were no significant differences between the four groups in baseline characteristics . One hundred and seventeen subjects completed the study . After 26-week supplementation , both SBP and DBP were significantly lower in the MMS group compared to the placebo group ( p < 0.05 ) . There was also a non-significant trend of lower DBP at 26-week in the MMS and calcium groups compared to baseline ( p < 0.08 ) . At 26-week , the MMS group also had significantly lower serum concentrations of CRP compared with that of baseline and the placebo group ( p < 0.05 ) . CONCLUSIONS Our results showed that supplementation with adequate multivitamin and mineral supplement could reduce blood pressure and serum CRP in obese women with increased cardiovascular disease risk Importance Long-term multivitamin use had no effect on risk of cardiovascular disease ( CVD ) in the Physicians ’ Health Study II . Baseline nutritional status may have modified the lack of effect . Objective To investigate effect modification by various baseline dietary factors on CVD risk in the Physicians ’ Health Study II . Design , Setting , and Participants The Physicians ’ Health Study II was a r and omized , double-blind , placebo-controlled trial testing multivitamin use ( multivitamin [ Centrum Silver ] or placebo daily ) among US male physicians . The Physicians ’ Health Study II included 14 641 male physicians 50 years or older , 13 316 of whom ( 91.0 % ) completed a baseline 116-item semiquantitative food frequency question naire and were included in the analyses . This study examined effect modification by baseline intake of key foods , individual nutrients , dietary patterns ( Alternate Healthy Eating Index and Alternate Mediterranean Diet Score ) , and dietary supplement use . The study began in 1997 , with continued treatment and follow-up through June 1 , 2011 . Interventions Multivitamin or placebo daily . Main Outcomes and Measures Major cardiovascular events , including nonfatal myocardial infa rct ion , nonfatal stroke , and CVD mortality . Secondary outcomes included myocardial infa rct ion , total stroke , CVD mortality , and total mortality individually . Results In total , 13 316 male physicians ( mean [ SD ] age at r and omization , 64.0 [ 9.0 ] years in those receiving the active multivitamin and 64.0 [ 9.1 ] years in those receiving the placebo ) were observed for a mean ( SD ) follow-up of 11.4 ( 2.3 ) years . There was no consistent evidence of effect modification by various foods , nutrients , dietary patterns , or baseline supplement use on the effect of multivitamin use on CVD end points . Statistically significant interaction effects were observed between multivitamin use and vitamin B6 intake on myocardial infa rct ion , between multivitamin use and vitamin D intake on CVD mortality , and between multivitamin use and vitamin B12 intake on CVD mortality and total mortality . However , there were inconsistent patterns in hazard ratios across tertiles of each dietary factor that are likely explained by multiple testing . Conclusions and Relevance The results suggest that baseline nutritional status does not influence the effect of r and omized long-term multivitamin use on major CVD events . Future studies are needed to investigate the role of baseline nutritional biomarkers on the effect of multivitamin use on CVD and other outcomes . Trial Registration clinical trials.gov Identifier : BACKGROUND Multivitamin-mineral ( MVM ) products are the most commonly used supplements in the United States , followed by multivitamin ( MV ) products . Two r and omized clinical trials ( RCTs ) did not show an effect of MVMs or MVs on cardiovascular disease ( CVD ) mortality ; however , no clinical trial data are available for women with MVM supplement use and CVD mortality . OBJECTIVE The objective of this research was to examine the association between MVM and MV use and CVD-specific mortality among US adults without CVD . METHODS A nationally representative sample of adults from the restricted data NHANES III ( 1988 - 1994 ; n = 8678 ; age ≥40 y ) were matched with mortality data reported by the National Death Index through 2011 to examine associations between MVM and MV use and CVD mortality by using Cox proportional hazards models , adjusting for multiple potential confounders . RESULTS We observed no significant association between CVD mortality and users of MVMs or MVs compared with nonusers ; however , when users were classified by the reported length of time products were used , a significant association was found with MVM use of > 3 y compared with nonusers ( HR : 0.65 ; 95 % CI : 0.49 , 0.85 ) . This finding was largely driven by the significant association among women ( HR : 0.56 ; 95 % CI : 0.37 , 0.85 ) but not men ( HR : 0.79 ; 95 % CI : 0.44 , 1.42 ) . No significant association was observed for MV products and CVD mortality in fully adjusted models . CONCLUSIONS In this nationally representative data set with detailed information on supplement use and CVD mortality data ∼20 y later , we found an association between MVM use of > 3 y and reduced CVD mortality risk for women when models controlled for age , race , education , body mass index , alcohol , aspirin use , serum lipids , blood pressure , and blood glucose/glycated hemoglobin . Our results are consistent with the 1 available RCT in men , indicating no relation with MVM use and CVD mortality Objective : To investigate the association of dietary folate , vitamin B6 ( VB6 ) and vitamin B12 ( VB12 ) with the risk of coronary heart disease among middle-aged persons . Methods : A total of 40,803 subjects aged 40–59 years living in the community who were free of prior diagnoses of cardiovascular disease and cancer and who completed a food frequency question naire were followed from 1990–1992 to the end of 2001 in the Japan Public Health Center-based Prospect i ve Study . Results : After 468,472 person-years of follow-up , 251 coronary heart disease incidents were documented . Coronary heart disease and definite myocardial infa rct ion were inversely associated with dietary intake of folate , VB6 and VB12 after adjustment for age and sex , but the associations were attenuated after further adjustment for smoking , dietary and other cardiovascular risk factors . However , among non-multivitamin supplement users , multivariable hazard ratios ( 95 % confidence intervals ) in the highest vs. lowest quintiles of VB6 intake were 0.60 ( 0.37–0.97 ) for total coronary heart disease and 0.52 ( 0.29–0.91 ) for definite myocardial infa rct ion , and the inverse associations with VB12 were marginally significant . The combination of below-median intake of three vitamins or of only B6 conferred a twice excess risk of total coronary heart disease . Conclusions : Dietary intake of VB6 was associated with a reduced risk of coronary heart disease among middle-aged non-multivitamin supplement users . Dietary folate and VB12 were also suggested to be protective factors for coronary heart disease BACKGROUND It has been suggested that a low dietary intake of antioxidant vitamins and minerals increases the incidence rate of cardiovascular disease and cancer . To date , however , the published results of r and omized , placebo-controlled trials of supplements containing antioxidant nutrients have not provided clear evidence of a beneficial effect . We tested the efficacy of nutritional doses of supplementation with a combination of antioxidant vitamins and minerals in reducing the incidence of cancer and ischemic cardiovascular disease in the general population . METHODS The Supplementation en Vitamines et Mineraux Antioxydants ( SU.VI.MAX ) study is a r and omized , double-blind , placebo-controlled primary prevention trial . A total of 13 017 French adults ( 7876 women aged 35 - 60 years and 5141 men aged 45 - 60 years ) were included . All participants took a single daily capsule of a combination of 120 mg of ascorbic acid , 30 mg of vitamin E , 6 mg of beta carotene , 100 mug of selenium , and 20 mg of zinc , or a placebo . Median follow-up time was 7.5 years . RESULTS No major differences were detected between the groups in total cancer incidence ( 267 [ 4.1 % ] for the study group vs 295 [ 4.5 % ] for the placebo group ) , ischemic cardiovascular disease incidence ( 134 [ 2.1 % ] vs 137[2.1 % ] ) , or all-cause mortality ( 76 [ 1.2 % ] vs 98 [ 1.5 % ] ) . However , a significant interaction between sex and group effects on cancer incidence was found ( P = .004 ) . Sex-stratified analysis showed a protective effect of antioxidants in men ( relative risk , 0.69 [ 95 % confidence interval [ CI ] , 0.53 - 0.91 ] ) but not in women ( relative risk , 1.04 [ 95 % CI , 0.85 - 1.29 ] ) . A similar trend was observed for all-cause mortality ( relative risk , 0.63 [ 95 % CI , 0.42 - 0.93 ] in men vs 1.03 [ 95 % CI , 0.64 - 1.63 ] in women ; P = .11 for interaction ) . CONCLUSIONS After 7.5 years , low-dose antioxidant supplementation lowered total cancer incidence and all-cause mortality in men but not in women . Supplementation may be effective in men only because of their lower baseline status of certain antioxidants , especially of beta carotene The use of dietary supplements has increased substantially in most industrialized countries . The aim of this study was to prospect ively examine the association between use of dietary supplements and all-cause mortality , cancer mortality and CVD mortality in men . We used the population -based prospect i ve cohort of 38 994 men from central Sweden , 45 - 79 years of age , with no cancer or CVD at baseline and who completed a self-administered FFQ including questions on dietary supplement use and life-style factors in 1997 . During average 7.7 years of follow-up , 3403 deaths were ascertained ; among them , 771 due to cancer and 930 due to CVD ( during 5.9 years of follow-up ) . In multivariate adjusted models including all men there was no association observed between use of any dietary supplement or of multivitamins , vitamin C , vitamin E or fish oil specifically and all-cause mortality , cancer or CVD mortality . Among current smokers , regular use of any supplement was associated with statistically significant increased risk of cancer mortality : relative risk ( RR ) 1.46 ( 95 % CI 1.06 , 1.99 ) . Among men reporting an inadequate diet at baseline ( assessed by Recommended Food Score ) , there was a statistically significant inverse association between use of any dietary supplement and CVD mortality ( RR 0.72 ; 95 % CI 0.57 , 0.91 ) , no associations were observed among men with adequate diets . In conclusion , we can not exclude that the use of dietary supplements is harmful for smokers . On the other h and , among men with an insufficient diet , the use of supplements might be beneficial in reducing CVD mortality Summary of the Recommendations The U.S. Preventive Services Task Force ( USPSTF ) concludes that the evidence is insufficient to recommend for or against the use of supplements of vitamins A , C , or E ; multivitamins with folic acid ; or antioxidant combinations for the prevention of cancer or cardiovascular disease . This is a grade I recommendation . ( See Appendix Table 1 for a description of the USPSTF classification of recommendations . ) The USPSTF found poor evidence to determine whether supplementation with these vitamins reduces the risk for cardiovascular disease or cancer . ( See Appendix Table 2 for a description of the USPSTF classification of levels of evidence . ) The available evidence from r and omized trials is either inadequate or conflicting , and the influence of confounding variables on observed outcomes in observational studies can not be determined . As a result , the USPSTF could not determine the balance of benefits and harms of routine use of supplements of vitamins A , C , or E ; multivitamins with folic acid ; or antioxidant combinations for the prevention of cancer or cardiovascular disease . The USPSTF recommends against the use of beta-carotene supplements , either alone or in combination , for the prevention of cancer or cardiovascular disease . This is a grade D recommendation . The USPSTF found good evidence that -carotene supplementation provides no benefit in the prevention of cancer or cardiovascular disease in middle-aged and older adults . In two trials restricted to heavy smokers , -carotene supplementation was associated with higher incidence of lung cancer and higher all-cause mortality . The USPSTF concludes that -carotene supplements are unlikely to provide important benefits and might cause harm in some groups . Clinical Considerations The USPSTF did not review evidence regarding vitamin supplementation for patients with known or potential nutritional deficiencies , including pregnant and lactating women , children , elderly persons , and people with chronic illnesses . Dietary supplements may be appropriate for people whose diet does not provide the recommended dietary intake of specific vitamins . Individuals may wish to consult a health care provider to discuss whether dietary supplements are appropriate . With the exception of vitamins for which there is compelling evidence of net harm ( for example , beta-carotene supplementation in smokers ) , there is little reason to discourage people from taking vitamin supplements . Patients should be reminded that taking vitamins does not replace the need to eat a healthy diet . All patients should receive information about the benefits of a diet high in fruits and vegetables , as well as information on other foods and nutrients that should be emphasized or avoided in their diet ( see the 2002 USPSTF recommendations on counseling to promote a healthy diet [ 1 ] ) . Patients who choose to take vitamins should be encouraged to adhere to the dosages recommended in the Dietary Reference Intakes of the Institute of Medicine . Some vitamins , such as A and D , may be harmful in higher doses ; therefore , doses greatly exceeding the Recommended Dietary Allowance or Adequate Intake should be taken with care while considering whether potential harms outweigh potential benefits . Vitamins and minerals sold in the United States are classified as dietary supplements , and there is a degree of quality control over content if they have a U.S. Pharmacopeia seal ( 2 ) . Nevertheless , imprecision in the content and concentration of ingredients could pose a theoretical risk not reflected in clinical trials using calibrated compounds . The adverse effects of beta-carotene on smokers have been observed primarily in those taking large supplemental doses . There is no evidence to suggest that beta-carotene is harmful to smokers at levels occurring naturally in foods . The USPSTF did not review evidence supporting folic acid supplementation among pregnant women to reduce neural tube defects . In 1996 , the USPSTF recommended folic acid for all women who are planning , or capable of , pregnancy ( see the 1996 USPSTF chapter on screening for neural tube defects [ 3 ] ) . Clinicians and patients should discuss the possible need for vitamin supplementation when taking certain medications ( for example , folic acid supplementation for patients taking methotrexate ) . Scientific Evidence The USPSTF review s ( 4 - 6 ) focused on the quality of the evidence regarding the effect of routine supplementation with certain vitamins on primary prevention of cancer and cardiovascular disease . These review s were undertaken because of the growing epidemiologic evidence that dietary factors may play a role in the etiology of these diseases ( 7 - 9 ) . The review s focused on prospect i ve trials of vitamin supplementation and observational studies of associations between the use of specific supplements and the risk for cancer or cardiovascular disease . The value of vitamins naturally occurring in food , the use of vitamin supplements for the prevention of other conditions ( for example , neural tube defects ) , and the use of vitamin supplements for the secondary prevention of complications in patients with existing disease were outside the scope of these review s. Vitamin A No prospect i ve trials have examined the effect of vitamin A supplements alone on the risk for cancer . Observational studies provide no evidence that such supplements prevent cancer in men . In women , observational studies have reported a statistically significant inverse association between use of vitamin A supplements and risk for colon and breast cancer ( 10 , 11 ) . Despite efforts to adjust for confounding variables , the observational , nonr and om design of these studies makes it difficult to assess the extent to which the reduced cancer risk is attributable to vitamin A or to other characteristics of women who take vitamin A supplements . No evidence from prospect i ve trials is available regarding the benefits of vitamin A alone in preventing cardiovascular disease . One good- quality cohort study found no effect of vitamin A supplementation in reducing cardiovascular disease mortality ( 12 ) . Vitamin C No primary prevention trial of the effect of vitamin C supplementation alone on cancer or cardiovascular disease has been reported . Observational studies have generally shown no statistically significant associations between use of vitamin C supplements and risk for cancer of the breast , prostate , colon , or lung ( 12 - 14 ) . The observational cohort studies examining the effects of vitamin C on cardiovascular disease have produced inconsistent results ( 12 , 15 , 16 ) . Vitamin E Only a few trials have examined the effects of vitamin E on the primary prevention of cancer or cardiovascular disease . A r and omized , controlled trial ( RCT ) involving Finnish male smokers found that vitamin E supplementation is not protective against lung cancer but may have a beneficial impact on prostate cancer ( 14 ) . Because prostate cancer was not a primary end point of the trial and the trial had other limitations , further evidence is needed to confirm this finding . Observational studies have shown no statistically significant association between use of vitamin E supplements and risk for prostate , lung , or breast cancer ( 5 ) . One study suggested that vitamin E protects against colon cancer , but the influence of confounding variables can not be fully excluded ( 17 ) . Among primary prevention trials , two good- quality trials ( 14 , 18 ) and one fair- quality trial ( 19 ) found no statistically significant benefit of vitamin E supplementation in preventing cardiovascular disease ( 20 ) . Only one of seven trials of vitamin E supplementation for secondary prevention demonstrated a statistically significant reduction in cardiac events ( 4 ) . Some prospect i ve cohort studies have suggested a significant benefit , but the results are mixed and the influence of confounding variables can not be excluded ( 4 ) . -Carotene A consistent body of evidence from clinical trials suggests that beta-carotene supplementation does not decrease the risk for lung , prostate , colon , breast , or nonmelanoma skin cancer ( 14 , 21 - 25 ) . -Carotene supplements were associated with an increased risk for lung cancer among smokers , especially heavy smokers , in two RCTs ( 14 , 25 ) . Results from four RCTs demonstrated no reduced risk for cardiovascular events or death after beta-carotene supplementation ( 14 , 21 , 22 , 26 - 28 ) . Antioxidant Vitamin Combinations Studies of the effects of antioxidant vitamin combinations to prevent cancer have yielded mixed results . A recent RCT reported no statistically significant effect of daily supplementation with a combination of antioxidants : vitamin E , vitamin C , and beta-carotene ( 29 ) . Some studies have suggested an adverse effect of antioxidant combinations on cancer , but the results may have been confounded by the inclusion of beta-carotene ( 5 ) . Some observational studies of antioxidant vitamin combinations have suggested a benefit in preventing cardiovascular disease ( 13 , 30 , 31 ) , but other studies , including well- design ed RCTs , have shown no benefit ( 29 , 32 , 33 ) . One secondary prevention trial showed an increase in all-cause mortality among women taking antioxidant supplements ( 34 ) . Multiple Vitamin Combinations The incremental benefit of taking supplemental doses of folic acid and B vitamins has been examined by comparing the outcomes of observational studies while controlling for the total intake of antioxidant vitamin supplements ( 35 ) . In these analyses , folic acid supplementation was associated with significantly decreased risk for colon cancer , but the protective effect requires confirmation in prospect i ve trials . There is conflicting evidence regarding the use of multivitamins and the risk for cardiovascular disease . Among cohort studies , one good- quality study reported a statistically significant reduction in coronary events ( 36 ) , two good- quality studies reported no statistically significant effect on mortality ( 16 , 37 ) , and one BACKGROUND Although multivitamins are widely used by US adults , few prospect i ve studies have investigated their association with the long- and short-term risks of cardiovascular disease ( CVD ) . OBJECTIVE The aim of this study was to investigate how multivitamin use is associated with the risk of CVD in initially healthy men at baseline . METHODS We studied 18,530 male physicians aged ≥40 y from the Physicians ' Health Study I cohort who were free of CVD and cancer at baseline ( 1982 ) . All men provided a wide range of self-reported lifestyle and clinical factors plus intake of selected foods and dietary supplements . Cox proportional hazards models were used to calculate multivariable-adjusted HRs ( 95 % CIs ) . RESULTS During a mean follow-up of 12.2 y ( total of 225,287 person-years ) , there were 1697 incident cases of major CVD ( defined as nonfatal myocardial infa rct ion , nonfatal stroke , and CVD death ) . In multivariable-adjusted analyses , no significant associations were observed among baseline multivitamin users compared with nonusers for the risk of major CVD events ( HR : 0.94 ; 95 % CI : 0.84 , 1.05 ) , whereas a self-reported duration of ≥20 y at baseline was associated with lower risk ( HR : 0.56 ; 95 % CI : 0.35 , 0.90 ; P-trend = 0.05 ) . Baseline multivitamin use was also significantly inversely associated with the risk of cardiac revascularization ( HR : 0.86 ; 95 % CI : 0.75 , 0.98 ) . Baseline use of multivitamins was not significantly associated with other CVD endpoints . CONCLUSION In this long-term prospect i ve study in initially healthy men , multivitamin use for ≥20 y was associated with a lower risk of major CVD events To determine the relation between multivitamin use and death from heart disease , cerebrovascular disease , and cancer , the authors examined a prospect i ve cohort of 1,063,023 adult Americans in 1982 - 1989 and compared the mortality of users of multivitamins alone ; vitamin A , C , or E alone ; and multivitamin and vitamin A , C , or E in combination with that of vitamin nonusers by using multivariate Cox proportional hazard models . Multivitamin users had heart disease and cerebrovascular disease mortality risks similar to those of nonusers , whereas combination users had mortality risks that were 15 % lower than those of nonusers . Multivitamin and combination use had minimal effect on cancer mortality overall , although mortality from all cancers combined was increased among male current smokers who used multivitamins alone ( relative risk ( RR ) = 1.13 , 95 % confidence interval ( CI ) : 1.05 , 1.23 ) or in combination with vitamin A , C , or E ( RR = 1.16 , 95 % CI : 1.06 , 1.26 ) , but decreased in male combination users who had never ( RR = 0.86 , 95 % CI : 0.74 , 0.99 ) or had formerly ( RR = 0.90 , 95 % CI : 0.82 , 0.98 ) smoked . No such associations were seen in women . These observational data provide limited support for the hypothesis that multivitamin use in combination with vitamin A , C , or E may reduce heart disease and cardiovascular disease mortality , but add to concerns raised by r and omized studies that some vitamin supplements may adversely affect male smokers Objective : To determine whether calcium supplementation is associated with the development of dementia in women after a 5-year follow-up . Methods : This was a longitudinal population -based study . The sample was derived from the Prospect i ve Population Study of Women and H70 Birth Cohort Study in Gothenburg , Sweden , and included 700 dementia-free women aged 70–92 years . At baseline in 2000–2001 , and at follow-up in 2005–2006 , the women underwent comprehensive neuropsychiatric and somatic examinations . A CT scan was performed in 447 participants at baseline . Information on the use and dosage of calcium supplements was collected . Dementia was diagnosed according to DSM-III-R criteria . Results : Women treated with calcium supplements ( n = 98 ) were at a higher risk of developing dementia ( odds ratio [ OR ] 2.10 , 95 % confidence interval [ CI ] 1.01–4.37 , p = 0.046 ) and the subtype stroke-related dementia ( vascular dementia and mixed dementia ) ( OR 4.40 , 95 % CI 1.54–12.61 , p = 0.006 ) than women not given supplementation ( n = 602 ) . In stratified analyses , calcium supplementation was associated with the development of dementia in groups with a history of stroke ( OR 6.77 , 95 % CI 1.36–33.75 , p = 0.020 ) or presence of white matter lesions ( OR 2.99 , 95 % CI 1.28–6.96 , p = 0.011 ) , but not in groups without these conditions . Conclusions : Calcium supplementation may increase the risk of developing dementia in elderly women with cerebrovascular disease . Because our sample was relatively small and the study was observational , these findings need to be confirmed BACKGROUND Although basic research suggests that vitamins may have an important role in the prevention of cardiovascular diseases ( CVD ) , the data from cohort studies and clinical trials are inconclusive . METHODS This prospect i ve cohort study was conducted among 83 639 male physicians residing in the United States who had no history of CVD or cancer . At baseline , data on use of vitamin E , ascorbic acid ( vitamin C ) , and multivitamin supplements were provided by a self-administered question naire . Mortality from CVD and coronary heart disease ( CHD ) was assessed by death certificate review . RESULTS Use of supplements was reported by 29 % of the participants . During a mean follow-up of 5.5 years , 1037 CVD deaths occurred , including 608 CHD deaths . After adjustment for several cardiovascular risk factors , supplement use was not significantly associated with total CVD or CHD mortality . For vitamin E use , the relative risks ( RRs ) were 0.92 ( 95 % confidence interval [ CI ] , 0.70 - 1.21 ) for total CVD mortality and 0.88 ( 95 % CI , 0.61 - 1.27 ) for CHD mortality ; for use of vitamin C , the RRs were 0.88 ( 95 % CI , 0.70 - 1.12 ) for total CVD mortality and 0.86 ( 95 % CI , 0.63 - 1.18 ) for CHD mortality ; and for use of multivitamin supplements , the RRs were 1.07 ( 95 % CI , 0.91 - 1.25 ) for total CVD mortality and 1.02 ( 95 % CI , 0.83 - 1.25 ) for CHD mortality . CONCLUSIONS In this large cohort of apparently healthy US male physicians , self-selected supplementation with vitamin E , vitamin C , or multivitamins was not associated with a significant decrease in total CVD or CHD mortality . Data from ongoing large r and omized trials will be necessary to definitely establish small potential benefits of vitamin supplements on subsequent cardiovascular risk BACKGROUND Dietary supplements are widely used in industrialized countries . OBJECTIVE The objective was to examine the association between multivitamin use and myocardial infa rct ion ( MI ) in a prospect i ve , population -based cohort of women . DESIGN The study included 31,671 women with no history of cardiovascular disease ( CVD ) and 2262 women with a history of CVD aged 49 - 83 y from Sweden . Women completed a self-administered question naire in 1997 regarding dietary supplement use , diet , and lifestyle factors . Multivitamins were estimated to contain nutrients close to recommended daily allowances : vitamin A ( 0.9 mg ) , vitamin C ( 60 mg ) , vitamin D ( 5 μg ) , vitamin E ( 9 mg ) , thiamine ( 1.2 mg ) , riboflavin ( 1.4 mg ) , vitamin B-6 ( 1.8 mg ) , vitamin B-12 ( 3 μg ) , and folic acid ( 400 μg ) . RESULTS During an average of 10.2 y of follow-up , 932 MI cases were identified in the CVD-free group and 269 cases in the CVD group . In the CVD-free group , use of multivitamins only , compared with no use of supplements , was associated with a multivariable-adjusted hazard ratio ( HR ) of 0.73 ( 95 % CI : 0.57 , 0.93 ) . The HR for multivitamin use together with other supplements was 0.70 ( 95 % CI : 0.57 , 0.87 ) . The HR for use of supplements other than multivitamins was 0.93 ( 95 % CI : 0.81 , 1.08 ) . The use of multivitamins for ≥5 y was associated with an HR of 0.59 ( 95 % CI : 0.44 , 0.80 ) . In the CVD group , use of multivitamins alone or together with other supplements was not associated with MI . CONCLUSIONS The use of multivitamins was inversely associated with MI , especially long-term use among women with no CVD . Further prospect i ve studies with detailed information on the content of preparations and the duration of use are needed to confirm or refute our findings The Supplementation in Vitamins and Mineral Antioxidants Study was a double-blind , placebo-controlled , r and omized trial , in which 12,741 French adults ( 7,713 women aged 35 - 60 years and 5,028 men aged 45 - 60 years ) received a combination of ascorbic acid ( 120 mg ) , vitamin E ( 30 mg ) , beta-carotene ( 6 mg ) , selenium ( 100 microg ) and zinc ( 20 mg ) , or placebo daily for a median follow-up time of 7.5 years [ October 1994 to September 2002 ] . Antioxidant supplementation decreased total cancer incidence and total mortality in men . Postintervention follow-up assessment of total cancer incidence , ischemic cardiovascular disease incidence and total mortality was carried out for 5 years [ September 1 , 2002 , to September 1 , 2007 ] . No late effect of antioxidant supplementation was revealed 5 years after ending the intervention neither on ischemic cardiovascular disease incidence and mortality in both genders nor on cancer incidence in women . Regarding duration of intervention effects in men , the reduced risk of total cancer incidence and total mortality was no longer evident after the 5-year postintervention follow-up . During the postsupplementation period , the relative risk ( RR ) for total cancer incidence ( n = 126 ) was 0.98 ( 95 % confidence interval [ CI ] , 0.75 - 1.27 ) among antioxidant recipients compared to nonrecipients . For total mortality ( n = 90 ) , the RR was 0.98 ( 95 % CI , 0.75 - 1.26 ) for men receiving antioxidants compared to nonrecipients . In conclusion , beneficial effects of antioxidant supplementation in men disappeared during postintervention follow-up Although multivitamin/mineral supplements are commonly used in the United States , the efficacy of these supplements in preventing chronic disease or premature death is unclear . To assess the relation of multivitamin use with mortality and cancer , the authors prospect ively examined these associations among 182,099 participants enrolled in the Multiethnic Cohort Study between 1993 and 1996 in Hawaii and California . During an average 11 years of follow-up , 28,851 deaths were identified . In Cox proportional hazards models controlling for tobacco use and other potential confounders , no associations were found between multivitamin use and mortality from all causes ( for users vs. nonusers : hazard ratio = 1.07 , 95 % confidence interval : 0.96 , 1.19 for men ; hazard ratio = 0.96 , 95 % confidence interval : 0.85 , 1.09 for women ) , cardiovascular diseases , or cancer . The findings did not vary across subgroups by ethnicity , age , body mass index , preexisting illness , single vitamin/mineral supplement use , hormone replacement therapy use , and smoking status . There also was no evidence indicating that multivitamin use was associated with risk of cancer , overall or at major sites , such as lung , colorectum , prostate , and breast . In conclusion , there was no clear decrease or increase in mortality from all causes , cardiovascular disease , or cancer and in morbidity from overall or major cancers among multivitamin supplement users CONTEXT Although multivitamins are used to prevent vitamin and mineral deficiency , there is a perception that multivitamins may prevent cardiovascular disease ( CVD ) . Observational studies have shown inconsistent associations between regular multivitamin use and CVD , with no long-term clinical trials of multivitamin use . OBJECTIVE To determine whether long-term multivitamin supplementation decreases the risk of major cardiovascular events among men . DESIGN , SETTING , AND PARTICIPANTS The Physicians ' Health Study II , a r and omized , double-blind , placebo-controlled trial of a common daily multivitamin , began in 1997 with continued treatment and follow-up through June 1 , 2011 . A total of 14,641 male US physicians initially aged 50 years or older ( mean , 64.3 [ SD , 9.2 ] years ) , including 754 men with a history of CVD at r and omization , were enrolled . INTERVENTION Daily multivitamin or placebo . MAIN OUTCOME MEASURES Composite end point of major cardiovascular events , including nonfatal myocardial infa rct ion ( MI ) , nonfatal stroke , and CVD mortality . Secondary outcomes included MI and stroke individually . RESULTS During a median follow-up of 11.2 ( interquartile range , 10.7 - 13.3 ) years , there were 1732 confirmed major cardiovascular events . Compared with placebo , there was no significant effect of a daily multivitamin on major cardiovascular events ( 11.0 and 10.8 events per 1000 person-years for multivitamin vs placebo , respectively ; hazard ratio [ HR ] , 1.01 ; 95 % CI , 0.91 - 1.10 ; P = .91 ) . Further , a daily multivitamin had no effect on total MI ( 3.9 and 4.2 events per 1000 person-years ; HR , 0.93 ; 95 % CI , 0.80 - 1.09 ; P = .39 ) , total stroke ( 4.1 and 3.9 events per 1000 person-years ; HR , 1.06 ; 95 % CI , 0.91 - 1.23 ; P = .48 ) , or CVD mortality ( 5.0 and 5.1 events per 1000 person-years ; HR , 0.95 ; 95 % CI , 0.83 - 1.09 ; P = .47 ) . A daily multivitamin was also not significantly associated with total mortality ( HR , 0.94 ; 95 % CI , 0.88 - 1.02 ; P = .13 ) . The effect of a daily multivitamin on major cardiovascular events did not differ between men with or without a baseline history of CVD ( P = .62 for interaction ) . CONCLUSION Among this population of US male physicians , taking a daily multivitamin did not reduce major cardiovascular events , MI , stroke , and CVD mortality after more than a decade of treatment and follow-up . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00270647 |
13,694 | 26,594,837 | There were no significant differences in tolerability .
The limited evidence available to date suggests that bupropion and varenicline are effective and tolerable for smoking cessation in adults with serious mental illnesses | BACKGROUND AND AIMS To assess the efficacy and tolerability of adjunctive pharmacotherapy for smoking cessation in adults with serious mental illness ( SMI ) by means of a systematic review and network meta- analysis . | Abstract Alcohol and nicotine dependence are common in schizophrenia . Varenicline is effective in smoking cessation and has also been shown to decrease alcohol consumption in smokers . The present pilot study assessed the safety and effectiveness of varenicline for treatment of concurrent nicotine and alcohol dependence in schizophrenia . Out patients with schizophrenia or schizoaffective disorder and concurrent alcohol and nicotine dependence were enrolled in this 8-week , double-blind , r and omized , placebo-controlled trial . Alcohol use and smoking were assessed using self-report ( Timeline Follow-Back ) and biological measures . Adverse events were recorded . Changes in the number of st and ard drinks per week and cigarettes per week were compared in the 2 groups . Because of safety concerns or loss to follow-up , of 55 patients enrolled , only 10 started study medication , 5 each on varenicline and placebo . Gastrointestinal adverse effects , such as severe abdominal pain , limited study completion to only 4 subjects . Number of st and ard alcoholic drinks consumed per week decreased by [ mean ( SD ) ] 16.6 ( 20.1 ) in the varenicline group and by 2.4 ( 27.4 ) in the placebo group . Mean ( SD ) number of cigarettes smoked per week decreased by 66 ( 65 ) in the varenicline group and by 47 ( 77 ) in the placebo group . Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia may be problematic because of safety concerns limiting recruitment and poor tolerability ( gastrointestinal adverse effects ) limiting retention . There was no increased number of serious neuropsychiatric adverse events in the varenicline group . Based on this small sample , concurrent alcohol and nicotine dependence in schizophrenia may present special obstacles to successful treatment with varenicline BACKGROUND Schizophrenic patients have high rates of cigarette smoking compared with the general population . We compared sustained-release ( SR ) bupropion with placebo for smoking cessation in patients with schizophrenic disorders . We also examined how antipsychotic class predicts smoking cessation outcomes with bupropion . METHODS Thirty-two subjects meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and nicotine dependence were r and omized to bupropion SR ( BUP , 300 mg/day ) or placebo ( PLA ) . Outcomes included treatment retention , smoking abstinence rates , expired breath carbon monoxide ( CO ) levels , psychotic symptoms , and medication side effects . RESULTS Bupropion significantly increased trial endpoint 7-day point prevalence smoking abstinence rates compared with placebo [ BUP , 8/16 ( 50.0 % ) , PLA , 2/16 ( 12.5 % ) ; chi(2 ) = 5.24 , df = 1 , p < .05 ] , and reduced CO levels during the trial [ Medication x Time interaction ; Z = 3.09 , p < .01 ] . Positive schizophrenia symptoms were not altered by BUP , but negative symptoms were significantly reduced . Atypical antipsychotic drug treatment enhanced smoking cessation responses to BUP . Major side effects were dry mouth , gastrointestinal symptoms , headache , and insomnia . CONCLUSIONS Our results suggest that 1 ) BUP enhances smoking abstinence rates compared with PLA in nicotine-dependent schizophrenic smokers ; 2 ) BUP is well-tolerated and safe for use in these patients ; and 3 ) atypical antipsychotics may enhance smoking cessation outcomes with BUP Smoking cessation treatment is now integrated into many health-care systems and a major research effort is under way to improve current success rates . Until now results from r and omized clinical trials have been reported in many different ways , leading to problems of interpretation . We propose six st and ard criteria comprising the ' Russell St and ard ' ( RS ) . These criteria are applicable to trials of cessation aids where participants have a defined target quit date and there is face-to-face contact with research ers or clinic staff , as follows . ( 1 ) Follow-up for 6 months ( RS6 ) or 12 months ( RS12 ) from the target quit date or the end of a predefined ' grace period ' ; ( 2 ) self-report of smoking abstinence over the whole follow-up period allowing up to five cigarettes in total ; ( 3 ) biochemical verification of abstinence at least at the 6-month or 12-month follow-up point ; ( 4 ) use of an ' intention-to-treat ' approach in which data from all r and omized smokers are included in the analysis unless they have died or moved to an untraceable address ( participants who are included in the analysis are counted as smokers if their smoking status at the final follow-up can not be determined ) ; ( 5 ) following-up ' protocol violators ' and using their true smoking status in the analysis ; and ( 6 ) collecting follow-up data blind to smokers ' allocation to trial group . We believe that these criteria provide the best compromise between practicability and surrogacy for long-term cessation and will enable meaningful comparison between studies . There may be good reasons why other outcome criteria would also be reported , and studies that involve interventions with special groups or where there is no design ated target quit date or face to face contact would need to adapt these criteria accordingly Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed OBJECTIVE Virtually no clinical trials for smoking cessation have been undertaken in bipolar disorder . Varenicline has shown efficacy for smoking cessation , but warnings about neuropsychiatric adverse events have been issued . We assessed the efficacy and safety of varenicline in euthymic bipolar subjects motivated to quit smoking . METHOD Clinical ly stable adult patients with DSM-IV bipolar disorder ( n = 60 ) who smoked ≥ 10 cigarettes per day were r and omized to a 3-month , double-blind , placebo-controlled varenicline trial and a 3-month follow-up . Study enrollment was completed from February 2010 through March 2013 . Varenicline was dosed using st and ard titration , and smoking cessation counseling was provided to all patients . The primary outcome was defined as a 7-day point prevalence of self-reported no smoking verified by expired carbon monoxide level < 10 ppm at 12 weeks . Psychopathology and side-effects were assessed at each visit . RESULTS At 3 months ( end of treatment ) , significantly more subjects quit smoking with varenicline ( n/n = 15/31 , 48.4 % ) than with placebo ( n/n = 3/29 , 10.3 % ) ( OR = 8.1 ; 95 % CI , 2.03 - 32.5 ; P < .002 ) . At 6 months , 6 of 31 varenicline-treated subjects ( 19.4 % ) remained abstinent compared to 2 of 29 ( 6.90 % ) assigned to placebo ( OR = 3.2 ; 95 % CI , 0.60 - 17.6 ; P = .17 ) . Psychopathology scores remained stable . Ten serious adverse events occurred ( n = 6 , varenicline ; n = 4 , placebo ) . Abnormal dreams occurred significantly more often in varenicline-treated subjects ( n/n = 18/31 , 61.3 % ) than in those receiving placebo ( n/n = 9/29 , 31 % ; Fisher exact test , P = .04 ) . Eight varenicline-treated and 5 placebo-assigned subjects expressed fleeting suicidal ideation , a nonsignificant difference . CONCLUSIONS Varenicline shows efficacy for initiating smoking cessation in bipolar patients , but medication trials of longer duration are warranted for maintaining abstinence . Vigilance for neuropsychiatric adverse events is prudent when initiating varenicline for smoking cessation in this patient population . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01010204 The aim of this study is to examine the effects of treatment with varenicline , a partial agonist at the α4β2 and full agonist at the α7 nicotine acetylcholine receptor , on cognitive impairments in people with schizophrenia . In all , 120 clinical ly stable people with schizophrenia participated in r and omized , double-blind , placebo-controlled 8-week trial . Antipsychotic and concomitant medication doses remained fixed throughout the study . Varenicline was titrated up to 1 mg twice daily for weeks 2–8 . Neuropsychological , clinical , and safety assessment s were administered at baseline and weeks 1 , 2 , 4 , and 8 . In the primary analyses of neurocognitive differences at week 8 , no varenicline – placebo differences were significant . In secondary longitudinal analyses , varenicline improved compared with placebo on the Digital Symbol Substitution Test ( p=0.013 ) and the Wisconsin Card Sorting Test non-perseverative errors ( p=0.043 ) . Some treatment effects were different between smokers and non-smokers . In smokers , Continuous Performance Test hit reaction time ( p=0.008 ) and Stroop Interference ( p=0.004 ) were reduced for varenicline compared with placebo , while there were no treatment differences in non-smokers . No significant treatment main effects or interactions were noted for total scores on the Positive and Negative Syndrome Scale or the Scale for the Assessment for Negative Symptoms . Our findings suggest beneficial effects of adjunctive varenicline treatment with antipsychotics for some cognitive impairments in people with schizophrenia . In some cases , effects of treatment varied between smokers and non-smokers . Further study is required to assess the functional significance of these changes The purpose of this study was to investigate the effect of adding sustained-release ( SR ) bupropion to cognitive behavioral therapy ( CBT ) on smoking behavior and stability of psychiatric symptoms in patients with schizophrenia . We conducted a 3-month , double-blind , placebo-controlled trial of bupropion SR , 150 mg/day , added to a concurrent CBT program with 3-month follow-up in 19 stable out patients with schizophrenia who wanted to quit smoking . Eighteen subjects completed the trial . Bupropion treatment was associated with significantly greater reduction in smoking , as measured by self-report verified by expired-air carbon monoxide ( 6/9 subjects , 66 % ) , than placebo ( 1/9 subjects , 11 % ) during the 3-month active treatment period and the 3-month follow-up period . One subject in the bupropion group ( 11 % ) and no subjects in the placebo group achieved sustained tobacco abstinence for the 6-month trial . Bupropion treatment was associated with improvement in negative symptoms and greater stability of psychotic and depressive symptoms , compared with placebo , during the quit attempt . Subjects in the bupropion group experienced significant weight loss , compared with those on placebo during the smoking cessation attempt . These data suggest that bupropion SR , 150 mg/day , combined with CBT , may facilitate smoking reduction in patients with schizophrenia while stabilizing psychiatric symptoms during a quit attempt OBJECTIVE In 2009 , the U.S. Food and Drug Administration issued a black box warning for varenicline regarding neuropsychiatric events . The authors used data from r and omized controlled trials and from a large Department of Defense ( DOD ) observational study to assess the efficacy and safety of varenicline . METHOD The authors reanalyzed data from the 17 placebo-controlled r and omized controlled trials ( N=8,027 ) of varenicline conducted by Pfizer , using complete intent-to-treat person-level longitudinal data to assess smoking abstinence and reports of suicidal thoughts and behavior , depression , aggression/agitation , and nausea and to compare effects in patients with ( N=1,004 ) and without ( N=7,023 ) psychiatric disorders . The authors also analyzed a large DOD data set to compare acute ( 30-day and 60-day ) rates of neuropsychiatric adverse events in patients receiving varenicline or nicotine replacement therapy ( N=35,800 ) and to assess reports of anxiety , mood , and psychotic symptoms and disorders , other mental disorders , and suicide attempt . RESULTS In the r and omized controlled trials , varenicline increased the risk of nausea ( odds ratio=3.69 , 95 % CI=3.03 - 4.48 ) but not rates of suicidal events , depression , or aggression/agitation . It significantly increased the abstinence rate , by 124 % compared with placebo and 22 % compared with bupropion . Having a current or past psychiatric illness increased the risk of neuropsychiatric events equally in treated and placebo patients . In the DOD study , after propensity score matching , the overall rate of neuropsychiatric disorders was significantly lower for varenicline than for nicotine replacement therapy ( 2.28 % compared with 3.16 % ) . CONCLUSIONS This analysis revealed no evidence that varenicline is associated with adverse neuropsychiatric events . The evidence supports the superior efficacy of varenicline relative to both placebo and bupropion , indicating considerable benefit without evidence of risk of serious neuropsychiatric adverse events , in individuals with and without a recent history of a psychiatric disorder BACKGROUND Long-term success rates of smoking cessation programs for patients with schizophrenia are unknown . This study , conducted between June 2001 and November 2002 , evaluated the rate of smoking cessation and reduction in patients with schizophrenia ( DSM-IV ) 2 years after they had participated in a smoking cessation study in order to determine whether subjects who significantly reduced smoking during the original trial resumed their previous level of smoking at 2 years . METHOD Two years following a double-blind placebo-controlled trial of bupropion sustained release , 150 mg/day , added to cognitive-behavioral therapy for smoking cessation in patients with schizophrenia , subjects were interviewed , medical charts were review ed , and carbon monoxide in expired air was measured . RESULTS Seventeen of 18 subjects completed the follow-up assessment . More subjects were abstinent ( 22 % [ N = 4 ] ) at the 2-year follow-up than were abstinent at the end of the trial ( 6 % [ N = 1 ] ) . Subjects who achieved significant smoking reduction during the trial were more likely to be abstinent at 2 years ( 4/7 ) than those who did not significantly reduce smoking during the trial ( 0/11 ) ( chi(2 ) = 8.1 , p < .005 ) . Most subjects who achieved > or = 50 % reduction in smoking at the end of the trial maintained at least that level of reduction at 2 years . Smoking reduction during the treatment intervention was correlated with smoking reduction at follow-up ( r = 0.60 , p = .01 ) . CONCLUSION The results from this naturalistic study suggest that behavior changes achieved in smoking cessation programs for patients with schizophrenia may be durable and may predict future smoking behavior . We conclude that further investigation into the relationship between smoking reduction and future smoking cessation in special population s is indicated OBJECTIVE Effective smoking cessation treatments are needed for patients with schizophrenia , who , compared with the general population , have high rates of cigarette smoking and more difficulty quitting . We evaluated the safety and efficacy of varenicline for smoking cessation in out patients with stable schizophrenia or schizoaffective disorder . METHOD In this 12-week , r and omized , double-blind , multicenter trial ( May 8 , 2008 , to April 1 , 2010 ) , 127 smokers ( ≥ 15 cigarettes/d ) with DSM-IV-confirmed schizophrenia or schizoaffective disorder received varenicline or placebo ( 2:1 ratio ) . The primary outcome was safety and tolerability of varenicline assessed by adverse events frequency and changes in ratings on the Positive and Negative Syndrome Scale and other psychiatric scales from baseline to 24 weeks . Abstinence was defined as no smoking 7 days prior to weeks 12 and 24 , verified by carbon monoxide level . RESULTS Eighty-four participants received varenicline ; 43 , placebo . At 12 weeks ( end of treatment ) , 16/84 varenicline-treated patients ( 19.0 % ) met smoking cessation criteria versus 2/43 ( 4.7 % ) for placebo ( P = .046 ) . At 24 weeks , 10/84 ( 11.9 % ) varenicline-treated and 1/43 ( 2.3 % ) placebo-treated patients , respectively , met abstinence criteria ( P = .090 ) . Total adverse event rates were similar between groups , with no significant changes in symptoms of schizophrenia or in mood and anxiety ratings . Rates of suicidal ideation adverse events were 6.0 % ( varenicline ) and 7.0 % ( placebo ) ( P = 1.0 ) . There was 1 suicide attempt by a varenicline patient with a lifetime history of similar attempts and no completed suicides . CONCLUSIONS Varenicline was well tolerated , with no evidence of exacerbation of symptoms , and was associated with significantly higher smoking cessation rates versus placebo at 12 weeks . Our findings suggest varenicline is a suitable smoking cessation therapy for patients with schizophrenia or schizoaffective disorder . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT00644969 CONTEXT The administration of nicotine transiently improves many neurobiological and cognitive functions in schizophrenia and schizoaffective disorder . It is not yet clear which nicotinic acetylcholine receptor ( nAChR ) subtype or subtypes are responsible for these seemingly pervasive nicotinic effects in schizophrenia and schizoaffective disorder . OBJECTIVE Because α4β2 is a key nAChR subtype for nicotinic actions , we investigated the effect of varenicline tartrate , a relatively specific α4β2 partial agonist and antagonist , on key biomarkers that are associated with schizophrenia and are previously shown to be responsive to nicotinic challenge in humans . DESIGN A double-blind , parallel , r and omized , placebo-controlled trial of patients with schizophrenia or schizoaffective disorder to examine the effects of varenicline on biomarkers at 2 weeks ( short-term treatment ) and 8 weeks ( long-term treatment ) , using a slow titration and moderate dosing strategy for retaining α4β2-specific effects while minimizing adverse effects . SETTING Outpatient clinics . PARTICIPANTS A total of 69 smoking and nonsmoking patients ; 64 patients completed week 2 , and 59 patients completed week 8 . Intervention Varenicline . MAIN OUTCOME MEASURES Prepulse inhibition , sensory gating , antisaccade , spatial working memory , eye tracking , processing speed , and sustained attention . RESULTS A moderate dose of varenicline ( 1 ) significantly reduced the P50 sensory gating deficit in nonsmokers after long-term treatment ( P = .006 ) , ( 2 ) reduced startle reactivity ( P = .02 ) regardless of baseline smoking status , and ( 3 ) improved executive function by reducing the antisaccadic error rate ( P = .03 ) regardless of smoking status . A moderate dose of varenicline had no significant effect on spatial working memory , predictive and maintenance pursuit measures , processing speed , or sustained attention by Conners ' Continuous Performance Test . Clinical ly , there was no evidence of exacerbation of psychiatric symptoms , psychosis , depression , or suicidality using a gradual titration ( 1-mg daily dose ) . CONCLUSIONS Moderate-dose treatment with varenicline has a unique treatment profile on core schizophrenia-related biomarkers . Further development is warranted for specific nAChR compounds and dosing and duration strategies to target subgroups of schizophrenic patients with specific biological deficits BACKGROUND The relative effectiveness of second-generation ( atypical ) antipsychotic drugs as compared with that of older agents has been incompletely addressed , though newer agents are currently used far more commonly . We compared a first-generation antipsychotic , perphenazine , with several newer drugs in a double-blind study . METHODS A total of 1493 patients with schizophrenia were recruited at 57 U.S. sites and r and omly assigned to receive olanzapine ( 7.5 to 30 mg per day ) , perphenazine ( 8 to 32 mg per day ) , quetiapine ( 200 to 800 mg per day ) , or risperidone ( 1.5 to 6.0 mg per day ) for up to 18 months . Ziprasidone ( 40 to 160 mg per day ) was included after its approval by the Food and Drug Administration . The primary aim was to delineate differences in the overall effectiveness of these five treatments . RESULTS Overall , 74 percent of patients discontinued the study medication before 18 months ( 1061 of the 1432 patients who received at least one dose ) : 64 percent of those assigned to olanzapine , 75 percent of those assigned to perphenazine , 82 percent of those assigned to quetiapine , 74 percent of those assigned to risperidone , and 79 percent of those assigned to ziprasidone . The time to the discontinuation of treatment for any cause was significantly longer in the olanzapine group than in the quetiapine ( P<0.001 ) or risperidone ( P=0.002 ) group , but not in the perphenazine ( P=0.021 ) or ziprasidone ( P=0.028 ) group . The times to discontinuation because of intolerable side effects were similar among the groups , but the rates differed ( P=0.04 ) ; olanzapine was associated with more discontinuation for weight gain or metabolic effects , and perphenazine was associated with more discontinuation for extrapyramidal effects . CONCLUSIONS The majority of patients in each group discontinued their assigned treatment owing to inefficacy or intolerable side effects or for other reasons . Olanzapine was the most effective in terms of the rates of discontinuation , and the efficacy of the conventional antipsychotic agent perphenazine appeared similar to that of quetiapine , risperidone , and ziprasidone . Olanzapine was associated with greater weight gain and increases in measures of glucose and lipid metabolism OBJECTIVE The objective of this study was to examine the effects of tobacco abstinence and bupropion treatment on cognitive functioning in adult smokers with schizophrenia in the setting of a r and omized , double-blind , placebo-controlled clinical trial of bupropion for smoking cessation . METHOD Fifty-three adults with schizophrenia ( DSM-IV ) took part in a trial of bupropion for smoking cessation . Subjects were enrolled in the study from August 1999 to March 2003 . Forty-five subjects remained in the trial at week 4 ; 41 subjects , 19 taking bupropion and 22 taking placebo , completed the baseline and week 4 cognitive assessment s and were included in the analysis of adjusted effects of abstinence and bupropion treatment on cognitive function . RESULTS Controlling for bupropion treatment and baseline performance , 7 days of tobacco abstinence was associated with slowed motor speed ( finger tapping ) but was not associated with worsening of performance on tests of attention ( AX Continuous Performance Test [ AX-CPT ] ) , verbal learning and memory ( California Verbal Learning Test [ CVLT ] ) , working memory ( digit span ) , or executive function/inhibition ( Stroop ) and was not associated with worsening of any clinical measures . Controlling for abstinence status , bupropion was associated with reduction ( improvement ) in reaction time variability on the AX-CPT and with reduction in perseverative errors on the CVLT . CONCLUSION We conclude that 1 week of tobacco abstinence is associated with slowed motor speed but is not associated with detectable worsening in performance on a range of neuropsychological tests or clinical symptoms in the subset of patients who were able to quit smoking . We also conclude that bupropion treatment may be associated with improvement in variability of attention Abstract : The objective of this study was to examine the efficacy of bupropion for smoking cessation in patients with schizophrenia . Adults with schizophrenia who smoked more than 10 cigarettes per day and wished to try to quit smoking were recruited from community mental health centers , enrolled in a 12-week group cognitive behavioral therapy intervention , and r and omly assigned to receive either bupropion sustained-release 300 mg/d or identical placebo . Fifty-three adults , 25 on bupropion and 28 on placebo , were r and omized , completed at least 1 postbaseline assessment and were included in the analysis . The primary outcome measures were 7-day point prevalence abstinence in the week after the quit date ( week 4 ) and at the end of the intervention ( week 12 ) . Subjects in the bupropion group were significantly more likely to be abstinent for the week after the quit date ( 36 % [ 9/25 ] vs. 7 % [ 2/28 ] , P = 0.016 ) and at end of the intervention ( 16 % [ 4/25 ] vs. 0 % , P = 0.043 ) . Subjects in the bupropion group also had a higher rate of 4-week continuous abstinence ( weeks 8 - 12 ) ( 16 % [ 4/25 ] vs. 0 % , P = 0.043 ) and a longer duration of abstinence ( 4.2 [ 3.2 ] weeks vs. 1.8 [ 0.96 ] weeks , t = 2.30 , P = 0.037 ) . The effect of bupropion did not persist after discontinuation of treatment . Subjects in the bupropion group had no worsening of clinical symptoms and had a trend toward improvement in depressive and negative symptoms . We conclude that bupropion does not worsen clinical symptoms of schizophrenia and is modestly effective for smoking cessation in patients with schizophrenia . The relapse rate is high after treatment discontinuation The objective of this study was to examine whether there is a benefit of adding bupropion SR to high-dose combination nicotine replacement therapy ( NRT ) and weekly group cognitive behavioral therapy ( CBT ) for smoking reduction or cessation in schizophrenia . Fifty-one adult smokers with schizophrenia were r and omly assigned to a 12-week trial of bupropion SR 300 mg/d or placebo added to transdermal nicotine patch , nicotine polacrilex gum , and CBT . The treatment goal was smoking cessation . The primary outcome measure was biochemically confirmed 7-day point-prevalence of 50 % to 100 % smoking reduction at week 12 . Secondary outcomes were biochemically confirmed tobacco abstinence and change from baseline in expired air carbon monoxide ( CO ) and psychiatric symptoms . Subjects on bupropion + NRT had a greater rate of 50 % to 100 % smoking reduction at weeks 12 ( 60 % vs. 31 % ; P = 0.036 ) and 24 , a lower expired air CO in the treatment and follow-up periods , ( F = 13.8 ; P < 0.001 ) and a greater continuous abstinence rate at week 8 , before NRT taper , ( 52 % vs. 19 % ; P = 0.014 ) . However , relapse rates in subjects on bupropion + dual NRT were 31 % during NRT taper ( weeks 8 - 12 ) and 77 % at the 12-month follow-up . Abstinence rates did not differ by treatment group at weeks 12 ( 36 % vs. 19 % ) , 24 ( 20 % vs. 8 % ) , or 52 ( 12 % vs. 8 % ) . Because abstinence rates were high during treatment with combination pharmacotherapy and relapse rates were very high during taper and after discontinuation of treatment , study of longer term treatment with combination pharmacotherapy and CBT for sustained abstinence is warranted in those who attain initial abstinence with this intervention In the current study , we investigated how individual variants in the serotonin promoter gene , previously associated with smoking cessation and linked to anxiety-related personality traits , were associated with individual differences in responsiveness to bupropion and cognitive behavioral therapy ( CBT ) in a clinical population . We hypothesize that subjects with the long allele may be less responsive to treatment . Altogether 61 schizophrenic patients ( 46 M , 15 F ) on stable neuroleptic medication were initially enrolled in a smoking reduction program ( prospect i ve , double-blind , placebo-controlled ) including cognitive behavioral therapy plus placebo or CBT plus bupropion . Additionally , subjects were genotyped for a polymorphism in the serotonin transporter ( SLC6A4 ) . Thirty-two subjects ( 23 M , 9 F ) completed a 14-week course of treatment . While both groups of subjects demonstrated significant reductions in smoking behavior due to CBT , subjects receiving bupropion did not show significant differences in smoking behavior when compared to placebo . In addition , analysis by SPSS repeated measures multivariate showed a significant sex by SLC6A4 genotype interaction on the number of cigarettes smoked . Only male subjects with at least one short promoter region allele ( short/short and short/long combined ) showed a reduction in cigarette consumption as a result of treatment . This study provides preliminary evidence of how polymorphisms in the serotonin transporter can be informative in predicting individual responses to smoking reduction therapy |
13,695 | 23,015,617 | Our findings suggest that metoclopramide 10 mg i.v .
is effective to prevent PONV in patients having surgical procedures under general anaesthesia .
Metoclopramide seems to be a reasonable agent to prevent PONV | Previous evidence suggested that 10 mg systemic metoclopramide is not effective to prevent postoperative nausea and /or vomiting ( PONV ) in patients receiving general anaesthesia .
However , the evidence included data with question ed validity by the author Yoshitaka Fujii .
The objective of the current study was to examine the effect of a systemic dose of 10 mg metoclopramide to prevent PONV . | Background A prospect i ve r and omized study was performed to assess the value of some individual risk factors for postoperative nausea and vomiting ( PONV ) , and to compare the efficacy of ondansetron , metoclopramide , dexamethason , and combinations of these antiemetics in preventing PONV in patients after laparoscopic cholecystectomy . Methods The study enrolled 210 patients ( 157 women and 53 men ) scheduled for laparoscopic cholecystectomy . The patients were r and omly divided into seven groups . In groups 1 to 6 , antiemetic drugs were administered . Group 7 , the control group , received no antiemetic . For all the patients , individual risk factors for the incidence of nausea also were analyzed . Both nausea and vomiting were assessed separately 1 , 4 , 8 , and 12 h after the procedure . Results Postoperative nausea and vomiting were significantly less frequent in menopausal women and more frequent in patients with a history of motion sickness . A comparison of mean values for the incidence of nausea and vomiting in groups 1 to 6 with the same values in group 7 showed that the mean PONV incidences were highest in groups 3 and 7 , and the difference was significant . Conclusions Administration of antiemetic drugs significantly decreases the incidence of PONV in patients after laparoscopic cholecystectomy . The best decreases were achieved when ondansetron and dexamethason were applied together This prospect i ve clinical trial evaluates the feasibility and safety of elective cholecystectomy in a simulated outpatient protocol in 40 patients . Results were compared with a 19-patient control group managed by conventional postoperative methods . Oral liquids were begun in the recovery room , intravenous fluids were discontinued 4 hours after surgery , and enteral analgesics and antiemetics were provided on the ward . Protocol patients were r and omized in a double-blind fashion to receive metoclopramide or placebo after surgery to assess its influence on the early tolerance of oral intake . In the protocol group , nausea without emesis occurred in nine patients ( 23 % ) ; 11 others ( 28 % ) had nausea with emesis . This was not significantly different from the control group . Metoclopramide-treated patients did not demonstrate a lower incidence of nausea or emesis but did tolerate oral liquids earlier after surgery than the placebo group ( P less than 0.05 ) . After release from recovery , eight protocol patients ( 20 % ) requested parenteral narcotics for relief of pain . Postoperative urinary catheterization was required in nine protocol patients ( 23 % ) and five control patients ( 26 % ) . No major complications occurred . Outpatient cholecystectomy is both feasible and safe . Metoclopramide may allow earlier tolerance of enteral liquids postoperatively During the past decade the dem and for outpatient surgery has grown rapidly . Postoperative nausea and vomiting is one of the more common undesirable consequences of surgery , which may significantly delay the patient 's discharge from the ambulatory surgery center . None of the currently used antiemetic drugs is considered totally effective in abolishing nausea or vomiting . The purpose of this study was to compare the efficacy of ondansetron , a highly selective 5-hydroxytryptamine subtype-3 receptor antagonist , with that of metoclopramide for the prevention of postoperative emesis in patients undergoing cataract surgery . The incidence of postoperative nausea was significantly less in the ondansetron group than that in the metoclopramide group ( p = 0.046 ) . Although the incidence of vomiting was clinical ly less frequent in the ondansetron group , there were no significant differences between both treatment groups . To our knowledge , this is the first study to demonstrate that ondansetron is effective to prevent postoperative emesis after extracapsular cataract extraction OBJECTIVE To compare the clinical efficacy of acupressure with treatment induced by ondansetron and metoclopramide on reduction of the severity of postoperative nausea and vomiting ( PONV ) after strabismus surgery . METHODS There were 200 patients with ASA classes I-II , ages 10 to 60 years old , who underwent strabismus surgery that were included in this r and omized , prospect i ve , double-blind , placebo-controlled trial . Group I was the control , group II received metoclopramide 0.2 mg/kg , and group III received ondansetron 0.15 mg/kg intravenously immediately prior to anesthesia induction . In Group IV , acupressure wristb and s were applied at the P6 points . Acupressure wrist b and s were not placed appropriately for subjects of groups I-III . The acupressure wrist b and s were applied 30 minutes before anesthesia induction and removed six hours after surgery completion . Anesthesia was st and ardized . PONV was evaluated within 0 - 2 hours and 2 - 24 hours after surgery by a blinded observer . Results were analyzed by the Chi-square or Fisher exact test . A P value of < 0.05 was considered significant . RESULTS The incidence of PONV was not significantly different among acupressure , metoclopramide and ondansetron groups during 24 hours . Also , the severity of PONV was not significantly different between acupressure , metoclopramide , and ondansetron in the recovery and ward . CONCLUSION Acupressure at the P6 point causes a significant reduction in the incidence and severity of PONV 24 hours after strabismus surgery as well as metoclopramide ( 0.2 mg/kg ) and ondansetron ( 0.15 mg/kg ) intravenous for patients aged 10 or older . ( I rct ID : I RCT 138807152556N1 ) OBJECTIVE To compare the administration of sub hypnotic dose of propofol with metoclopramide and placebo in prevention of postoperative nausea and vomiting ( PONV ) after middle ear surgery . METHODS This clinical research was performed in the Faculty of Medicine , Gazi University , Besevler , Ankara , Turkey , between December 2004 and October 2005 . Following approval by the hospital ethics committee , 60 adult patients scheduled for a middle ear operation were r and omly assigned into 3 groups . The patients in group P received 0.5 mg x kg(-1 ) propofol ; in group M , 0.2 mg x kg(-1 ) metoclopramide , and in group C , 0.9 % saline solution . The number of patients suffering from nausea and vomiting at 0 - 4 , 4 - 12 , and 12 - 24 hours postoperatively , and additional use of antiemetics was recorded . RESULTS Comparisons of the data showed that at 0 - 4th hours , the incidence of vomiting was 25 % in group P , 40 % in group M , and 75 % in group C. The incidence rate of group P was significantly lower than that of group C ( p=0.002 ) , and the rate of antiemetics use in group C was higher than that in group P ( p=0.028 ) . The Nausea Vomiting Scale scores of group C were also significantly higher than those of group P ( p=0.005 ) . There were no significant differences between the values at 4 - 12 and 12 - 24 hours . CONCLUSION The administration of a sub hypnotic dose of propofol at the end of surgery was found to be at least as effective as metoclopramide in preventing PONV in the early postoperative period in adult patients undergoing middle ear surgery BACKGROUND Untreated , one third of patients who undergo surgery will have postoperative nausea and vomiting . Although many trials have been conducted , the relative benefits of prophylactic antiemetic interventions given alone or in combination remain unknown . METHODS We enrolled 5199 patients at high risk for postoperative nausea and vomiting in a r and omized , controlled trial of factorial design that was powered to evaluate interactions among as many as three antiemetic interventions . Of these patients , 4123 were r and omly assigned to 1 of 64 possible combinations of six prophylactic interventions : 4 mg of ondansetron or no ondansetron ; 4 mg of dexamethasone or no dexamethasone ; 1.25 mg of droperidol or no droperidol ; propofol or a volatile anesthetic ; nitrogen or nitrous oxide ; and remifentanil or fentanyl . The remaining patients were r and omly assigned with respect to the first four interventions . The primary outcome was nausea and vomiting within 24 hours after surgery , which was evaluated blindly . RESULTS Ondansetron , dexamethasone , and droperidol each reduced the risk of postoperative nausea and vomiting by about 26 percent . Propofol reduced the risk by 19 percent , and nitrogen by 12 percent ; the risk reduction with both of these agents ( i.e. , total intravenous anesthesia ) was thus similar to that observed with each of the antiemetics . All the interventions acted independently of one another and independently of the patients ' baseline risk . Consequently , the relative risks associated with the combined interventions could be estimated by multiplying the relative risks associated with each intervention . Absolute risk reduction , though , was a critical function of patients ' baseline risk . CONCLUSIONS Because antiemetic interventions are similarly effective and act independently , the safest or least expensive should be used first . Prophylaxis is rarely warranted in low-risk patients , moderate-risk patients may benefit from a single intervention , and multiple interventions should be reserved for high-risk patients This r and omized , double-blind , multicentre , parallel-group study compared the efficacy and safety of an intravenous dose of ondansetron 4 mg for the prevention of postoperative nausea and vomiting ( PONV ) with metoclopramide 10 mg and placebo in patients undergoing major gynaecological surgery . A total of 1044 patients ( 465 ondansetron , 462 metoclopramide , 117 placebo ) received study medication immediately prior to induction of anaesthesia and were included in the analysis of data . The proportion of patients experiencing no emesis and no nausea or provided with rescue antiemetic medication , the number of emetic episodes , and the duration and severity of nausea were recorded during the 24-h period after recovery . Significantly more patients who received ondansetron had no emetic episodes ( 44 % ) than those who received metoclopramide ( 36 % , P = 0.049 ) or placebo ( 25 % , P < 0.001 ) . A higher proportion of patients receiving ondansetron ( 32 % ) did not experience nausea ( metoclopramide 24 % , P = 0.009 ; placebo 16 % , P < 0.001 ) . Significantly fewer patients in the ondansetron group required rescue medication or were withdrawn due to treatment failure ( P < 0.05 ) . In the ondansetron group the total number of emetic episodes , the median time to the first emetic episode or treatment failure , and the duration and severity of nausea were reduced significantly compared with metoclopramide or placebo ( P < 0.05 ) . The safety profile was similar for each treatment group Background : Nausea and vomiting are the most common causes of postoperative complications , and they are seen most often after operations performed using general anesthesia and sedation . We design ed this study to compare the effects of droperidol , metoclopramide , tropisetron , and ondansetron for the prevention of postoperative nausea and vomiting in patients undergoing gynecologic operations . Methods : One hundred patients were r and omly assigned to 1 of 5 groups : group D was given 2.5 mg droperidol ; group M , 10 mg metoclopramide ; group T , 2.5 mg tropisetron ; group O , 4 mg ondansetron 5 min after induction , and group C was the control group and received no prophylactic antiemetic treatment . All patients were observed for sedation and postoperative nausea and vomiting for 48 h. Results : Within 24 h after the operation , severe postoperative nausea and vomiting were seen in 4 patients ( 20 % ) in group D , 8 ( 40 % ) in group M , 5 ( 25 % ) in group T , 3 ( 15 % ) in group O , and 12 patients ( 60 % ) in the control group . Patients receiving droperidol , tropisetron , and ondansetron had significantly less serious emesis than the control group ( p < 0.05 ) . Sedation was seen in 5 patients receiving droperidol ( 4 patients score 2 ; and 1 patient score 3 ) and tropisetron ( 2 patients score 2 ; and 3 patients score 3 ) 15 min after surgery ; this was significantly higher than in the control group ( p < 0.05 ) . Conclusion : We conclude that metoclopramide is not effective in preventing postoperative nausea and vomiting after gynecologic operations . Droperidol , tropisetron , and ondansetron are effective ; however , the sedating effects of droperidol and tropisetron should be considered Abstract Objectives To determine whether 10 mg , 25 mg , or 50 mg metoclopramide combined with 8 mg dexamethasone , given intraoperatively , is more effective in preventing postoperative nausea and vomiting than 8 mg dexamethasone alone , and to assess benefit in relation to adverse drug reactions . Design Four-armed , parallel group , double blind , r and omised controlled clinical trial . Setting Four clinics of a university hospital and four district hospitals in Germany . Participants 3140 patients who received balanced or regional anaesthesia during surgery . Main outcome measures Postoperative nausea and vomiting within 24 hours of surgery ( primary end point ) ; occurrence of adverse reactions . Results Cumulative incidences ( 95 % confidence intervals ) of postoperative nausea and vomiting were 23.1 % ( 20.2 % to 26.0 % ) , 20.6 % ( 17.8 % to 23.4 % ) , 17.2 % ( 14.6 % to 19.8 % ) , and 14.5 % ( 12.0 % to 17.0 % ) for 0 mg , 10 mg , 25 mg , and 50 mg metoclopramide . In the secondary analysis , 25 mg and 50 mg metoclopramide were equally effective at preventing early nausea ( 0 - 12 hours ) , but only 50 mg reduced late nausea and vomiting ( > 12 hours ) . The most frequent adverse drug reactions were hypotension and tachycardia , with cumulative incidences of 8.8 % ( 6.8 % to 10.8 % ) , 11.2 % ( 9.0 % to 13.4 % ) , 12.9 % ( 10.5 % to 15.3 % ) , and 17.9 % ( 15.2 % to 20.6 % ) for 0 mg , 10 mg , 25 mg , and 50 mg metoclopramide . Conclusion The addition of 50 mg metoclopramide to 8 mg dexamethasone ( given intraoperatively ) is an effective , safe , and cheap way to prevent postoperative nausea and vomiting . A reduced dose of 25 mg metoclopramide intraoperatively , with additional postoperative prophylaxis in high risk patients , may be equally effective and cause fewer adverse drug reactions . Trial registration Current Controlled Trials IS RCT Background : In this prospect i ve , r and omized , double-blind study , we compared the efficacy of ondansetron versus dehydrobenzoperidol ( droperidol ) or metoclopramide in the treatment of established postoperative nausea and vomiting in 200 adult patients undergoing laparoscopic surgery under general anesthesia . Methods : One hundred seventy-three American Society of Anesthesiologists ( ASA ) I and II patients satisfied inclusion criteria . Fifty-seven patients received ondansetron 4 mg ( group O ) , 57 patients were given droperidol 1.25 mg ( group D ) , and 59 patients received metoclopramide 10 mg ( group M ) . Antiemetic efficacy was compared at 10 minutes and 30 minutes after the administration of the study drug . Results : At 10 minutes , nausea scores in group O dropped from 8.3 to 3.7 , in group D from 8.5 to 5 , and in group M from 8.4 to 6.7 ; ( P < 0.05 between the three groups ) . At 30 minutes , nausea scores were 1.3 in group O , 1.7 in group D , and 5 in group M ; ( P < 0.05 between group M and the other two groups ) . In the droperidol group , 25 % of patients developed sedation . Patient satisfaction was best with ondansetron . Conclusions : Both ondansetron and droperidol were more effective in the treatment of established postoperative nausea and vomiting than was metoclopramide . However , patients were satisfied best with ondansetron , which acts faster and causes less sedation than droperidol OBJECTIVES To compare the efficacy of ondansetron to that of metoclopramide , dehydrobenzperidol and placebo for the prevention of postoperative nausea and vomiting ( PONV ) after laparoscopic cholecystectomy in a double-blind r and om study . PATIENTS AND METHOD A total of 100 ASA I , II and III patients undergoing scheduled laparoscopic cholecystectomy were divided into 4 groups according to whether they received one of the following intravenously just prior to anesthetic induction : 1.25 mg dehydrobenzperidol ( group D ) , 10 mg metoclopramide ( group M ) , 4 mg ondansetron ( group O ) or 2 ml of saline ( group P ) . All received general anesthesia with induction by thiopental , analgesia with fentanyl , muscle relaxation with atracurium and maintenance with oxygen-air and isoflurane . Episodes of nausea and /or vomiting during the first 24 h after surgery were recorded . Treatment was considered effective if no episodes occurred during this period . RESULTS Nine of the 100 patients were excluded from the study . There were no significant differences in demographic variables among the 4 groups . The incidence of PONV was significantly greater in group P than in any of the other groups . There were no significant differences in PONV among groups D , M and O. CONCLUSIONS Ondansetron provides safe , effective prophylaxis for PONV after laparoscopic cholecystectomy , but it is not superior to the antiemetic drugs usually used . Its use may be justified in patients in whom dehydrobenzperidol or metoclopramide are contraindicated The efficacy of domperidone 20 mg , droperidol 2.5 mg , metoclopramide 10 mg or placebo ( saline ) administered i.v . before induction of anaesthesia , was studied in 199 women undergoing gynaecological surgery as day cases . Following a st and ardized general anaesthetic technique , droperidol or metoclopramide significantly reduced the incidence of nausea and vomiting ; domperidone decreased the incidence of postoperative nausea alone . The occurrence of extrapyramidal reactions was similar in all groups . Patients treated with antiemetics were no more se date d than those given placebo . Those receiving droperidol complained of significantly less postoperative pain than those who had received domperidone or metoclopramide BACKGROUND Postoperative nausea and vomiting ( PONV ) is one of the most significant problems in laparoscopic surgery . The antiemetic effects of metoclopramide and droperidol used alone or in combination for prevention of PONV after laparoscopic cholecystectomy ( LC ) were assessed in this prospect i ve , double blind , placebo controlled r and omized study . PATIENTS AND METHODS A series of 140 patients , ASA physical status I or II , were included in the study . Patients were r and omized to one of the following groups : 1 , placebo ; 2 , metoclopramide 10 mg after the induction of anesthesia and placebo at 12 h postoperatively ; 3 , droperidol 1.25 mg after the induction of anesthesia and droperidol 1.25 mg at 12 h postoperatively ; and 4 , droperidol 1.25 mg plus metoclopramide 10 mg after the induction of anesthesia and droperidol 1.25 mg at 12 h postoperatively . Patients were observed for 24 hours for PONV , pain , need for rescue analgesics , and adverse events . RESULTS Data were analyzed using the Student 's t-test and chi-square test , with P < 0.05 considered statistically significant . The mean incidence of PONV was 54 % with placebo , 42 % with metoclopramide , 14 % with two doses of droperidol alone , and 11 % with a combination of metoclopramide plus droperidol . The patients receiving a combination of metoclopramide and droperidol had a significantly lower rate of PONV than those administered metoclopramide alone ( P < 0.05 ) or placebo ( P < 0.001 ) . Those receiving two-dose droperidol alone also had a significantly lower incidence of PONV compared with metoclopramide ( P < 0.05 ) and placebo ( P < 0.001 ) . There was no statistically significant difference between the metoclopramide and placebo groups . Sedation was significantly greater in patients administered droperidol 12 h postoperatively . CONCLUSION The combination of metoclopramide and droperidol , and two-dose droperidol alone , were found to significantly decrease the incidence of PONV after LC , whereas metoclopramide alone proved inefficient The effectiveness of ginger ( Zingiber officinale ) as an antiemetic agent was compared with placebo and metoclopramide in 60 women who had major gynaecological surgery in a double‐blind , r and omised study . There were statistically significantly fewer recorded incidences of nausea in the group that received ginger root compared with placebo ( p < 0.05 ) . The number of incidences of nausea in the groups that received either ginger root or metoclopramide were similar . The administration of antiemetic after operation was significantly greater in the placebo group compared to the other two groups ( p < 0.05 ) OBJECTIVE To compare total intravenous anesthesia ( TIVA ) with ondansetron , and metoclopramide in preventing postoperative nausea and vomiting ( PONV ) in laparoscopic cholecystectomy patients . METHODS A prospect i ve r and omized double-blinded study was performed at King Abdulaziz University Hospital , Jeddah , Saudi Arabia in 2007 . Seventy-five patients scheduled for laparoscopic cholecystectomy under TIVA were r and omized to receive either : metoclopramide 10 mg ( n=25 ) , 4 mg ondansetron ( n=25 ) , or placebo ( n=25 ) at the end of surgery . Postoperative nausea and vomiting episodes , analgesic supply , rescue medication , adverse events , and patient satisfaction were collected over 24 hours . RESULTS Nineteen patients developed PONV . The frequencies of PONV were equal for the 2 groups ( 28 % ) , and lower among the ondansetron group ( 20 % ) ( p>0.05 ) . Female gender , lengthy surgery , and longer hospital stay were associated with more frequent PONV regardless of the study group ( p<0.05 ) . Patient 's satisfaction was more frequent among the ondansetron group ( p>0.05 ) . Morphine consumption was associated with more PONV , but it was statistically significant only in the placebo group . There was no difference between the 3 groups with regard to the VAS pain score , cardiovascular parameters , or oxygen saturation . CONCLUSION It is unlikely that a single technique or drug will ever be effective in treating emesis under all surgical circumstances . Therefore , a multimodal regimen incorporating avoidance of emesis triggering factors , and administration of antiemetic medications is recommended The efficacy of ondansetron 4 mg was compared with metoclopramide 10 mg for the prevention of post-operative nausea and vomiting in patients after major gynaecological abdominal surgery . Anaesthesia was st and ardized using thiopentone , atracurium and methadone for induction followed by isoflurane in nitrous oxide-oxygen mixture . Fifty patients were r and omized in a double-blind fashion to either receive intravenous ( i.v . ) ondansetron 4 mg or metoclopramide 10 mg during closure of the pelvic peritoneum . The incidence and frequency of vomiting , and the incidence of severe nausea was recorded for 24 h after surgery . One patient was excluded because of respiratory depression . In the first 4 h after surgery , five patients ( 20 % ) in the ondansetron group ( n = 25 ) and eight patients ( 33 % ) in the metoclopramide group ( n = 24 ) vomited , whereas at 4 - 12 h , this increased to 11 patients ( 44 % ) and nine patients ( 37.5 % ) respectively . The incidence was 52 and 37.5 % respectively in the subsequent 12 - 24 h. The highest incidence of nausea was in the first 4 h after surgery , being 56 and 37.5 % in the ondansetron and the metoclopramide groups respectively . This decreased to less than 25 % in both groups in the 12 - 24 h period . Ondansetron 4 mg and metoclopramide 10 mg had similar but short lasting efficacy for the prevention of vomiting in patients who received continued opioid analgesia after major gynaecological surgery We have compared the efficacy of ondansetron , metoclopramide , droperidol and placebo in the prevention of postoperative nausea and vomiting in 118 day stay patients undergoing laparoscopic gynaecological procedures . All received a st and ardised general anaesthetic offentanyl , propofol , nitrous oxide in oxygen and isoflurane . Three to five min before induction of anaesthesia , patients were allocated to receive ondansetron 4 mg , metoclopramide 10 mg , droperidol 1 mg or placebo in a r and omised , double‐blind manner . Visual analogue scores for nausea , the incidence of emetic episodes , and analgesic and antiemetic consumption were recorded for 48 h postoperatively . The scores for nausea were significantly lower in the ondansetron group ( p < 0.01 ) compared with the other three groups at 1 , 2 and 4h after operation ; thereafter there was no difference . The incidence of erne sis was lower ( p = 0.063 ) and time to first oral fluids was shorter ( p < 0.05 ) in the ondansetron group . Oral analgesic requirements were significantly greater in the ondansetron group over the 48 h study period . Two patients , one each in the placebo and metoclopramide groups , had to remain in hospital overnight because of persistent emetic symptoms Women ( 182 ) undergoing elective orthopaedic surgery under general anaesthesia received 100 or 200 mg alizapride , 1.25 mg droperidol , 20 mg metoclopramide or a saline placebo intravenously 5 - 10 min before the end of anaesthesia in a double-blind r and om fashion to prevent post-operative nausea and vomiting . Administration of the same anti-emetic was repeated during 24 h post-operatively if the patient complained of nausea or retched or vomited . Significantly fewer patients given any of the anti-emetics prophylactically were nauseated or vomited in comparison with patients given saline . The incidence of nausea and vomiting in the saline group was 83 % , while in those patients who received an anti-emetic it was as follows : droperidol 35 % ( P less than 0.001 vs. saline ) , alizapride , 100 mg 46 % ( P less than 0.01 ) , alizapride 200 mg 53 % ( P less than 0.05 ) and metoclopramide 58 % ( P less than 0.05 ) . The number of patients needing an additional dose of the same substance in the post-operative period was significantly higher in the saline group ( 67 % ) than in the groups which had received droperidol ( 32 % , P less than 0.01 ) and alizapride 100 mg ( 37 % , P less than 0.05 ) or 200 mg ( 33 % , P less than 0.05 ) . The patients who received metoclopramide , however , did not differ statistically from the saline group in the treatment of nausea and vomiting . It is concluded that droperidol was the most effective , and metoclopramide the least effective , anti-emetic in this study Tiapride ( Tiapridal , Delagrange ) , a dopaminergic D2 receptor blocking agent having anxiolytic , sedative , antiemetic and analgesic properties was compared with metoclopramide and placebo in a r and omized double-blind trial to determine its effects on post-operative nausea , vomiting , and sedation . The agents were given intravenously immediately before induction of anaesthesia to 75 women scheduled for minor elective gynaecological surgery . A st and ardized anaesthetic technique was used in all the patients . In the recovery room anti-emetic and sedative effects of tiapride and metoclopramide were similar and significantly better ( P < 0.001 ) than placebo . In the ward at the end of 5 h anti-emetic ( P < 0.05 ) , and sedative ( P < 0.01 ) effects of tiapride were significantly better than both metoclopramide and placebo UNLABELLED Opposing effects of ondansetron and tramadol on the serotonin pathway have been suggested which possibly increase tramadol consumption and emesis when co-administered . In a r and omized , double-blinded study , 179 patients received intravenous ondansetron , metoclopramide , or placebo for emesis prophylaxis . Analgesic regimen consisted of tramadol intraoperative loading and subsequent patient-controlled analgesia . Tramadol consumption and response to antiemetic treatment were compared . Additionally , plasma concentrations of ondansetron and (+)O-demethyltramadol and CYP2D6 genetic variants were analyzed as possible confounders influencing analgesic and antiemetic efficacy . Tramadol consumption did not differ between the groups . Response rate to antiemetic prophylaxis was superior in patients receiving ondansetron ( 85.0 % ) compared with placebo ( 66.7 % , P = .046 ) , with no difference to metoclopramide ( 69.5 % ) . Less vomiting was reported in the immediate postoperative hours in the verum groups ( ondansetron 5.0 % , metoclopramide 5.1 % ) compared with placebo ( 18.6 % ; P = .01 ) . Whereas plasma concentrations of (+)O-demethyltramadol were significantly correlated to CYP2D6 genotype , no influence was detected for ondansetron . Co-administration of ondansetron neither increased tramadol consumption nor frequency of PONV in this postoperative setting . PERSPECTIVE Controversial findings were reported for efficacy of tramadol and ondansetron when co-administered due to their opposing serotonergic effects . Co-medication of these drugs neither increased postoperative analgesic consumption nor frequency of emesis in this study enrolling patients recovering from major surgery BACKGROUND AND OBJECTIVE This study was conducted in a tertiary hospital with the aim of comparing the efficacy of a combination of dexamethasone and metoclopramide with dexamethasone and ondansetron for the prophylaxis of postoperative nausea and vomiting [ PONV ] after diagnostic gynaecological laparoscopic procedures . SUBJECTS AND METHODS In this prospect i ve , r and omised , double-blind study , 120 women received either saline I.V. [ Group I , n=40 ] ; a combination of dexamethasone [ 8 mg ] with metoclopramide [ 10 mg ] [ Group II , n=40 ] ; or a combination of dexamethasone [ 8 mg ] with ondansetron [ 4 mg ] [ Group III , n=40 ] prior to induction of general anaesthesia . PONV was evaluated at regular intervals . The results were analysed using one-way ANOVA , post-hoc , Chi-square , Kruskal-Wallace tests and Z test for proportions where appropriate through a SPSS V.9 package . RESULTS The 3 groups were well matched for demographic characteristics . The incidence of nausea and emesis was significantly lower in Group III [ [ 17.5 % , P < 0.02 ] and [ 10 % , P < 0.01 ] respectively ] . Nausea scores were also lower in Group III [ P < 0.02 ] . Rescue anti-emetic requirements were higher in Group I [ P < 0.05 ] as compared to Groups II and III . CONCLUSIONS A combination of dexamethasone and ondansetron was more efficacious as compared to that of metoclopramide and dexamethasone . The combination of metoclopramide and dexamethasone seems to offer no additional benefit as compared to saline placebo BACKGROUND Postoperative nausea and vomiting ( PONV ) remains a very troublesome concomitant phenomenon after general anesthesia . The present study was design ed to compare the efficacy and safety of ondansetron with metoclopramide for prophylaxis of PONV in patients undergoing major gynecological surgery . MATERIAL AND METHOD A prospect i ve , r and omized , double-blind , 382 female patients received either ondansetron 4 mg or metoclopramide 10 mg intravenous administration immediately before the induction of anesthesia . A st and ard general anesthetic technique was employed throughout . Nausea , vomiting , and safety assessment s were performed continuously during the 24 h postoperative period . RESULTS Of the 380 patients evaluated , significantly fewer ondansetron 4 mg treated patients ( 89/189 ; 47 % ) experienced postoperative nausea and /or vomiting compared with metoclopramide treated patients ( 115/ 191 ; 60 % ) during the study period ( p = 0.007 , 95 % CI : 1.07 , 1.66 ) . Postoperative adverse events were not significantly different between the groups . CONCLUSION Prophylactic use of ondansetron is more effective than metoclopramide for preventing PONV in patients undergoing major gynecological surgery Background Postoperative nausea and vomiting ( PONV ) are one of the most common complaints following anesthesia and surgery . This study was design ed to evaluate the efficacy of dexamethasone , metoclopramide , and their combination to prevent PONV in patients undergoing laparoscopic cholecystectomy . Methods A total of 160 ASA physical status I and II patients were included in this r and omized , double blind , placebo-controlled study . Patients were r and omly assigned to 4 groups ( n = 40 each ) : group 1 consisting of control patients administered 0.9 % NaCl ; group 2 patients received metoclopramide 10 mg just before the end of anesthesia ; group 3 patients received dexamethasone 8 mg after the induction of anesthesia ; and group 4 patients received dexamethasone 8 mg after the induction of anesthesia and metoclopramide 10 mg before the end of anesthesia . The incidence of PONV , mean visual analog pain scores at rest and on movement , time to the first request for analgesia , side effects , and well-being score were recorded during the first 24 h postoperatively . Results Data were analyzed using one-way analysis of variance ( ANOVA ) and the χ2 test , with p < 0.05 considered statistically significant . The total incidence of PONV was 60 % with placebo , 45 % with metoclopramide , 23 % with dexamethasone , and 13 % with the combination of dexamethasone plus metoclopramide . None of the dexamethasone plus metoclopramide group patients ( p < 0.05 versus groups 1 and 2 ) and one dexamethasone group patient ( p < 0.05 versus group 1 ) required antiemetic rescue , as compared with four patients in the metoclopramide group and six patients in the placebo group . Pain scores , the time to the first request for analgesia , and side effects were similar across the study groups . Conclusions Dexamethasone and the combination of dexamethasone plus metoclopramide were more effective in preventing PONV than metoclopramide and placebo We have studied the antiemetic efficacy of droperidol alone , and in combination with metoclopramide in first trimester termination of pregnancy in day surgery . The aim was to determine whether the addition of metoclopramide could further reduce the incidence of postoperative nausea and vomiting ( PONV ) but avoid excessive sedation . Group I ( control , n = 40 ) received i.v . droperidol 0.625 mg at induction . Group II ( study , n = 40 ) received i.v . droperidol 0.625 mg and i.v . metoclopramide 10 mg at induction . The incidence of nausea at 1 and 2 hours postoperatively was 23 % and 10 % in group I , and 5 % and nil in group II respectively . The difference in the incidence of nausea was significant at p < 0.05 at one hour but not at two hours postoperatively . No patients vomited . There was no difference in the sedation and pain score between them . We did not observe any significant side effects attributable to either drug . All patients were discharged home within 3 hours . We conclude that in the prevention of PONV , the combination of metoclopramide and droperidol is superior to the use of droperidol alone at one hour but not at two hours postoperatively Background : Ondansetron has a well documented antiemetic prophylactic effect , whereas in most studies of postoperative nausea and vomiting ( PONV ) , metoclopramide is less efficacious . This can be attributed to the short‐lasting effect of metoclopramide when a low dose is given at the beginning of surgery . We wanted to test a 20‐mg dose of metoclopramide given at the end of surgery , using ondansetron 8 mg as a reference Postoperative nausea and vomiting are common complications of anaestnesia . This double-blind clinical trial assessed the incidence of nausea and vomiting after cataract surgery with intravenous anaesthesia in 100 patients r and omly assigned to preinduction placebo ( saline ) , metoclopramide ( 10 mg ) , dexamethasone ( 8 mg ) or the 2 drugs combined . The incidence of nausea in the recovery room was 44 % with placebo , 20 % with metoclopramide , 16 % with dexamethasone and 8 % with the combination . The incidence of vomiting was 20 % , 4 % , 4 % and 0 % respectively in the 4 groups . Metoclopramide plus dexamethasone combination significantly decreased nausea and vomiting both in the recovery room and 24 hours afterwards and is recommended for high-risk groups , especially in outpatient surgeries STUDY OBJECTIVE To compare the efficacy of a low dose of dexamethasone ( 5 mg ) with metoclopramide 10 mg and saline in preventing nausea and vomiting after epidural morphine in posthysterectomy analgesia . DESIGN R and omized , placebo-controlled study . SETTING Inpatient surgery at Municipal Women 's and Children 's General Hospital . PATIENTS 120 ASA physical status I and II women receiving epidural morphine for posthysterectomy analgesia . INTERVENTIONS All patients received epidural morphine 3 mg for postoperative analgesia . The dexamethasone group ( n = 40 ) received dexamethasone 5 mg , the metoclopramide group ( n = 40 ) received metoclopramide 10 mg , and the saline group ( n = 40 ) received saline . MEASUREMENTS AND MAIN RESULTS The occurrence of nausea and vomiting appeared more frequently during 6 to 24 hours following the administration of epidural morphine . The total frequency of nausea and vomiting in the dexamethasone group was significantly lower than that of the metoclopramide and saline groups during this period , with reporting frequencies of 21 % , 49 % , and 53 % , respectively ( p < .05 each ) . However , the difference between metoclopramide and saline did not reach statistical significance . CONCLUSIONS Dexamethasone 5 mg was more effective than metoclopramide or saline in the prevention of nausea and vomiting associated with epidural morphine for postoperative analgesia STUDY OBJECTIVE To compare the prophylactic administration of ondansetron plus droperidol , droperidol plus metoclopramide , and perphenazine to determine effects on postoperative nausea , vomiting , and sedation after laparoscopic cholecystectomy . DESIGN Prospect i ve , r and omized , double-blind study . SETTING University medical center . PATIENTS 212 ASA physical status I and II adults presenting for laparoscopic cholecystectomy . INTERVENTIONS Patients were r and omly assigned to receive one of three prophylactic antiemetic drug combinations : ondansetron 4 mg plus droperidol 0.625 mg ( Group OD ) , droperidol 0.625 mg plus metoclopramide 10 mg ( Group DM ) , or perphenazine 5 mg ( Group P ) . Study drugs were administered intravenously after induction of general anesthesia . MEASUREMENTS AND MAIN RESULTS The groups were similar with respect to gender , age , weight , duration of surgery , numbers of patients receiving intraoperative atropine or ephedrine , number admitted overnight , and time to discharge home . Patients in Group P used lower total doses of opioids than did patients in Group OD . There were no significant differences in postoperative nausea , pain , or sedation scores , in numbers of patients requiring antiemetics ( Group OD , 13 of 66 ; Group DM , 15 of 66 ; Group P , 14 of 68 ) , or in numbers of patients vomiting , either in hospital or during the first postoperative day . CONCLUSIONS These three drug regimens are equivalent for antiemetic prophylaxis before laparoscopic cholecystectomy BACKGROUND Postoperative nausea and vomiting are significant problems in laparoscopic surgery . This double-blind , r and omized , prospect i ve trial compares the prophylactic use of metoclopramide , ondansetron , and placebo for the treatment of postoperative nausea and vomiting in patients undergoing outpatient laparoscopic cholecystectomy . METHODS Two hundred thirty-two patients aged 18 to 73 years were r and omized into three groups . Patients received intravenously 10 mg of metoclopramide , 4 mg of ondansetron , or placebo in a double-blinded manner prior to surgery . RESULTS The incidence of nausea was 32 % for metoclopramide , 45 % for ondansetron , and 44 % for placebo in the postanesthesia care unit or day surgery , which was not statistically significant . The incidence of vomiting was 8 % for metoclopramide , 4 % for ondansetron , and 22 % for placebo in the postanesthesia care unit or day surgery . These differences were statistically significant when comparing both drugs to placebo but not when comparing both drugs to each other . CONCLUSION Prophylactic administration of metoclopramide or ondansetron significantly reduces the incidence of postoperative vomiting for laparoscopic cholecystectomy , but neither drug was found to be significantly more effective than the other . Metoclopramide is a more cost-effective treatment The prophylactic antiemetic efficacy of ondansetron was evaluated in a r and omized , double-blind comparison with droperidol and metoclopramide in 66 patients undergoing general anesthesia for dilatation and curettage . Ten minutes before induction of anesthesia , 22 patients received a single intravenous dose of 8 mg of ondansetron , 22 others received 1.25 mg of droperidol , and the remaining 22 received 10 mg of metoclopramide . Anesthesia was induced with 3.3 - 5 mg/kg of intravenous thiopental and maintained with 65 % nitrous oxide in oxygen and 2%-3 % enflurane . Postoperatively , the incidence of vomiting was 13 % with ondansetron , 45 % with droperidol , and 54 % with metoclopramide ( P less than 0.05 ; overall chi 2 test ) . There was no statistically significant difference in the incidence of nausea among the groups . Postoperative sedation and well-being scores were not significantly different among the groups . We conclude that preoperative prophylactic administration of ondansetron is superior to droperidol or metoclopramide in the prevention of emetic sequelae after general anesthesia for dilatation and curettage The prophylactic antiemetic efficacy of intravenous ( IV ) ondansetron , droperidol , perphenazine , and metoclopramide was evaluated in a prospect i ve , doubleblind study of 360 ASA physical status I-III patients undergoing total abdominal hysterectomy ( TAH ) . Subjects were r and omized to receive IV , one of ondansetron 4 mg , droperidol 1.25 mg , perphenazine 5 mg , metoclopramide 10 mg , or placebo prior to induction of anesthesia . Hypotension immediately after administration of metoclopramide was observed in two patients and four patients given ondansetron developed profound systolic hypotension at induction of anesthesia . Twenty-two percent of patients receiving droperidol became se date d. Postoperatively , patients developing severe nausea , retching , or vomiting , defined as severe emetic sequelae ( SES ) , were deemed to have failed antiemetic prophylaxis and received antiemetic rescue . A significantly larger number of patients who received IV ondansetron ( 63 % ) , droperidol ( 76 % ) , and perphenazine ( 70 % ) were free of SES when compared to placebo ( 43 % ) ; P < 0.05 . Metoclopramide was ineffective . Although ondansetron , droperidol , and perphenazine were effective in providing antiemetic prophylaxis , only IV perphenazine was free of side effects . Hence , we conclude that perphenazine is the best choice for antiemetic prophylaxis after TAH . ( Anesth Analg 1995;81:139 - 43 PURPOSE Postoperative nausea and vomiting ( PONV ) is a distressing adverse effect of general anaesthesia . The aim of the current study was to compare the antiemetic activity of different 5-hydroxytryptamine3 receptor antagonists with that of metoclopramide and placebo . METHODS In a prospect i ve , r and omized , double-blind study we have compared the antiemetic activity of the prophylactic administration of ondansetron 4 mg , tropisetron 5 mg and granisetron 3 mg with that of metoclopramide 10 mg and placebo in 132 patients undergoing laparoscopic cholecystectomy . All study drugs and placebo were given as a short iv infusion ten minutes before the induction of anaesthesia . Perioperative anaesthetic care was st and ardized in all patients . Nausea and vomiting were assessed by direct question ing of the patient at 1 , 4 , 9 , 12 , 18 and 24 hr after recovery from anaesthesia . If patients experienced nausea and /or vomiting , rescue antiemetic treatment ( metoclopramide 10 mg iv ) was administered . RESULTS For the 24-hr recovery period after surgery , the percentages of emesis-free patients were 65.5 % , 52 % , 48 % , 29.2 % and 27.6 % in the ondansetron , granisetron , tropisetron , metoclopramide and placebo groups , respectively . Prophylactic antiemetic treatment with ondansetron result ed in a lower incidence ( P = 0.02 ) of PONV than with metoclopramide or placebo . The times at which rescue antiemetic was first received were longer ( P < 0.01 ) in ondansetron group than in the placebo and metoclopramide groups . There were no statistical differences between ondansetron , tropisetron and granisetron groups . CONCLUSIONS Ondansetron , when given prophylactically result ed in a significantly lower incidence of PONV than metoclopramide and placebo . Metoclopramide was ineffective This study determined the overall incidence of postoperative nausea and vomiting ( PONV ) in 38 patients undergoing laparoscopic gynaecological procedures who received a st and ardized propofol/isoflurane anaesthetic but no preoperative antiemetic . A further 166 patients similarly anaesthetized were then r and omly allocated to receive either metoclopramide 10 mg . ondansetron 4 mg , or cyclizine 50 mg as an intravenous antiemetic immediately preinduction . Overall incidence of PONV was determined for all groups and the relative efficacy of the three antiemetic agents assessed . Fifty per cent of patients in the initial group ( no antiemetic ) reported significant nausea and /or vomiting up to 24 hours postoperatively . The incidence of PONV in the metoclopramide group was 24 % , in the ondansetron group 20 % , and in the cyclizine group 51 % . There was no detectable difference in relative efficacy between ondansetron 4 mg and metoclopramide 10 mg . The incidence of PONV in the group who received cyclizine was similar to that found in the pilot group who received no PONV prophylaxis . Both metoclopramide and ondansetron may potentially decrease the incidence of PONV following gynaecologic laparoscopy by up to 50 % when administered intravenously prior to a propofol/isoflurane anaesthetic Ondansetron 4 mg was compared with metoclopramide 10 mg for prevention of post-operative nausea and emesis in in- patients undergoing major gynaecological surgery in this double-blind , r and omized , placebo-controlled , multicentre study . A total of 1044 patients received a single intravenous ( i.v . ) injection of study medication immediately before induction of anaesthesia . Nausea and emesis were assessed over the 24 h post-operative period . Significantly more patients who received ondansetron experienced no emetic episodes ( 44 % ) compared with those who received metoclopramide ( 37 % , P = 0.049 ) or placebo ( 25 % , P < 0.001 ) . No nausea was experienced by significantly more patients who received ondansetron ( 32 % ) than with patients who received metoclopramide ( 24 % , P = 0.009 ) or placebo ( 16 % , P < 0.001 ) . In addition , fewer emetic episodes , less severe nausea and a reduced need for rescue antiemetics were also observed with ondansetron ( P < 0.05 vs. metoclopramide and placebo ) . Metoclopramide and placebo-treated patients were also 1.5 times ( 95 % Cl 1.5 - 4.2 ) and 2.5 times ( 95 % Cl 1.1 - 2.0 ) more likely , respectively , to experience nausea post-operatively . Overall , ondansetron was the most effective antiemetic in this patient population A r and omised double-blind investigation was undertaken to assess the value of domperidone and metoclopramide as prophylactic anti-emetics in unpremedicated patients undergoing general anaesthesia for therapeutic abortion on a day care basis . Sixty patients were divided into three groups , and received , at induction , one of three drugs intravenously . The incidences of postoperative nausea and vomiting were 35 % in the group receiving normal saline as placebo , 30 % in the group receiving 10 mg domperidone and 25 % in the group receiving 10 mg metoclopramide ; these were not statistically significantly different . Furthermore , there was no statistically significant difference in the incidence of postoperative nausea and vomiting as influenced by age , weight , length of gestation , anaesthetic time and a history of nausea and vomiting during the pregnancy Purpose “ To evaluate the prophylactic effect of low-dose dexamethasone ( 5 mg ) on postoperative nausea and vomiting ( PONV ) in women undergoing ambulatory laparoscopic surgery . Metoclopramide and saline served as controls . Methods One hundred twenty women ( n=40 in each of the three groups ) undergoing ambulatory laparoscopic tubal ligation under general anesthesia were enrolled in this r and omized , double-blinded , placebo-controlled study . After tracheal intubation , group I receivediv dexamethasone 5 mg , whereas groups II and III receivediv metoclopramide 10 mg and saline , respectively . Results Patients in group I reported a lower incidence of PONV and requested less rescue antiemetics than those in group III during the first four postoperative hours ( P < 0.0l ) . Patients in group I reported a lower incidence of PONV than those in groups II ( P < 0.05 ) and III ( P < 0.0l ) during the 24-hr postoperative period . Groups II and III did not differ from each other in the incidence of PONV and the proportion of patients who requested rescue antiemetics . Conclusion Prophylacticiv dexamethasone 5 mg significantly reduces the incidence of PONV in women undergoing ambulatory laparoscopic tubal ligation . At this dose , dexamethasone is more effective than metoclopramide 10 mg or placebo . RésuméObjectifÉvaluer l’effet prophylactique d’une faible dose de dexaméthasone ( 5 mg ) sur les nausées et vomissements postopératoires ( NVPO ) chez des patientes de chirurgie laparoscopique ambulatoire . Le métoclopramide et une solution salée ont servi de témoins . MéthodeCent vingt femmes ( n = 40 dans chacun des trois groupes formés de façon aléatoire ) , devant subir une ligature des trompes sous anesthésle générale en chirurgie laparoscopique ambulatoire , ont participé à l’étude r and omisée , en double Insu et contrôlée contre placebo . Après l’intubation endotrachéale , les patientes du groupe I ont reçu 5 mg de dexaméthasone iv t and is que celles des groupes II et III ont reçu 10 mg de métoclopramide ou de solution salée iv , respectivement . RésultatsLes patientes du groupe I ont signalé une plus faible Incidence de NVPO et ont dem and é moins d’antiémétiques de secours que les patientes du groupe III pendant les quatre premières heures postopératoires ( P < 0,01 ) . Les patients du groupe I ont eu moins de NVPO que celles des groupes II ( P < 0,05 ) et III ( P < 0,01 ) pendant une période de 24 h après l’intervention . Aucune différence intergroupe quant à l’incidence de NVPO et au nombre de patientes qui ont eu recours aux antiémétiques n’a été notée entre les patientes des groupes II et III . Conclusion L’administration iv de 5 mg de dexaméthasone réduit significativement l’incidence de NVPO chez des patientes qui subissent une ligature des trompes en chirurgie laparoscopique ambulatoire . Cést plus efficace que 10 mg de métoclopramide ou de placebo OBJECTIVES Dimenhydrinate and metoclopramide are inexpensive antiemetic drugs . Metoclopramide , especially , has been studied extensively in the past , but there are no studies that used the combination of both drugs for prevention of postoperative nausea and vomiting ( PONV ) . METHODS 120 female in patients undergoing endonasal surgery were r and omised to receive one of four antiemetic regimes : placebo , dimenhydrinate ( 1 mg x kg-1 ) , metoclopramide ( 0.3 mg x kg-1 ) , or the combination of both drugs ( 1 mg x kg-1 + 0.3 mg x kg-1 ) were administered intravenously after induction of anaesthesia and repeated 6 hours after the first administration . For general anaesthesia a st and ardised technique including benzodiazepine premedication , propofol , desflurane in N2O/O2 vecuronium and a continuous infusion of remifentanil was used . Postoperative analgesia ( diclofenac or metamizole supplemented with piritramide ) and antiemetic rescue medication ( dolasetron and droperidol ) were st and ardised . Episodes of vomiting , retching , nausea , and the need for additional antiemetics were recorded in the recovery room and 2 , 5 , 8 , and 24 hours after surgery . The main goal of the study was to increase the number of females staying completely free from PONV ( Chi 2-test ) . Furthermore , the severity of PONV was analysed , using a st and ardised scoring algorithm . RESULTS There were no differences between the two groups with regard to biometric data and distribution of risk factors for developing PONV . In all four groups nearly the similar number of patients stayed completely free from PONV : Placebo : 60.7 % , metoclopramide : 66.7 % , dimenhydrinate : 64.3 % , combination : 64.4 % ( differences not significant ) . There was also no difference in the severity of nausea and emetic sequel . DISCUSSION In females undergoing endonasal surgery under propofol-desflurane-remifentanil anaesthesia the incidence of PONV is about 40 % . In this setting , both metoclopramide and dimenhydrinate were ineffective to reduce the incidence and the severity of PONV . The combination of both drugs revealed no additional synergistic effect OBJECTIVES The efficacy and reliability of prophylactic antiemetic therapy with low dose propofol , droperidol , metoclopramide , and ondansetron were evaluated in a r and omized , double-blind , and prospect i ve design . PATIENTS AND METHODS A total of 101 ASA I-II patients ( 34 females , 67 males ; age range 16 to 53 years ) undergoing middle ear surgery for chronic otitis media or its sequelae were r and omly assigned to receive prophylactic antiemetic therapy with propofol ( n=21 , 0.5 mg/kg ) , droperidol ( n=19 , 20 mg/kg ) , metoclopramide ( n=23 , 0.2 mg/kg ) , ondansetron ( n=21 , 4 mg ) , and placebo ( n=20 , 0.9 % NaCl ) . All drugs were administered intravenously five minutes before extubation . RESULTS In the early postoperative period ( 0 to 3 hours ) , the percentages of patients free from nausea and vomiting were 100 % with droperidol , 71.4 % with ondansetron and propofol , 52.1 % with metoclopramide , and 35 % with placebo . Ondansetron ( 90.4 % ) was found the most effective to prevent and control nausea and vomiting during the postoperative 3 to 24 hours , followed by droperidol ( 84.2 % ) , propofol ( 57.1 % ) , metoclopramide ( 47.8 % ) , and placebo ( 40 % ) . Compared with controls , the number of patients without nausea and vomiting was significantly greater in each treatment group but metoclopramide ( p<0.05 ) . No significant differences were detected with respect to adverse effects . CONCLUSION Droperidol and ondansetron seem to exert the highest efficacy to prevent nausea and vomiting during the postoperative 0 to 3 hours and 3 to 24 hours , respectively Domperidone 20 mg , droperidol 2.5 mg , metoclopramide 10 mg and placebo ( saline ) were given i.v . 10 min before the end of anaesthesia , to 200 women undergoing major gynaecological surgery , and the incidence of postoperative nausea and vomiting following a st and ard anaesthetic technique was assessed . Droperidol was significantly more effective than domperidone , metoclopramide or placebo in reducing emetic sequelae . There were no significant differences between the groups in the incidence of extrapyramidal effects and postoperative sedation . Patients given droperidol required less postoperative analgesia than those given domperidone or metoclopramide . It was concluded that , of the drugs studied , droperidol alone was effective in protecting against nausea and vomiting after major gynaecological surgery In a prospect i ve , r and omised , double‐blind trial , we assessed the relative efficacy of prophylactic ondansetron and metoclopramide administration in the reduction of postoperative nausea and vomiting in 60 patients undergoing routine major neurosurgical procedures . The patients were r and omly allocated into one of two groups . Both groups received a st and ardised anaesthetic . When the dura mater was closed , patients in group A received an intravenous injection of metoclopramide 10 mg whilst group B received ondansetron 8 mg intravenously . Patients who received metoclopramide experienced less postoperative nausea and vomiting than those who received ondansetron in the 48 h following surgery ( 17 ( 56 % ) versus 9 ( 30 % ) p = 0.038 ) . In the light of these findings , we believe that ondansetron is an inappropriate agent for the prevention of postoperative nausea and vomiting in the neurosurgical population OBJECTIVE To compare the results of Tropisetron , Metoclopramide and placebo on postoperative nausea and vomiting in patients undergoing minilaparotomy cholecystectomy . SETTING Patients operated for minilaparotomy cholecystectomy in two private hospitals in Karachi . SUBJECTS Fifty consecutive patients of all ages and both sex who had simple cholelithiasis and underwent minilaparotomy cholecystectomy by a single surgeon . MAIN OUTCOME MEASURES Postoperative nausea and vomiting ( PONV ) at 2 hours and within 24 hours and requirement of rescue antiemetic . RESULTS Tropisetron was better than Metoclopramide and placebo in controlling postoperative nausea and vomiting . CONCLUSION Tropisetron when given at induction at a dose of 2 mg . intravenously prevents PONV better than Metoclopramide and placebo in 2 hours and 24 hours . It also reduces the need for rescue antiemetic significantly BACKGROUND Gynaecological surgery including laparoscopy is frequently associated with PONV . Therefore , choosing an anaesthetic with only little side effects in operations eligible for outpatient surgery is at least as important as applying anaesthetics that enable fast-tracking . STUDY GOAL To assess the incidence and severity of PONV after balanced desflurane-N(2)O-anaesthesia and to compare the antiemetic efficacy of dolasetron or metoclopramide versus placebo . METHODS 120 ASA physical status I and II women aged 18 to 55 scheduled for elective laparoscopic surgery were enrolled . Anaesthesia was st and ardized : fentanyl ( 2 microg/kg ) , etomi date ( 0 . 25 mg/kg ) and succinylcholine ( 1 mg/kg ) for induction and desflurane 3 - 5 % et along with 30 % O(2 ) in N(2)O , fentanyl ( max . 0.1 mg/h ) and cis-atracurium for maintenance . Patients were r and omly allocated to receive one of the following : dolasetron 12.5 mg ( group-D ) , metoclopramide 10 mg ( group-M ) or placebo ( group-P ) . RESULTS Within the first 24 h , postoperative nausea ( PON ) and postoperative vomiting ( POV ) were reduced significantly in group D ( 38%/19 % ) and group M ( 36%/27 % ) compared to group P ( 69%/56 % ) . Furthermore , PON and POV proved to be less intense in groups D and -M compared to group P : Episodes of severe nausea were recorded 17 times in 10 patients ( 17/10 ) in group P , compared to 5/4 in group M and 5/3 in group D , episodes of repeated vomiting 13 times in 8 patients ( 13/8 ) in group P , compared to 2/2 in group M and 2/1 in group D. CONCLUSIONS Our results confirm the increased incidence of PONV after gynaecological laparoscopic surgery under balanced anaesthesia compared to the predicted rates . Both dolasetron and metoclopramide proved to be effective prophylactic measures . Given a PONV-incidence of 38 % in group D and 39 % in group M , it is doubtful , whether the anaesthetic technique chosen in this study is the most suitable regimen for ambulatory gynaecological laparoscopies BACKGROUND Postoperative nausea and vomiting ( PONV ) are some of the most-common and undesirable adverse effects after surgery performed under general anesthesia . We investigated the prophylactic value of dexamethasone as an alternate to ondansetron or metoclopramide to prevent PONV after gynecologic surgery . MATERIAL / METHODS One hundred sixty ASA I-II patients scheduled for elective gynecologic surgery were enrolled . Before induction of anesthesia , patients were r and omly allocated to receive intravenously dexamethasone ( 8 mg ) in group D , ondansetron ( 4 mg ) in group O , metoclopramide ( 10 mg ) in group M , and saline ( 2 mL ) in group P. Total incidence of nausea and vomiting , rescue antiemetic requirement , pain scores , and any adverse effects were recorded at 3 observational periods ( 0 - 2 hours , 2 - 12 hours , and 12 - 24 hours ) . RESULTS Total rates of PON , POV , and PONV were significantly higher in group P at 0 - 2 hours and 2 - 12 hours compared with group D , O , and M ( P<.05 ) . There was no difference in PON , POV , and PONV among D , O , and M groups . None of the groups differed in PONV in the subsequent 12 - 24 hours . Number of patients requiring rescue antiemetic was significantly higher in group P than the other groups at 0 - 2 hours ( 10 % , 10 % , 15 % , and 45 % in group D , O , M , and P ) ( P<.05 ) . CONCLUSIONS Prophylactic IV dexamethasone 8 mg significantly reduces the incidence of PONV in gynecologic surgery . At this dosage , dexamethasone is as effective as ondansetron 4 mg and metoclopramide 10 mg , and is more-effective than placebo Frequency of nausea and vomiting following day case termination of pregnancy was found to be rather high ( 42 % ) without anti-emetic prophylaxis . Droperidol in doses of 2.5 mg , 1.25 mg and 0.25 mg were found to be equally effective as prophylactic anti-emetic , but not metoclopramide 10 mg . This study confirms that low dose droperidol 0.25 mg is effective as a prophylactic anti-emetic , without any delay in immediate recovery and hence suitable for day surgery cases STUDY DESIGN Prospect i ve , r and omized , double-blind , placebo-controlled study involving one hundred ASA I-II patients undergoing major gynaecological surgery . OBJECTIVE To study anti-emetic efficacy of intravenous ( IV ) ondansetron ( 4 mg ) , droperidol ( 2.5 mg ) , metoclopramide ( 10 mg ) , and placebo . PATIENTS AND METHODS 100ASA physical status I-II undergoing major gynaecological surgery were r and omized to receive intravenously ( IV ) , one of the four test drugs 10 minutes before the end of anaesthesia . The incidence of postoperative nausea and vomiting following a st and ard anaesthetic technique was assessed . RESULTS A significantly large number of patients who received ondansetron ( 88 % ) and droperidol ( 72 % ) were free of emetic sequelae when compared to placebo ( 41 % ) ; p < 0.05 ( power of this observation is approximately 80 % at the given significance level ) . Metoclopramide was ineffective . Patients given droperidol were significantly more se date d than those receiving ondansetron ; p < 0.05 . This is not surprising , as the dose of droperidol used in this study was higher than that currently recommended because we found lower doses to be ineffective in controlling nausea and vomiting in this group of patients . CONCLUSION It was concluded that , of the drugs studied ondansetron is the best choice for anti-emetic prophylaxis after major gynaecological surgery Background : Breast surgery is associated with a relatively high incidence of postoperative nausea and vomiting ( PONV ) . This study was undertaken to evaluate the efficacy of granisetron , droperidol and metoclopramide for preventing PONV after breast surgery PURPOSE The purpose of this study was to compare the efficacy of ondansetron and metoclopramide , administered for the prophylaxis of vomiting in patients undergoing oral and maxillofacial surgery under general anesthesia . METHODS One hundred patients undergoing m and ibular osteotomy surgery were studied . Patients were allocated r and omly to receive 1 of 2 treatment regimens : 0.15 mg/kg ondansetron or 0.5 mg/kg metoclopramide intravenously 30 minutes before extubation . All were adults and were treated by one surgeon and all operations were the same and lasted 2.5 to 3.0 hours . The patients were assessed at 3 time periods : 0 to 3 hours , 3 to 12 hours , and 12 to 24 hours postoperatively for emesis . RESULT The data from this study showed that during the first 24-hour postoperative period , patients receiving ondansetron following general anesthesia had an 11 % ( 11 patients ) incidence of emesis compared with 28 % ( 22 patients ) in the group that received metoclopramide . CONCLUSION In this study , ondansetron ( 0.1 mg/kg ) was twice as effective in preventing postoperative vomiting compared with metoclopramide The prophylactic anti‐emetic efficacy and safety of pre‐operative intravenous ondansetron was evaluated in a r and omised , double‐blind , comparison with droperidol , metoclopramide and placebo in 160 ASA grade 1 and 2 patients undergoing laparoscopic cholecystectomy under total intravenous anaesthesia . The patients were r and omly allocated to receive ondansetron ( 4 mg ) , droperidol ( 1.25 mg ) , metoclopramide ( 10 mg ) or placebo given as a single intravenous dose immediately before induction of a st and ardised general anaesthetic . There were no significant differences between the four study groups with regard to the demographic and anaesthetic data , postoperative analgesia , postoperative sedation scores , duration of postoperative hospital stay and incidence of adverse events . The incidence of nausea and vomiting was significantly lower ( p < 0.05 ) between 1 h and 4 h after surgery in the ondansetron group compared with the droperidol , metoclopramide and placebo groups . The incidence of nausea was similar in the four groups in the other study periods : 0–1 h and 4–24 h. The incidence of vomiting was lower in the ondansetron , droperidol and metoclopramide groups than in the placebo group between 1 and 4 h but was the same between 4 and 24 h. As a result of the lower incidence of nausea and vomiting between 1 h and 4 h in the ondansetron group , the overall incidence of nausea and vomiting was lower during the first 24 h after surgery in this group than in the other three groups This study evaluates the prophylactic anti-emetic efficacy of granisetron , droperidol and metoclopramide , for the prevention of post-operative nausea and vomiting in female patients undergoing elective laparoscopic cholecystectomy . The patients were r and omly assigned to one of four groups ( n = 30 for each group ) : granisetron 3 mg , droperidol 1.25 mg , metoclopramide 10 mg and placebo ( saline ) . These medications were given immediately before the induction of anaesthesia . During the first 24 h after anaesthesia , the incidence of post-operative nausea and vomiting was 13 , 30 , 33 and 37 % after administration of granisetron , droperidol , metoclopramide and placebo , respectively ( P < 0.05 , overall Fisher 's exact probability test ) . No clinical ly important adverse effects were observed in either group . Our results suggest that granisetron is a better anti-emetic than droperidol or metoclopramide for the prevention of post-operative nausea and vomiting after laparoscopic cholecystectomy when compared with a placebo OBJECTIVE Patients who undergo laparoscopic cholecystectomy may be at risk of experiencing postoperative nausea and vomiting . This prospect i ve , r and omized , double-blind study compared the prophylactic use of metoclopramide and ondansetron for the treatment of postoperative nausea and vomiting in patients who underwent elective laparoscopic cholecystectomy . METHODS Eighty patients were r and omized into two groups . Patients received ondansetron 4 mg or metoclopramide 10 mg intravenously in a double-blind manner at the end of anaesthesia . RESULTS The incidence of nausea was 45 % for metoclopramide and 20 % for ondansetron in the 24 hours postoperatively ; the difference was statistically insignificant ( p = 0.05 ) . Postoperative nausea score did not show any significant difference between the two group in the first 2 hours ( p = 0.3 ) and 4 hours ( p = 0.12 ) but was significant between 4 and 24 hours ( p = 0.02 ) . The incidence of vomiting was 20 % for metoclopramide and 2.5 % for ondansetron . This difference was statistically significant ( p = 0.02 ) . CONCLUSION Ondansetron 4 mg given intravenously at the end of surgery is effective for preventing vomiting after laparoscopic cholecystectomy |
13,696 | 25,092,578 | Trials comparing different dietary approaches indicated that reducing carbohydrate intake promoted greater initial weight loss than other approaches but did not appear to significantly improve long-term outcomes .
Food provision appears to enhance adherence to reduction in energy intake and produce greater initial weight losses .
The long-term benefits of food provision are less clear .
Trials comparing alternative treatment modalities suggest that phone-based treatment produce short- and long-term weight reductions equivalent to face-to-face interventions .
The use of Internet and mobile technologies are associated with smaller reductions in body weight than face-to-face interventions . | The purpose of this systematic review was to evaluate , synthesize , and interpret findings from recent r and omized controlled trials ( RCTs ) of dietary and lifestyle weight loss interventions examining the effects of ( 1 ) diet composition , ( 2 ) use of food provision , and ( 3 ) modality of treatment delivery on weight loss . | BACKGROUND The appropriate dietary intervention for overweight persons with type 2 diabetes mellitus ( DM2 ) is unclear . Trials comparing the effectiveness of diets are frequently limited by short follow-up times and high dropout rates . AIM The effects of a low carbohydrate Mediterranean ( LCM ) , a traditional Mediterranean ( TM ) , and the 2003 American Diabetic Association ( ADA ) diet were compared , on health parameters during a 12-month period . METHODS In this 12-month trial , 259 overweight diabetic patients ( mean age 55 years , mean body mass index 31.4 kg/m(2 ) ) were r and omly assigned to one of the three diets . The primary end-points were reduction of fasting plasma glucose , HbA1c and triglyceride ( TG ) levels . RESULTS 194 patients out of 259 ( 74.9 % ) completed follow-up . After 12 months , the mean weight loss for all patients was 8.3 kg : 7.7 kg for ADA , 7.4 kg for TM and 10.1 kg for LCM diets . The reduction in HbA1c was significantly greater in the LCM diet than in the ADA diet ( -2.0 and -1.6 % , respectively , p < 0.022 ) . HDL cholesterol increased ( 0.1 mmol/l + /- 0.02 ) only on the LCM ( p < 0.002 ) . The reduction in serum TG was greater in the LCM ( -1.3 mmol/l ) and TM ( -1.5 mmol/l ) than in the ADA ( -0.7 mmol/l ) , p = 0.001 . CONCLUSIONS An intensive 12-month dietary intervention in a community-based setting was effective in improving most modifiable cardiovascular risk factors in all the dietary groups . Only the LCM improved HDL levels and was superior to both the ADA and TM in improving glycaemic control Context In 2003 , the authors reported that severely obese adults lost more weight and had better serum lipid patterns after 6 months of a low-carbohydrate diet rather than a conventional low-fat diet . Contribution After 1 year , these same patients still had more favorable triglyceride and high-density lipoprotein cholesterol levels on the low-carbohydrate diet than on the conventional diet . However , weight loss and the other metabolic parameters were similar in the 2 diet groups . Caution s The effect of the modest improvements in high-density lipoprotein cholesterol and triglyceride levels on the development of diabetes and cardiovascular disease is unknown . The Editors The prevalence of obesity and its associated metabolic abnormalities has increased markedly over the past 2 decades ( 1 , 2 ) . Although guidelines to follow a highcomplex carbohydrate , low-fat , energy-deficient diet to achieve weight loss are generally accepted ( 3 ) , considerable public interest has focused on low-carbohydrate diets ( 4 ) . We recently reported that persons with severe obesity lost more weight and had greater improvements in triglyceride levels , insulin sensitivity , and glycemic control after 6 months of a low-carbohydrate diet as compared with a conventional weight loss diet based on calorie and fat restriction ( 5 ) . However , these findings were preliminary because of the short duration of that study ( 6 ) . A simultaneously published study by Foster and colleagues suggested that persons on a low-carbohydrate diet tended to regain weight by 1 year ( 7 ) . These findings were limited , however , because few participants completed the study and because the study used a self-help approach , which is less effective than direct counseling for maintaining weight loss ( 8) . Foster and colleagues also excluded persons with diabetes , which is highly prevalent in the obese population . During the development of this study , we decided to analyze and report preliminary results at 6 months and final results at 1 year . We thought that the short-term results would be important , given the high-risk nature of our study sample , but that long-term outcomes would provide more information about the sustainability of any diet-related outcomes . We now report our findings 1 year after r and omization to a low-carbohydrate diet versus a low-fat weight loss diet ( conventional diet ) in severely obese adults with a high prevalence of diabetes or the metabolic syndrome . Methods Study Participants The study design has been previously described ( 5 ) . Participants were recruited from the outpatient practice s of the Philadelphia Veterans Affairs Medical Center and included persons 18 years of age and older with a body mass index ( BMI ) of 35 kg/m2 or greater . The exclusion criteria were a serum creatinine level greater than 133 mol/L ( > 1.5 mg/dL ) , hepatic disease , severe life-limiting medical illness , inability to self-monitor glucose levels , or active use of a weight loss program or weight loss medication . Between May 2001 and November 2001 , 132 persons were r and omly assigned to either a low-carbohydrate diet ( n = 64 ) or a conventional diet ( n = 68 ) . The Institutional Review Committee at the Philadelphia Veterans Affairs Medical Center approved the study , and all participants provided written informed consent . Interventions Diet groups met in weekly counseling sessions for 4 weeks , followed by 11 monthly sessions . Participants on the low-carbohydrate diet were instructed only to reduce carbohydrate intake to less than 30 g per day . Participants on the conventional diet were instructed to reduce caloric intake by 500 calories per day , with less than 30 % of calories derived from fat , in accordance with the National Heart , Lung , and Blood Institute guidelines ( 3 ) . Outcome Measures We collected data , including weight ( single calibrated scale , SR Instruments , Inc. , Tonaw and a , New York ) , medical history ( self-reported ) , and blood pressure , at baseline , 6 months , and 1 year . Fasting blood specimens were obtained for glucose , hemoglobin A1c , and serum lipid levels ( Synchron LX20 , Beckman Coulter , Inc. , Fullerton , California ) . Low-density lipoprotein ( LDL ) cholesterol level was calculated by using the Friedewald formula ( 9 ) . We defined the presence of diabetes by a historical fasting blood glucose level greater than 6.94 mmol/L ( > 125 mg/dL ) or use of antidiabetic medications . The metabolic syndrome was considered present if a participant had 3 or more of the following ( 10 ) : central obesity , fasting blood glucose level of 6.11 mmol/L ( 110 mg/dL ) or greater , fasting triglyceride level of 1.70 mmol/L ( 150 mg/dL ) or greater , high-density lipoprotein ( HDL ) cholesterol level less than 1.04 mmol/L ( < 40 mg/dL ) for men or less than 1.30 mmol/L ( < 50 mg/dL ) for women , blood pressure of 130/85 mm Hg or greater , or antihypertensive therapy . We assumed that all participants had central obesity because of the uniform severity of their obesity ( BMI range , 35.0 to 79.4 kg/m2 ) . Serum insulin was measured by radioimmunoassay ( Laboratory Corporation of America Holdings [ LabCorp ] , Burlington , North Carolina ] ) . Insulin resistance in nondiabetic persons was estimated by the quantitative insulin sensitivity check ( QUICK ) index : 1/[(log ( fasting insulin ( U/mL ) ) + ( log fasting glucose(mg/dL ) ) ] . Statistical Analysis Our primary end point was total weight loss at 1 year . Secondary analyses included the change from baseline in serum lipid levels , insulin sensitivity , and glycemic control . We estimated that we would need 100 persons ( 50 per group ) , assuming a 2-sided type I error of 5 % , for the study to have 80 % power to detect a 5-kg greater mean weight loss in the low-carbohydrate group than in the conventional diet group . These calculations were based on an anticipated maximum weight loss by 6 months , with weight stabilization in both diet groups between 6 months and 1 year . To compensate for an anticipated dropout rate of 25 % , we set our enrollment target at 135 persons . R and omization was performed by using a pre-established algorithm generated from a r and om set of numbers that was constructed and held in a separate center and concealed from those enrolling persons during r and omization . We used stratified r and omization , with blocking within strata , to ensure assignment of approximately equal numbers of women , diabetic persons , and severely obese persons ( BMI 40 kg/m2 ) to each study group . Changes in weight , dietary intake , and metabolic data were compared between the 2 diets by r and om-coefficient analysis ( 11 ) . This type of analysis was selected to allow for a variable number of observations for participants and to take into account that the repeated observations of the outcome variables over time for individuals were correlated . The r and om-coefficient analysis model takes these correlations into account by allowing the intercept to vary r and omly among persons . We used a restricted maximum likelihood analysis , which assumed that changes were distributed according to a bivariate normal distribution and that data were missing at r and om . The outcome variables were changes from baseline in weight , dietary macronutrient consumption , and metabolic measurements . For all of these analyses , the covariates included an indicator variable for time ( 6 months and 1 year ) , diet group , and a diet group by time interaction term . This diet group by time interaction term was kept in the model , regardless of its statistical significance ( P = 0.063 for the weight loss analysis ) . Separate analyses to adjust for baseline differences between diet groups were also made by entering the following covariates to each of these models : age ; race ( white or African American ) ; sex ; baseline BMI ; baseline caloric intake ; and the presence or absence of hypertension , use of lipid-lowering therapy , diabetes , active smoking , and sleep apnea ( 12 ) . All variables were assessed for normality before entry into the analyses . Triglyceride , insulin , and glucose levels were skewed and thus were log-transformed before the analyses . Baseline differences between diet groups were compared by chi-square analysis for dichotomous variables and by the unpaired t-test for continuous variables . All P values are 2-sided , and a P value of 0.05 was considered statistically significant . Analyses were performed with SPSS statistical software , version 11.1 ( SPSS , Inc. , Chicago , Illinois ) . Missing Data Of the 132 enrolled persons , follow-up was done at 6 months for 79 persons and at 1 year for 87 persons . For measurements at 6 months , we retrieved weights on an additional 16 persons on the low-carbohydrate diet and 23 persons on the conventional diet ( total , 39 persons at a mean [ SD ] of 6.6 1.2 months ) . For measurements at 1 year , we retrieved weights on 18 persons on the low-carbohydrate diet and 21 persons on the conventional diet ( total , 39 persons at a mean [ SD ] of 13.5 3.2 months ) . Thus , we had 6-month weights on 118 of 132 persons ( 89 % ) and 1-year weights on 126 of 132 persons ( 96 % ) . Of the 18 persons who missed the 6-month visit but returned for the 1-year visit ( 6 in the low-carbohydrate group and 12 in the conventional diet group ) , all but 2 had 6-month weights retrieved from medical records . Of the 6 persons for whom no 1-year weights were available , 2 were in the low-carbohydrate group and 4 in the conventional diet group . The weights retrieved from medical records were obtained on scales that were different from those used for the study and were probably obtained in a nonuniform manner with regard to clothing . We used several approaches to h and le the 45 participants with missing data for diet recall and metabolic measurements . For the primary analysis by r and om-coefficient analysis , we assumed data were missing at r and om . To verify this assumption , we performed sensitivity analyses based on comparisons of baseline characteristics and weight loss differences between those who dropped out and those who completed the study . We also performed 2 additional sensitivity Background Commercial Web-based weight-loss programs are becoming more popular and increasingly refined through the addition of enhanced features , yet few r and omized controlled trials ( RCTs ) have independently and rigorously evaluated the efficacy of these commercial programs or additional features . Objective To determine whether overweight and obese adults r and omized to an online weight-loss program with additional support features ( enhanced ) experienced a greater reduction in body mass index ( BMI ) and increased usage of program features after 12 and 24 weeks compared to those r and omized to a st and ard online version ( basic ) . Methods An assessor-blinded RCT comparing 301 adults ( male : n=125 , 41.5 % ; mean age : 41.9 years , SD 10.2 ; mean BMI : 32.2 kg/m2 , SD 3.9 ) who were recruited and enrolled offline , and r and omly allocated to basic or enhanced versions of a commercially available Web-based weight-loss program for 24 weeks . Results Retention at 24 weeks was greater in the enhanced group versus the basic group ( basic 68.5 % , enhanced 81.0 % ; P=.01 ) . In the intention-to-treat analysis of covariance with imputation using last observation carried forward , after 24 weeks both intervention groups had reductions in key outcomes with no difference between groups : BMI ( basic mean –1.1 kg/m2 , SD 1.5 ; enhanced mean –1.3 kg/m2 , SD 2.0 ; P=.29 ) , weight ( basic mean –3.3 kg , SD 4.7 ; enhanced mean –4.0 kg , SD 6.2 ; P=.27 ) , waist circumference ( basic mean –3.1 cm , SD 4.6 ; enhanced mean –4.0 cm , SD 6.2 ; P=.15 ) , and waist-to-height ratio ( basic mean –0.02 , SD 0.03 ; enhanced mean –0.02 , SD 0.04 , P=.21 ) . The enhanced group logged in more often at both 12 and 24 weeks , respectively ( enhanced 12-week mean 34.1 , SD 28.1 and 24-week mean 43.1 , SD 34.0 vs basic 12-week mean 24.6 , SD 25.5 and 24-week mean 31.8 , SD 33.9 ; P=.002 ) . Conclusions The addition of personalized e-feedback in the enhanced program provided limited additional benefits compared to a st and ard commercial Web-based weight-loss program . However , it does support greater retention in the program and greater usage , which was related to weight loss . Further research is required to develop and examine Web-based features that may enhance engagement and outcomes and identify optimal usage patterns to enhance weight loss using Web-based programs . Trial Registration Australian New Zeal and Clinical Trials Registry ( ANZCTR ) trial number : ACTRN12610000197033 ; https://www.anzctr.org.au/Trial/ Registration /Trial Review .aspx?id=335159 ( Archived by WebCite at http://www.webcitation.org/6HoOMGb8j ) Background : Internet-based weight-loss programs appear promising in the short-term but , to data , have not been able to produce the level of weight loss seen in traditional in-person treatment ; thus , novel approaches are necessary . Using a combination of interactive technology and in-person support has been beneficial in other areas of medicine . Purpose : The aim of this study is to compare 12-month weight-loss outcomes of an Internet-only behavioral weight-loss treatment with the same program supplemented with monthly in-person meetings . Methods : One hundred and twenty-three participants were r and omized to an Internet-only ( n=62 ) or an Internet + in-person treatment ( I+IPS ; n=61 ) . All participants then participated in a 12-month behavioral weight-loss program conducted over the Internet . The groups met online weekly for the first 6 months and biweekly for the second half of the intervention . The I+IPS group had access to the same Web site as the Internet-only group but , once a month , attended an in-person meeting in place of an online chat . Assessment s included body weight , program adherence , and social support measures . Results : An intent-to-treat analysis ( n=123 ) revealed there were no significant Group x Time differences ( p=.15 ) in weight loss at either 6 ( −6.8±7.8 vs. −5.1±4.8 , p=.15 ) or 12 months ( −5.1±7.1 kg vs. −3.5±5.1 kg , p=.17 , for Internet-only and I+IPS , respectively ) . Differences between groups for those completing all measures ( n=77 ) also revealed no significant differences at 6 months ( −9.2±7.0 kg vs. −6.9±4.2 kg , p=.08 ) or 12 months ( −8.0±7.5 kg vs. −5.6±5.5 kg , p=.10 for the Internet-only and I+IPS conditions , respectively ) . Conclusions : Supplementation of an Internet weight-loss treatment with monthly in-person meetings did not result in greater weight losses over 12 months . Dynamic , socially supportive , and interactive elements of the Web site may have obviated the need for further interpersonal behavioral counseling BACKGROUND Obese , insulin-resistant persons are at risk of cardiovascular disease . How best to achieve both weight loss and clinical benefit in these persons is controversial , and recent reports question ed the superiority of low-fat diets . OBJECTIVE We aim ed to ascertain the effects of moderate variations in the carbohydrate and fat content of calorie-restricted diets on weight loss and cardiovascular disease risk in obese , insulin-resistant persons . DESIGN Fifty-seven r and omly assigned , insulin-resistant , obese persons completed a 16-wk calorie-restricted diet with 15 % of energy as protein and either 60 % and 25 % or 40 % and 45 % of energy as carbohydrate and fat , respectively . Baseline and postweight-loss insulin resistance ; daylong glucose , insulin , and triacylglycerol concentrations ; fasting lipid and lipoprotein concentrations ; and markers of endothelial function were quantified . RESULTS Weight loss with 60 % or 40 % of energy as carbohydrate ( 5.7 + /- 0.7 or 6.9 + /- 0.7 kg , respectively ) did not differ significantly , and improvement in insulin sensitivity correlated with the amount of weight lost ( r = 0.50 , P < 0.001 ) . Subjects following the diet with 40 % of energy as carbohydrate had greater reductions in daylong insulin and triacylglycerol ( P < 0.05 ) and fasting triacylglycerol ( 0.53 mmol/L ; P = 0.04 ) concentrations , greater increases in HDL-cholesterol concentrations ( 0.12 mmol/L ; P < 0.01 ) and LDL particle size ( 1.82 s ; P < 0.05 ) , and a greater decrease in plasma E-selectin ( 5.6 ng/L ; P = 0.02 ) than did subjects following the diet with 60 % of energy as carbohydrate . CONCLUSIONS In obese , insulin-resistant persons , a calorie-restricted diet , moderately lower in carbohydrate and higher in unsaturated fat , is as efficacious as the traditional low-fat diet in producing weight loss and may be more beneficial in reducing markers for cardiovascular disease risk BACKGROUND When substituted for carbohydrate in an energy-reduced diet , dietary protein enhances fat loss in women . It is unknown whether the effect is due to increased protein or reduced carbohydrate . OBJECTIVE We compared the effects of 2 isocaloric diets that differed in protein and fat content on weight loss , lipids , appetite regulation , and energy expenditure after test meals . DESIGN This was a parallel , r and omized study in which subjects received either a low-fat , high-protein ( LF-HP ) diet ( 29 + /- 1 % fat , 34 + /- 0.8 % protein ) or a high-fat , st and ard-protein ( HF-SP ) diet ( 45 + /- 0.6 % fat , 18 + /- 0.3 % protein ) during 12 wk of energy restriction ( 6 + /- 0.1 MJ/d ) and 4 wk of energy balance ( 7.4 + /- 0.3 MJ/d ) . Fifty-seven overweight and obese [ mean body mass index ( in kg/m(2 ) ) : 33.8 + /- 0.9 ] volunteers with insulin concentrations > 12 mU/L completed the study . RESULTS Weight loss ( LF-HP group , 9.7 + /- 1.1 kg ; HF-SP group , 10.2 + /- 1.4 kg ; P = 0.78 ) and fat loss were not significantly different between diet groups even though the subjects desired less to eat after the LF-HP meal ( P = 0.02 ) . The decrease in resting energy expenditure was not significantly different between diet groups ( LF-HP , -342 + /- 185 kJ/d ; HF-SP , -349 + /- 220 kJ/d ) . The decrease in the thermic effect of feeding with weight loss was smaller in the LF-HP group than in the HF-SP group ( -0.3 + /- 1.0 % compared with -3.6 + /- 0.7 % ; P = 0.014 ) . Glucose and insulin responses to test meals improved after weight loss ( P < 0.001 ) with no significant diet effect . Bone turnover , inflammation , and calcium excretion did not change significantly . CONCLUSION The magnitude of weight loss and the improvements in insulin resistance and cardiovascular disease risk factors did not differ significantly between the 2 diets , and neither diet had any detrimental effects on bone turnover or renal function OBJECTIVE Face-to-face ( FTF ) weight management is costly and presents barriers for individuals seeking treatment ; thus , alternate delivery systems are needed . The objective of this study was to compare weight management delivered by FTF clinic or group conference calls ( phone ) . DESIGN AND METHODS R and omized equivalency trial in 295 overweight/obese men/women ( BMI = 35.1±4.9 , Age = 43.8±10.2 , Minority = 39.8 % ) . Weight loss ( 0 - 6 months ) was achieved by reducing energy intake between 1,200 and 1,500 kcal/day and progressing physical activity ( PA ) to 300 min/week . Weight maintenance ( 7 - 18 months ) provided adequate energy to maintain weight and continued 300 min/week of PA . Behavioral weight management strategies were delivered weekly for 6 months and gradually reduced during 7 - 18 months . A cost analysis provided a comparison of expenses between groups . RESULTS Weight change from baseline to 6 months was -13.4 ± 6.7 % and -12.3 ± 7.0 % for FTF clinic and phone , respectively . Weight change from 6 - 18 months was 6.4 ± 7.0 % and 6.4 ± 5.2 % , for FTF clinic and phone , respectively . The cost to FTF participants was $ 789.58 more per person . CONCLUSIONS Phone delivery provided equivalent weight loss and maintenance and reduced program cost . Ubiquitous access to phones provides a vast reach for this approach CONTEXT The prevalence of overweight and obesity in the United States remains high . Commercial weight loss programs may contribute to efforts to reduce the prevalence of overweight and obesity , although few studies have examined their efficacy in controlled trials . OBJECTIVE To test whether a free prepared meal and incentivized structured weight loss program promotes greater weight loss and weight loss maintenance at 2 years compared with usual care . DESIGN , SETTING , AND PARTICIPANTS A r and omized controlled trial of weight loss and weight loss maintenance in 442 overweight or obese women ( body mass index , 25 - 40 ) aged 18 to 69 years ( mean age , 44 years ) conducted at US institutions over 2 years with follow-up between November 2007 and April 2010 . INTERVENTION The program , which involves in-person center-based or telephone-based one-to-one weight loss counseling , was available over a 2-year period . Behavioral goals were an energy-reduced , nutritionally adequate diet , facilitated by the inclusion of prepackaged food items in a planned menu during the initial weight loss phase , and increased physical activity . Participants assigned to usual care received 2 individualized weight loss counseling sessions with a dietetics professional and monthly contacts . MAIN OUTCOME MEASURES Weight loss and weight loss maintenance . RESULTS Weight data were available at 24 months for 407 women ( 92.1 % of the study sample ) . In an intent-to-treat analysis with baseline value substitution , mean weight loss was 7.4 kg ( 95 % confidence interval [ CI ] , 6.1 - 8.7 kg ) or 7.9 % ( 95 % CI , 6.5%-9.3 % ) of initial weight at 24 months for the center-based group , 6.2 kg ( 95 % CI , 4.9 - 7.6 kg ) or 6.8 % ( 95 % CI , 5.2%-8.4 % ) for the telephone-based group , and 2.0 kg ( 95 % CI , 0.6 - 3.3 kg ) or 2.1 % ( 95 % CI , 0.7%-3.5 % ) for the usual care control group after 24 months ( P < .001 for intervention effect ) . CONCLUSION Compared with usual care , this structured weight loss program result ed in greater weight loss over 2 years . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00640900 OBJECTIVES To evaluate the efficacy of an Internet behavioral weight loss program ; and determine if adding periodic in-person sessions to an Internet intervention improves outcomes . METHODS 481 healthy overweight adults ( 28 % minority ) were r and omized to one of 3 delivery methods of a behavioral weight loss program with weekly meetings : Internet ( n=161 ) , InPerson ( n=158 ) , or Hybrid ( Internet+InPerson , n=162 ) . Outcome variables were weight at baseline and 6 months and percent of subjects achieving a 5 and 7 % weight loss . The study took place in two centers in Vermont and Arkansas from 2003 to 2008 . RESULTS Conditions differed significantly in mean weight loss [ 8.0 ( 6.1 ) kg vs. 5.5 ( 5.6 ) kg vs. 6.0 ( 5.5 ) kg ] , for InPerson , Internet , and Hybrid respectively , p<0.01 , n=462 ) . Weight loss for InPerson was significantly greater than the Internet and Hybrid conditions ( p<0.05 ) . Although the proportion reaching a 5 % weight loss did not differ , the proportion losing 7 % did differ significantly ( 56.3 % vs. 37.3 % vs. 44.4 % for InPerson , Internet , and Hybrid respectively , p<0.01 ) . CONCLUSIONS These results demonstrate that the Internet is a viable alternative to in-person treatment for the delivery and dissemination of a behavioral weight-control intervention . The addition of periodic in-person sessions did not improve outcomes CONTEXT The results of clinical trials involving diet in the treatment of obesity have been inconsistent , possibly due to inherent physiological differences among study participants . OBJECTIVE To determine whether insulin secretion affects weight loss with 2 popular diets . DESIGN , SETTING , AND PARTICIPANTS R and omized trial of obese young adults ( aged 18 - 35 years ; n = 73 ) conducted from September 2004 to December 2006 in Boston , Mass , and consisting of a 6-month intensive intervention period and a 12-month follow-up period . Serum insulin concentration at 30 minutes after a 75-g dose of oral glucose was determined at baseline as a measure of insulin secretion . Outcomes were assessed at 6 , 12 , and 18 months . Missing data were imputed conservatively . INTERVENTIONS A low-glycemic load ( 40 % carbohydrate and 35 % fat ) vs low-fat ( 55 % carbohydrate and 20 % fat ) diet . MAIN OUTCOME MEASURES Body weight , body fat percentage determined by dual-energy x-ray absorptiometry , and cardiovascular disease risk factors . RESULTS Change in body weight and body fat percentage did not differ between the diet groups overall . However , insulin concentration at 30 minutes after a dose of oral glucose was an effect modifier ( group x time x insulin concentration at 30 minutes : P = .02 for body weight and P = .01 for body fat percentage ) . For those with insulin concentration at 30 minutes above the median ( 57.5 microIU/mL ; n = 28 ) , the low-glycemic load diet produced a greater decrease in weight ( -5.8 vs -1.2 kg ; P = .004 ) and body fat percentage ( -2.6 % vs -0.9 % ; P = .03 ) than the low-fat diet at 18 months . There were no significant differences in these end points between diet groups for those with insulin concentration at 30 minutes below the median level ( n = 28 ) . Insulin concentration at 30 minutes after a dose of oral glucose was not a significant effect modifier for cardiovascular disease risk factors . In the full cohort , plasma high-density lipoprotein cholesterol and triglyceride concentrations improved more on the low-glycemic load diet , whereas low-density lipoprotein cholesterol concentration improved more on the low-fat diet . CONCLUSIONS Variability in dietary weight loss trials may be partially attributable to differences in hormonal response . Reducing glycemic load may be especially important to achieve weight loss among individuals with high insulin secretion . Regardless of insulin secretion , a low-glycemic load diet has beneficial effects on high-density lipoprotein cholesterol and triglyceride concentrations but not on low-density lipoprotein cholesterol concentration . TRIAL REGISTRATION clinical trials.gov Identifier : NCT00130299 Background To our knowledge , no studies have evaluated whether weight loss can be promoted in overweight adults through the use of an intervention that is largely based on daily SMS ( Short Message Service : text ) and MMS ( Multimedia Message Service : small picture ) messages transmitted via mobile phones . Objective This paper describes the development and evaluation of a text message – based intervention design ed to help individuals lose or maintain weight over 4 months . Methods The study was a r and omized controlled trial , with participants being exposed to one of the following two conditions , lasting 16 weeks : ( 1 ) receipt of monthly printed material s about weight control ; ( 2 ) an intervention that included personalized SMS and MMS messages sent two to five times daily , printed material s , and brief monthly phone calls from a health counselor . The primary outcome was weight at the end of the intervention . A mixed-model repeated- measures analysis compared the effect of the intervention group to the comparison group on weight status over the 4-month intervention period . Analysis of covariance ( ANCOVA ) models examined weight change between baseline and 4 months after adjusting for baseline weight , sex , and age . Results A total of 75 overweight men and women were r and omized into one of the two groups , and 65 signed the consent form , completed the baseline question naire , and were included in the analysis . At the end of 4 months , the intervention group ( n = 33 ) lost more weight than the comparison group ( −1.97 kg difference , 95 % CI −0.34 to −3.60 kg , P = .02 ) after adjusting for sex and age . Intervention participants ’ adjusted average weight loss was 2.88 kg ( 3.16 % ) . At the end of the study , 22 of 24 ( 92 % ) intervention participants stated that they would recommend the intervention for weight control to friends and family . Conclusions Text messages might prove to be a productive channel of communication to promote behaviors that support weight loss in overweight adults . Trial Registration Clinical trials.gov NCT00415870 ; http:// clinical trials.gov/ct2/show/NCT00415870 ( Archived by WebCite at http://www.webcitation.org/5dnolbkFt Context Low-carbohydrate weight reduction diets are popular despite a dearth of data on long-term efficacy and adverse effects . Contribution Community-dwelling hyperlipidemic persons were r and omly assigned to either a low-carbohydrate , ketogenic diet or a low-fat , low-cholesterol , reduced-calorie diet for 24 weeks . Compared to the low-fat group , patients in the low-carbohydrate group lost more weight , had a greater decrease in triglyceride levels , and had higher high-density lipoprotein cholesterol levels . Levels of low-density lipoprotein cholesterol remained stable in both groups . Side effects were more common in the low-cholesterol group but were generally mild . Caution s While the study suggests the efficacy and relative safety of the low-cholesterol diet , the high dropout rate , self-directed adherence to the diet , and relatively short observation period challenge the generalizability of the findings . The Editors As the prevalence of obesity has increased over the past 20 years ( 1 ) , the difficulties faced by overweight patients and their health care practitioners have become apparent . Fewer than 25 % of Americans who attempt to lose weight actually reduce caloric intake and increase exercise as currently recommended ( 2 ) . Persons who successfully lose weight have difficulty maintaining their weight loss ( 3 ) . Therefore , it is not surprising that consumers spend $ 33 billion yearly on weight loss products and services in search of effective therapies ( 2 ) . Because many weight loss interventions are unproven and untested , practitioners often lack information with which to recommend a certain therapy or to monitor a patient once a therapy is chosen . One approach to weight loss that has gained recognition in the face of modest supportive scientific evidence is the low-carbohydrate diet . A popular version of this diet recommends extreme restriction of carbohydrate intake to less than 20 g/d initially ( 4 ) . This level of carbohydrate restriction can induce serum and urinary ketones and weight loss ( 5 , 6 ) . However , until recently , available data on low-carbohydrate diets came from small studies of short duration , most of which were uncontrolled ( 5 , 7 - 10 ) . We examined body weight , body composition , serum lipid levels , and adverse effects over 24 weeks in hyperlipidemic persons who were r and omly assigned to follow a low-carbohydrate , ketogenic diet or a low-fat , low-cholesterol , reduced-calorie diet commonly used to induce weight loss and decrease serum lipid levels . Methods Participants Generally healthy persons were recruited from the community . Inclusion criteria were age 18 to 65 years , body mass index of 30 to 60 kg/m2 , desire to lose weight , elevated lipid levels ( total cholesterol level > 5.17 mmol/L [ > 200 mg/dL ] , low-density lipoprotein [ LDL ] cholesterol level > 3.36 mmol/L [ > 130 mg/dL ] , or triglyceride level > 2.26 mmol/L [ 200 mg/dL ] ) , and no serious medical condition . Exclusion criteria were use of any prescription medication in the previous 2 months ( except for oral contraceptives , estrogen therapy , and stable thyroid medication ) , pregnancy or breastfeeding , use of any weight loss diet or diet pills in the previous 6 months , and baseline ketonuria . All participants provided written informed consent , and the institutional review board of Duke University Health System approved the study . Participants received no monetary incentive . Interventions By using a computer-generated simple r and omization list , participants were allocated to receive the low-carbohydrate diet or low-fat diet . The intervention for both groups included group meetings , diet instruction , and an exercise recommendation . Group meetings took place at an outpatient research clinic twice monthly for 3 months , then monthly for 3 months . These meetings typically lasted 1 hour and consisted of diet instruction , supportive counseling , question naires , and biomedical measurements . During the study , participants selected their own menus and prepared or bought their own meals according to the guidelines presented to them . Participants were encouraged to exercise for 30 minutes at least 3 times weekly , but no formal exercise program or incentives were provided . Low-Carbohydrate Diet Using a popular diet book published by a lay press and additional h and outs , trained research staff instructed participants to restrict intake of carbohydrates to less than 20 g/d ( 4 ) . Participants were permitted unlimited amounts of animal foods ( meat , fowl , fish , and shellfish ) , unlimited eggs , 4 oz of hard cheese , 2 cups of salad vegetables ( such as lettuce , spinach , or celery ) , and 1 cup of low-carbohydrate vegetables ( such as broccoli , cauliflower , or squash ) daily . Participants were encouraged to drink 6 to 8 glasses of water daily . When participants were halfway to their goal body weight ( determined at the week 10 visit with assistance from research personnel ) , they were advised to add approximately 5 g of carbohydrates to their daily intake each week until they reached a level at which body weight was maintained . To simulate the practice of the study sponsor , the low-carbohydrate diet group also received daily nutritional supplements ( multivitamin , essential oils , diet formulation , and chromium picolinate ; for a list of the composition of these supplements , see the Appendix ) ( 6 ) . Low-Fat Diet Using a commonly available booklet and additional h and outs , a registered dietitian instructed participants in a diet consisting of less than 30 % of daily energy intake from fat , less than 10 % of daily energy intake from saturated fat , and less than 300 mg of cholesterol daily ( 11 , 12 ) . The recommended energy intake was 2.1 to 4.2 MJ ( 500 to 1000 kcal ) less than the participant 's calculated energy intake for weight maintenance ( body weight in pounds 10 ) ( 13 ) . Primary Outcome Measure Body weight and body mass index were the primary outcome measures . At each visit , participants were weighed on the same calibrated scale while wearing lightweight clothing and no shoes . Body mass index was calculated as body weight in kilograms divided by height in meters squared . Secondary Outcome Measures Adherence Adherence to the diet was measured by self-report , food records , and , for the low-carbohydrate diet group , urinary ketone assessment . Diet Composition All participants completed a 24-hour recall of food intake at baseline and take-home food records ( 5 consecutive days , including a weekend ) that were collected at each meeting during the study . Participants were instructed on how to document food intake and were given h and outs with examples of how to complete the records . A sample of participants ( 13 in the low-carbohydrate diet group and 7 in the low-fat diet group ) who completed the study was selected for food record analysis by the research staff on the basis of adequacy of detail in their records . A registered dietitian analyzed the food records by using a nutrition software program ( Nutritionist Five , version 1.6 [ First Data Bank , Inc. , San Bruno , California ] ) . Ketonuria Restriction of dietary intake of carbohydrates to less than 40 g/d typically results in ketonuria that is detectable by dipstick analysis , which can be used to monitor adherence to the low-carbohydrate diet ( 14 , 15 ) . At each return visit , participants provided a fresh urine specimen for analysis . The following semi-quantitative scale was used to categorize ketone content : none , trace ( up to 0.9 mmol/L [ 5 mg/dL ] ) , small ( 0.9 to 6.9 mmol/L [ 5 to 40 mg/dL ] ) , moderate ( 6.9 to 13.8 mmol/L [ 40 to 80 mg/dL ] ) , large80 ( 13.8 to 27.5 mmol/L [ 80 to 160 mg/dL ] ) , and large160 ( > 27.5 mmol/L [ > 160 mg/dL ] ) . Body Composition Body composition was estimated by using bioelectric impedance ( model TBF-300A [ Tanita Corp. , Arlington Heights , Illinois ] ) at approximately the same time of day ( afternoon or evening ) at each return visit . In a subset of 33 participants , the percentage of body fat as measured by bioelectric impedance had excellent correlation with the percentage as measured by dual-energy x-ray absorptiometry ( r = 0.93 [ 95 % CI , 0.87 to 0.97 ] ) . Vital Signs Blood pressure and pulse rate were measured in the nondominant arm by using an automated digital cuff ( model HEM-725C [ Omron Corp. , Vernon Hills , Illinois ] ) after the participant had been sitting for 3 minutes . Two measurements were taken at each visit and averaged for the analysis . Serum Lipids and Lipoproteins Serum specimens for lipid measurement were obtained in the morning after at least 8 hours of fasting at the screening visit and at 8 , 16 , and 24 weeks . Other Metabolic Effects Serum tests for sodium , potassium , chloride , urea nitrogen , creatinine , calcium , phosphorus , total protein , albumin , uric acid , total bilirubin , alanine aminotransferase , aspartate aminotransferase , alkaline phosphatase , thyroid-stimulating hormone , iron , hemoglobin , leukocyte count , and platelet count were obtained at the screening visit and at 8 , 16 , and 24 weeks . The glomerular filtration rate was estimated by using an equation that included age ; sex ; race ; and serum levels of albumin , creatinine , and urea nitrogen ( Modification of Diet in Renal Disease Study equation ) ( 16 ) . Adverse Effects At all return visits , participants completed an open-ended question naire on side effects . At the 20- and 24-week visits , participants completed a checklist of the side effects that were most often mentioned during the study . Statistical Analysis Analyses were performed by using S-PLUS software , version 6.1 ( Insightful Corp. , Seattle , Washington ) , or SAS software , version 8.02 ( SAS Institute , Inc. , Cary , North Carolina ) . For categorical outcomes , groups were compared by using the chi-square test or Fisher exact test , as appropriate . For all primary and secondary continuous outcomes , linear mixed-effects models ( PROC MIXED procedure in SAS software ) that included fixed and r and om effects were used to determine expected mean values at each time point and to test hypotheses of group differences . In most body weight and Objective : Evaluate effectiveness of weight-loss interventions in a managed care setting . Methods : Three-arm r and omized clinical trial : usual care , mail , and phone intervention . Participants were 1801 overweight managed care organization ( MCO ) members . Measures included baseline height , weight at baseline and 24 months , self-reported weight at 18 months . Intervention and participation in other weight-related programs was monitored across 24 months . Results : Weight losses were 2.2 , 2.4 , and 1.9 kg at 18 months in the mail , phone , and usual care groups , respectively . Mail and phone group weight changes were not significantly different from usual care (P<0.35).Weight losses at 24 months did not differ by condition ( 0.7 kg mail , 1.0 kg phone , and 0.6 kg usual care , P=0.55 ) . Despite treatment availability over 24 months , participation diminished after 6 months . Participation was a significant predictor of outcomes in the mail and phone groups at 18 months and the mail group at 24 months . Cost-effectiveness of phone counseling was $ 132 per 1 kg of weight loss with mail and usual care achieving similar cost-efficiency of $ 72 per 1 kg of weight loss . Conclusion : Although mail- and phone-based weight-loss programs are a reasonably efficient way to deliver weight-loss services , additional work is needed to enhance their short- and long-term efficacy BACKGROUND Limited evidence suggests that a higher ratio of protein to carbohydrate during weight loss has metabolic advantages . OBJECTIVE The objective was to evaluate the effects of a diet with a high ratio of protein to carbohydrate during weight loss on body composition , cardiovascular disease risk , nutritional status , and markers of bone turnover and renal function in overweight women . DESIGN The subjects were r and omly assigned to 1 of 2 isocaloric 5600-kJ dietary interventions for 12 wk according to a parallel design : a high-protein ( HP ) or a high-carbohydrate ( HC ) diet . RESULTS One hundred women with a mean ( + /-SD ) body mass index ( in kg/m(2 ) ) of 32 + /- 6 and age of 49 + /- 9 y completed the study . Weight loss was 7.3 + /- 0.3 kg with both diets . Subjects with high serum triacylglycerol ( > 1.5 mmol/L ) lost more fat mass with the HP than with the HC diet ( x + /- SEM : 6.4 + /- 0.7 and 3.4 + /- 0.7 kg , respectively ; P = 0.035 ) and had a greater decrease in triacylglycerol concentrations with the HP ( -0.59 + /- 0.19 mmol/L ) than with the HC ( -0.03 + /- 0.04 mmol/L ) diet ( P = 0.023 for diet x triacylglycerol interaction ) . Triacylglycerol concentrations decreased more with the HP ( 0.30 + /- 0.10 mmol/L ) than with the HC ( 0.10 + /- 0.06 mmol/L ) diet ( P = 0.007 ) . Fasting LDL-cholesterol , HDL-cholesterol , glucose , insulin , free fatty acid , and C-reactive protein concentrations decreased with weight loss . Serum vitamin B-12 increased 9 % with the HP diet and decreased 13 % with the HC diet ( P < 0.0001 between diets ) . Folate and vitamin B-6 increased with both diets ; homocysteine did not change significantly . Bone turnover markers increased 8 - 12 % and calcium excretion decreased by 0.8 mmol/d ( P < 0.01 ) . Creatinine clearance decreased from 82 + /- 3.3 to 75 + /- 3.0 mL/min ( P = 0.002 ) . CONCLUSION An energy-restricted , high-protein , low-fat diet provides nutritional and metabolic benefits that are equal to and sometimes greater than those observed with a high-carbohydrate diet Context Some experts attribute a low incidence of heart disease in Mediterranean countries to dietary habits . Contribution In this multicenter , 3-group trial , investigators r and omly assigned 772 adults at high risk for cardiovascular disease to a low-fat diet or to a Mediterranean diet supplemented with either virgin olive oil ( 1 L per week ) or nuts ( 30 g per day ) . After 3 months , the Mediterranean diet groups had lower mean plasma glucose level , systolic blood pressure , and total cholesterolhigh-density lipoprotein cholesterol ratio than the low-fat diet group . Caution s The Mediterranean diet groups received more nutritional education than the low-fat diet group . Implication s Mediterranean diets supplemented with olive oil or nuts may improve cardiovascular risk factors . The Editors Cardiovascular disease is the main cause of death in industrialized countries , but incidence rates have marked geographic differences . The low incidence of coronary heart disease ( CHD ) in Mediterranean countries has been partly ascribed to dietary habits ( 1 - 3 ) . Recent findings from large European cohort studies ( 4 - 6 ) suggest that a high degree of adherence to the Mediterranean diet is associated with a reduction in mortality . In small clinical studies , the Mediterranean diet or some of its components have reduced blood pressure ( 7 ) and have improved lipid profiles ( 8 , 9 ) and endothelial function ( 10 ) . Moreover , a recent cross-sectional study ( 11 ) and a 2-year feeding trial ( 12 ) have shown that adherence to the Mediterranean diet is associated with reduced markers of vascular inflammation . These beneficial effects on surrogate markers of cardiovascular risk add biological plausibility to the epidemiologic evidence that supports a protective effect of the Mediterranean diet . Olive oil , a rich source of monounsaturated fatty acids , is a main component of the Mediterranean diet . Virgin olive oil retains all the lipophilic components of the fruit , -tocopherol , and phenolic compounds with strong antioxidant and anti-inflammatory properties ( 13 , 14 ) . Tree nuts , which are also typical in the Mediterranean diet , have a favorable fatty acid profile and are a rich source of nutrients and other bioactive compounds that may beneficially influence the risk for CHD , such as fiber , phytosterols , folic acid , and antioxidants ( 15 ) . Frequent nut intake has been associated with decreased CHD rates in prospect i ve studies ( 15 ) . Walnuts differ from all other nuts through their high content of polyunsaturated fatty acids , particularly -linolenic acid , a plant n-3 fatty acid ( 16 ) , which may confer additional antiatherogenic properties ( 17 ) . Therefore , we design ed a large-scale feeding trial in high-risk participants to assess the effects of 2 Mediterranean diets , one supplemented with virgin olive oil and the other supplemented with mixed nuts , compared with a low-fat diet on cardiovascular outcomes . We report the results of a 3-month intervention on intermediate markers of cardiovascular risk in the first 772 participants who were recruited into the trial . Supplement . Original Version ( PDF ) Methods Study Design The Prevencin con Dieta Mediterrnea ( PREDIMED ) Study is a large , parallel-group , multicenter , r and omized , controlled , 4-year clinical trial that aims to assess the effects of the Mediterranean diet on the primary prevention of cardiovascular disease ( www.predimed.org ) . An estimated 9000 high-risk participants ( > 5000 participants are already recruited ) will be assigned to 3 interventions : Mediterranean diet with virgin olive oil , Mediterranean diet with mixed nuts , or low-fat diet . The main outcome is an aggregate of cardiovascular events ( cardiovascular death , nonfatal myocardial infa rct ion , or nonfatal stroke ) . The anticipated completion date of the trial is December 2010 . We design ed our present study to assess the 3-month effects of the dietary interventions on surrogate markers of cardiovascular risk in participants entering the study during the first 6 months of recruitment . The institutional review boards of the 10 participating centers approved the study protocol . Participants and Recruitment From October 2003 to March 2004 , we selected 930 potential participants in primary care centers affiliated with 10 teaching hospitals across Spain . Eligible participants were community-dwelling men , 55 to 80 years of age , and women , 60 to 80 years of age , who fulfilled at least 1 of 2 criteria : type 2 diabetes or 3 or more CHD risk factors ( current smoking , hypertension [ blood pressure > 140/90 mm Hg or treatment with antihypertensive drugs ] , low-density lipoprotein [ LDL ] cholesterol level 4.14 mmol/L [ 160 mg/dL ] [ or treatment with hypolipidemic drugs ] , high-density lipoprotein [ HDL ] cholesterol level 1.04 mmol/L [ 40 mg/dL ] , body mass index [ BMI ] 25 kg/m2 , or a family history of premature CHD ) . Exclusion criteria were history of cardiovascular disease , any severe chronic illness , drug or alcohol addiction , history of allergy or intolerance to olive oil or nuts , or low predicted likelihood of changing dietary habits according to the stages-of-change model ( 18 ) . The primary care physicians based participants ' eligibility on review of clinical records and a screening visit . They obtained a list of c and i date s from computer-based records of patients who attended each participating center and review ed their clinical records to exclude those who did not meet eligibility criteria . They then invited suitable c and i date s by telephone to attend a screening visit . The visit included an interview with administration of a 26-item question naire to inquire about medical conditions and risk factors related to eligibility . Of the eligible c and i date s who met entry requirements , 95 % agreed to participate and provided informed consent . R and omization and Intervention After the screening visit , each center r and omly assigned eligible participants to 1 of 3 diet groups by using a computer-generated r and om-number sequence . The coordinating center constructed the r and omization table , and participants were r and omly assigned into blocks of 50 participants balanced by center , sex , and age group ( < 70 years and 70 years ) . We concealed allocation into the intervention groups by using closed envelopes with correlative numbers by prespecified subgroups of sex and age . The baseline examination included the administration of a 14-item question naire , an extension of a previously vali date d question naire ( 19 ) , that assessed the degree of adherence to the traditional Mediterranean diet . We assigned values of 0 or 1 to each item ( Appendix Table 1 ) . We also administered a 137-item vali date d food frequency question naire ( 20 ) ; the vali date d Spanish version ( 21 ) of the Minnesota Leisure Time Physical Activity Question naire ; and a 47-item question naire about education , lifestyle , history of illnesses , and medication use . We performed anthropometric and blood pressure measurements and obtained sample s of fasting blood and spot urine . We repeated all examinations at 3 months . The same dietitian delivered the interventions to the 3 r and omized groups in each center . On the basis of the assessment of individual Mediterranean diet scores , the dietitian gave personalized dietary advice during a 30-minute session to each participant , with recommendations on the desired frequency of intake of specific foods . We advised participants who were allocated to the low-fat diet to reduce intake of all types of fat , and we gave them a leaflet with written recommendations according to the American Heart Association guidelines ( 22 ) . For total fat intake , these recommendations were opposite to those given to participants in the 2 Mediterranean diet groups , who received instructions intended to increase the 14-item Mediterranean diet score , including increased consumption of vegetable fats and oils . We did not suggest any energy restriction . While the participants who were allocated to the low-fat diet did not receive further intervention , those assigned the 2 Mediterranean diet groups had access to more intense intervention in 2 ways . First , they were given a free provision of typical Mediterranean fatty foods ( olive oil or nuts ) . Depending on group assignment , participants were given either free virgin olive oil ( 15 L [ 1 L/wk ] for 3 months ) or free sachets of walnuts , hazelnuts , and almonds ( 1350 g of walnuts [ 15 g/d ] , 675 g of hazelnuts [ 7.5 g/d ] , and 675 g of almonds [ 7.5 g/d ] for 3 months ) . To improve adherence and account for family needs , participants in the corresponding Mediterranean diet groups were given excess olive oil or additional 1000-g packets of nuts . We analyzed the nutrient composition of the olive oil and nuts used in the study by st and ard methods in a reference laboratory ( Appendix Table 2 ) ) . Second , 1 week after inclusion , the dietitian delivered a 1-hour group session with up to 20 participants , with separate sessions for each Mediterranean diet group . Each group session consisted of informative talks and provision of written material s with elaborate descriptions of typical Mediterranean foods and seasonal shopping lists , meal plans , and cooking recipes . Throughout the study , all participants had free and continuous access to their center dietitian for advice and consultation . Measurements Trained personnel measured weight and height by using calibrated scales and a wall-mounted stadiometer , respectively ; waist circumference midway between the lowest rib and the iliac crest by using an anthropometric tape ; and blood pressure in triplicate with a vali date d semiautomatic oscillometer ( Omron HEM-705CP , Hoofddorp , the Netherl and s ) . We calculated energy and nutrient intake from Spanish food composition tables ( 23 ) . At the 3-month visit and when consulted by participants , dietitians assessed any adverse effects from the interventions by administering a checklist of symptoms and gave advice on how to remedy them . The checklist included mouth symptoms ; bloating , fullness , or indigestion ; altered bowel Intensive obesity treatment is m and ated by federal health care reform but is costly . A partial subsidy for obesity treatment could lower the cost of treatment , without reducing its efficacy . This study sought to test whether a partial subsidy for obesity treatment would be feasible , as compared to a fully subsidized intervention . The study was a pilot r and omized trial . Participants ( n = 50 ) were primary care patients with obesity and at least one comorbid condition ( diabetes , hypertension , dyslipidemia , or obstructive sleep apnea ) . Each participant received eight weight loss counseling visits as well as portion-controlled foods for weight loss . Participants were r and omized to full subsidy or partial subsidy ( 2 vs. 1 meal per day provided ) . The primary outcome was weight change after 4 months . Secondary outcomes included changes in blood pressure , waist circumference , and health-related quality of life . Participants in the full and partial subsidy groups lost 5.9 and 5.3 kg , equivalent to 5.3 % and 5.1 % of initial weight , respectively ( P = 0.71 ) . Changes in secondary outcomes were similar in the two groups . A partial subsidy was feasible and induced a clinical ly similar amount of weight loss , compared to a full subsidy . Large-scale testing of economic incentives for weight control is merited given the federal m and ate to offer weight loss counseling to obese patients BACKGROUND Despite the popularity of the low-carbohydrate , high-protein , high-fat ( Atkins ) diet , no r and omized , controlled trials have evaluated its efficacy . METHODS We conducted a one-year , multicenter , controlled trial involving 63 obese men and women who were r and omly assigned to either a low-carbohydrate , high-protein , high-fat diet or a low-calorie , high-carbohydrate , low-fat ( conventional ) diet . Professional contact was minimal to replicate the approach used by most dieters . RESULTS Subjects on the low-carbohydrate diet had lost more weight than subjects on the conventional diet at 3 months ( mean [ + /-SD ] , -6.8+/-5.0 vs. -2.7+/-3.7 percent of body weight ; P=0.001 ) and 6 months ( -7.0+/-6.5 vs. -3.2+/-5.6 percent of body weight , P=0.02 ) , but the difference at 12 months was not significant ( -4.4+/-6.7 vs. -2.5+/-6.3 percent of body weight , P=0.26 ) . After three months , no significant differences were found between the groups in total or low-density lipoprotein cholesterol concentrations . The increase in high-density lipoprotein cholesterol concentrations and the decrease in triglyceride concentrations were greater among subjects on the low-carbohydrate diet than among those on the conventional diet throughout most of the study . Both diets significantly decreased diastolic blood pressure and the insulin response to an oral glucose load . CONCLUSIONS The low-carbohydrate diet produced a greater weight loss ( absolute difference , approximately 4 percent ) than did the conventional diet for the first six months , but the differences were not significant at one year . The low-carbohydrate diet was associated with a greater improvement in some risk factors for coronary heart disease . Adherence was poor and attrition was high in both groups . Longer and larger studies are required to determine the long-term safety and efficacy of low-carbohydrate , high-protein , high-fat diets BACKGROUND Rural counties in the United States have higher rates of obesity , sedentary lifestyle , and associated chronic diseases than nonrural areas , yet the management of obesity in rural communities has received little attention from research ers . METHODS Obese women from rural communities who completed an initial 6-month weight-loss program at Cooperative Extension Service offices in 6 medically underserved rural counties ( n = 234 ) were r and omized to extended care or to an education control group . The extended-care programs entailed problem-solving counseling delivered in 26 biweekly sessions via telephone or face to face . Control group participants received 26 biweekly newsletters containing weight-control advice . RESULTS Mean weight at study entry was 96.4 kg . Mean weight loss during the initial 6-month intervention was 10.0 kg . One year after r and omization , participants in the telephone and face-to-face extended-care programs regained less weight ( mean [ SE ] , 1.2 [ 0.7 ] and 1.2 [ 0.6 ] kg , respectively ) than those in the education control group ( 3.7 [ 0.7 ] kg ; P = .03 and .02 , respectively ) . The beneficial effects of extended-care counseling were mediated by greater adherence to behavioral weight-management strategies , and cost analyses indicated that telephone counseling was less expensive than face-to-face intervention . CONCLUSIONS Extended care delivered either by telephone or in face-to-face sessions improved the 1-year maintenance of lost weight compared with education alone . Telephone counseling constitutes an effective and cost-efficient option for long-term weight management . Delivering lifestyle interventions via the existing infrastructure of the Cooperative Extension Service represents a viable means of adapting research for rural communities with limited access to preventive health services . Trial Registration clinical trials.gov Identifier : NCT00201006 OBJECTIVE Few multiple lifestyle behavior change programs have been design ed to reduce the risk of coronary heart disease in postmenopausal women with type 2 diabetes . This study tested the effectiveness of the Mediterranean Lifestyle Program ( MLP ) , a comprehensive lifestyle self-management program ( Mediterranean low-saturated fat diet , stress management training , exercise , group support , and smoking cessation ) , in reducing cardiovascular risk factors in postmenopausal women with type 2 diabetes . RESEARCH DESIGN AND METHODS Postmenopausal women with type 2 diabetes ( n = 279 ) were r and omized to either usual care ( control ) or treatment ( MLP ) conditions . MLP participants took part in an initial 3-day retreat , followed by 6 months of weekly meetings , to learn and practice program components . Biological end points were changes in HbA(1c ) , lipid profiles , BMI , blood pressure , plasma fatty acids , and flexibility . Impact on quality of life was assessed . RESULTS Multivariate ANCOVAs revealed significantly greater improvements in the MLP condition compared with the usual care group on HbA(1c ) , BMI , plasma fatty acids , and quality of life at the 6-month follow-up . Patterns favoring intervention were seen in lipids , blood pressure , and flexibility but did not reach statistical significance . CONCLUSIONS These results demonstrate that postmenopausal women with type 2 diabetes can make comprehensive lifestyle changes that may lead to clinical ly significant improvements in glycemic control , some coronary heart disease risk factors , and quality of life CONTEXT Weight loss programs on the Internet appear promising for short-term weight loss but have not been studied for weight loss in individuals at risk of type 2 diabetes ; thus , the longer-term efficacy is unknown . OBJECTIVE To compare the effects of an Internet weight loss program alone vs with the addition of behavioral counseling via e-mail provided for 1 year to individuals at risk of type 2 diabetes . DESIGN , SETTING , AND PARTICIPANTS A single-center r and omized controlled trial conducted from September 2001 to September 2002 in Providence , RI , of 92 overweight adults whose mean ( SD ) age was 48.5 ( 9.4 ) years and body mass index , 33.1 ( 3.8 ) . INTERVENTIONS Participants were r and omized to a basic Internet ( n = 46 ) or to an Internet plus behavioral e-counseling program ( n = 46 ) . Both groups received 1 face-to-face counseling session and the same core Internet programs and were instructed to su bmi t weekly weights . Participants in e-counseling su bmi tted calorie and exercise information and received weekly e-mail behavioral counseling and feedback from a counselor . MAIN OUTCOME MEASURES Measured weight and waist circumference at 0 and 12 months . RESULTS Intent-to-treat analyses showed the behavioral e-counseling group lost more mean ( SD ) weight at 12 months than the basic Internet group ( -4.4 [ 6.2 ] vs -2.0 [ 5.7 ] kg ; P = .04 ) , and had greater decreases in percentage of initial body weight ( 4.8 % vs 2.2 % ; P = .03 ) , body mass index ( -1.6 [ 2.2 ] vs -0.8 [ 2.1 ] ; P = .03 ) , and waist circumference ( -7.2 [ 7.5 ] vs -4.4 [ 5.7 ] cm ; P = .05 ) . CONCLUSION Adding e-mail counseling to a basic Internet weight loss intervention program significantly improved weight loss in adults at risk of diabetes Context Mediterranean-style diets improve control of coronary risk factors and hyperglycemia , but few direct comparisons of the diet with other st and ard diets have been done . Contribution In this r and omized clinical trial , patients with newly diagnosed type 2 diabetes who were assigned to a low-carbohydrate , Mediterranean-style diet had better glycemic control and were less likely to need oral antihyperglycemic therapy than patients assigned to a low-fat diet . Caution The trial was unblinded , and dietary intake was self-reported . Implication A low-carbohydrate , Mediterranean-style diet seems to be preferable to a low-fat diet for glycemic control in patients with newly diagnosed type 2 diabetes . The Editors The p and emic of type 2 diabetes is an enormous public health problem , with 380 million cases worldwide projected by 2025 ( 1 , 2 ) . Lifestyle intervention studies ( 3 ) have demonstrated large reductions in risk for type 2 diabetes that remain after lifestyle counseling is stopped ( 4 , 5 ) . Despite this beneficial effect , the American Diabetes Association ( ADA ) recommends that patients with newly diagnosed type 2 diabetes be treated with pharmacotherapy as well as lifestyle changes ( 6 ) . The rationale for combination therapy is presumably that each form of treatment alone is imperfect . Lifestyle changes are often inadequate because patients do not lose weight or regain weight or their diabetes worsens independent of weight ( 6 ) . Pharmacotherapy also often fails with time ( 7 ) , and some drugs have associated cardiovascular and other risks ( 8 , 9 ) . For those reasons , lifestyle changes proven to be more effective than what is typically recommended would be welcome . For example , Mediterranean-style ( MED ) diets with a high proportion of monounsaturated fat provide cardiovascular benefits and increase insulin sensitivity ( 1012 ) , and the ADA recommends low-carbohydrate or low-fat , calorie-restricted diets for weight loss in overweight and obese patients with type 2 diabetes ( 13 ) . However , few direct , long-term comparisons of the 2 diets in patients with diabetes have been done ( 11 ) . We conducted a r and omized trial to compare the effectiveness , durability , and safety of a low-carbohydrate MED diet and a low-fat diet on glycemic control in patients with newly diagnosed type 2 diabetes . Methods We conducted the trial between January 2004 ( first patient enrolled ) and September 2008 ( end of follow-up of the last patient ) at the research center of the Diabetes Clinic of the Azienda Ospedaliera Universitaria , Second University of Naples , Naples , Italy , in accordance with the Declaration of Helsinki and with the institutional review board 's approval . Screening Phase We recruited men and women with newly diagnosed type 2 diabetes by ADA criteria who had never been treated with antihyperglycemic drugs from the clinical practice s of trial investigators and screened them for eligibility . Inclusion criteria were age 30 to 75 years , body mass index ( BMI ) greater than 25 kg/m2 , and hemoglobin A1c ( HbA1c ) level less than 11 % . Participants also had to be sedentary ( < 1 hour of physical activity per week ) with no evidence of participation in weight-reduction programs and with a stable weight ( 2 kg ) in the past 6 months . Exclusion criteria included pregnancy or breastfeeding , use of any investigational drug in the previous 3 months , use of agents affecting glycemic control ( such as systemic glucocorticoids and weight loss drugs ) , and any condition that might compromise adherence to diet regimens . To minimize the likelihood of including participants with late-onset type 1 diabetes , we screened c and i date s by testing for antibodies to glutamate decarboxylase and measuring fasting plasma C-peptides . We excluded patients with positive antibodies or C-peptide levels less than 0.25 pmol/L ( < 0.76 ng/L ) . We also excluded patients with abnormal laboratory test results , including liver enzyme levels ( alanine aminotransferase , aspartate aminotransferase , and alkaline phosphatase ) greater than 3 times the upper limit of normal and serum creatinine levels greater than 123.8 mol/L ( > 1.4 mg/dL ) . We required that participants successfully self-monitor their diet and physical activity over a 2-week run-in period . We provided dietary education during that time that emphasized the importance of eating a healthy diet and being physically active for both weight loss and improvement of glycemic control . Participants were also taught to prepare their own meals at home . We encouraged all individuals who smoked to quit and provided self-help material s , referral to local programs , or both , as appropriate . R and omization and Blinding After obtaining informed consent , we r and omly assigned patients to 1 of the 2 study diets by using a computer-generated r and om-number sequence ( simple r and omization ) . Allocation was concealed in sealed study folders that were held in a central , secured location until after informed consent was obtained . The nurses who scheduled the study visits did not have access to the r and omization list , and laboratory staff did not know the participants ' group assignments . Staff members involved in the intervention were aware of group assignments , but those who assessed achievement of the primary outcome were blinded to the intervention . Participants received no financial compensation or gifts . Dietary Interventions We r and omly assigned patients to a low-carbohydrate MED diet or to a low-fat diet . The MED diet was rich in vegetables and whole grains and low in red meat , which was replaced with poultry and fish . We restricted energy intake to 1500 kcal/d for women and 1800 kcal/d for men , with the goal of no more than 50 % of calories from complex carbohydrates , based on evidence that , in the context of a MED diet , a carbohydrate content less than 50 % of daily energy is more beneficial than higher content for weight loss and cardiovascular risk reduction ( 14 ) . The diet had no less than 30 % calories from fat . The main source of added fat was 30 to 50 g of olive oil . The low-fat diet was based on American Heart Association guidelines ( 15 ) ; it was rich in whole grains and restricted additional fats , sweets , and high-fat snacks . We restricted energy intake to 1500 kcal/d for women and 1800 kcal/d for men , with the goal of no more than 30 % of calories from fat and no more than 10 % of calories from saturated fat . Nutritionists and dietitians gave dietary advice to participants in both groups in monthly sessions in the first year and bimonthly sessions thereafter . Participants kept diet diaries after being instructed how to record their intake using food models as examples of portion size and using actual weights or amounts in terms of common measures ( such as cups , teaspoons , and dessert spoons ) . We assessed adherence to the diets by session attendance and review of the diaries . Nondietary Interventions Patients in both groups also received guidance on increasing their level of physical activity , mainly walking for a minimum of 30 minutes per day , but also swimming or aerobic ball games . The physical activity program relied heavily on home-based exercise with gradual progression toward a goal of 175 minutes of moderate-intensity physical activity per week . Although walking was encouraged , participants were allowed to choose other types of moderate-intensity physical activity , and programs were tailored on the basis of the results of a baseline physical fitness test and safety concerns . We asked all patients to record occupational , household , and leisure time physical activity . Outcomes We followed patients for 4 years to assess trial outcomes . The primary outcome measure was time to introduction of antihyperglycemic drug therapy . Trial investigators were responsible for initiating drug therapy by the following protocol . As suggested by the ADA for clinical evaluation and management of diabetic patients ( 16 ) , we measured HbA1c at baseline and every 3 months thereafter . Participants who had a HbA1c level greater than 7 % were given an additional 3 months to reinforce dietary guidance and physical activity ; if the HbA1c level remained greater than 7 % , a drug regimen was introduced . Participants with an HbA1c level greater than 7 % at baseline were counted as having experienced the primary outcome if they still had that level at first follow-up . Trial investigators were also responsible for initiating or titrating antihypertensive or lipid-lowering therapy . Secondary outcome measures were changes in weight ( including BMI and waist circumference ) , glycemic control ( HbA1c , glucose , serum insulin , and adiponectin levels and homeostasis model assessment of insulin sensitivity ) , coronary risk factors ( lipid levels and blood pressure ) , and medications and meeting ADA coronary risk factor goals ( HbA1c level < 7 % , blood pressure < 130/80 mm Hg , and low-density lipoprotein cholesterol level < 2.59 mmol/L [ < 100 mg/dL ] ) ( 16 ) . Participants were weighed without shoes and in lightweight clothing to the nearest 0.1 kg at baseline and every month . Height at baseline ( for calculation of BMI ) was measured to the nearest millimeter with the use of a wall-mounted stadiometer ( Seca , Hamburg , Germany ) . Waist circumference was measured halfway between the last rib and the iliac crest . We measured HbA1c levels with high-pressure liquid chromatography by using the fully automated Glycosylated Hemoglobin Analyzer System ( Bio-Rad , Hercules , California ) traceable to the Diabetes Control and Complications Trial reference method , with a reference range of 4.0 % to 6.0 % . Insulin sensitivity in the fasting state was assessed with homeostasis model assessment and calculated with the following formula , as described by Matthews and colleagues ( 17 ) : fasting plasma glucose (mmol/L)fasting serum insulin (U/mL)/25 . High scores indicate low insulin sensitivity ( insulin resistance ) . We assayed plasma insulin and adiponectin levels by radioimmunoassay , as described elsewhere ( 18 ) . We performed assays for serum Objective : To compare the efficacy of a phone vs a traditional face-to-face clinic approach to achieve 10 % weight loss and weight maintenance . Design : Twenty-six week , r and omized , controlled trial . Subjects : Twenty-four men and 72 women , ages 25–68 years , with a body mass index ( BMI ) of 33.2±3.8 . Measurements : Weight loss at 12 weeks and weight maintenance at 26 weeks were the primary outcomes . Attendance , meal replacements ( MRs ) , fruits/vegetables ( F/V ) , and physical activity ( PA ) were measured weekly for process evaluation . Results : Median weight loss ( range ) from baseline at 12 weeks was significantly different for phone at 10.6 kg ( 16.6 ) or 10.4 % and clinic at 12.7 kg ( 19.9 ) or 13.7 % , and both were significantly different when compared with the control group with a weight loss of 0.25 kg ( 5.6 ) or 0.24 % . Median weight loss at 26 weeks was 12.8 kg ( 23.4 ) or 13.0 % from baseline for the phone group and 12.5 kg ( 35.2 ) or 12.6 % from baseline for the clinic group ( P>0.05 ) . Conclusion : The median weight loss for both phone and clinic groups at 12 and 26 weeks exceeded the NHLBI guideline of 10 % weight loss from baseline . The phone approach may be a viable option to the traditional weight management clinic for both service providers and participants BACKGROUND Obesity and its cardiovascular complications are extremely common medical problems , but evidence on how to accomplish weight loss in clinical practice is sparse . METHODS We conducted a r and omized , controlled trial to examine the effects of two behavioral weight-loss interventions in 415 obese patients with at least one cardiovascular risk factor . Participants were recruited from six primary care practice s ; 63.6 % were women , 41.0 % were black , and the mean age was 54.0 years . One intervention provided patients with weight-loss support remotely -- through the telephone , a study -specific Web site , and e-mail . The other intervention provided in-person support during group and individual sessions , along with the three remote means of support . There was also a control group in which weight loss was self-directed . Outcomes were compared between each intervention group and the control group and between the two intervention groups . For both interventions , primary care providers reinforced participation at routinely scheduled visits . The trial duration was 24 months . RESULTS At baseline , the mean body-mass index ( the weight in kilograms divided by the square of the height in meters ) for all participants was 36.6 , and the mean weight was 103.8 kg . At 24 months , the mean change in weight from baseline was -0.8 kg in the control group , -4.6 kg in the group receiving remote support only ( P<0.001 for the comparison with the control group ) , and -5.1 kg in the group receiving in-person support ( P<0.001 for the comparison with the control group ) . The percentage of participants who lost 5 % or more of their initial weight was 18.8 % in the control group , 38.2 % in the group receiving remote support only , and 41.4 % in the group receiving in-person support . The change in weight from baseline did not differ significantly between the two intervention groups . CONCLUSIONS In two behavioral interventions , one delivered with in-person support and the other delivered remotely , without face-to-face contact between participants and weight-loss coaches , obese patients achieved and sustained clinical ly significant weight loss over a period of 24 months . ( Funded by the National Heart , Lung , and Blood Institute and others ; Clinical Trials.gov number , NCT00783315 . ) OBJECTIVE Internet weight loss programs have become widely available as alternatives to st and ard treatment , but few data are available on their efficacy . This study aim ed to investigate the effectiveness of a structured behavioral weight loss website ( VTrim ) vs. a commercial weight loss website ( eDiets.com ) . RESEARCH METHODS AND PROCEDURES A r and omized , controlled trial was conducted from February 2003 to March 2005 , in 124 overweight and obese subjects ages 18 years and older with a BMI of 25 to 39.9 kg/m2 ( mean age , 47 + /- 9 years ; BMI , 32 + /- 3 kg/m2 ; 20 % men ) . Analyses were performed for the 88 subjects who had complete follow-up data . Participants were r and omly assigned to 12-month VTrim ( n = 62 ) or eDiets.com ( n = 62 ) intervention . VTrim participants had access to a therapist-led structured behavioral weight loss program delivered on-line . eDiets.com subjects had access to a self-help commercial on-line weight loss program . Body weight , social support , and use of website components were measured at 0 , 6 , and 12 months . RESULTS Repeated- measures analyses showed that the VTrim group lost significantly more weight than the eDiets.com group at 6 months ( 8.3 + /- 7.9 kg vs. 4.1 + /- 6.2 kg ; p = 0.004 ) and maintained a greater loss at 12 months ( 7.8 + /- 7.5 kg vs. 3.4 + /- 5.8 kg ; p = 0.002 ) . More participants in the VTrim group maintained a 5 % weight loss goal ( 65 % vs. 37.5 % ; p = 0.01 ) at 12 months . DISCUSSION An on-line , therapist-led structured behavioral weight loss website produced greater weight loss than a self-help commercial website . Because commercial sites have great potential public health impact , future research should investigate the feasibility of incorporating a more structured behavioral program into a commercial application BACKGROUND As obesity rates rise , new weight-loss methods are needed . Little is known about the use of podcasting ( audio files for a portable music player or computer ) to promote weight loss , despite its growing popularity . DESIGN A 12-week RCT was conducted . SETTING / PARTICIPANTS The study sample comprised overweight men and women ( BMI = 25 - 40 kg/m(2 ) ; n=78 ) in the Raleigh-Durham NC area . INTERVENTION In 2008 , participants were r and omly assigned to receive 24 episodes of a currently available weight-loss podcast ( control podcast ) or a weight-loss podcast based on social cognitive theory ( SCT ) design ed by the research ers ( enhanced podcast ) for 12 weeks . MAIN OUTCOME MEASURES Weight was measured on a digital scale at baseline and follow-up . Both groups also completed question naires assessing demographic information , food intake , physical activity , and SCT constructs at the introductory and 12-week meetings . Additional question naires at the 12-week meeting assessed perceptions of the intervention . RESULTS Data collection and analysis occurred in 2008 and intention-to-treat was used . Enhanced group participants ( n=41 ) had a greater decrease in weight ( -2.9+/-3.5 kg enhanced group vs -0.3+/-2.1 control group ; p<0.001 between groups ) and BMI ( -1.0+/-1.2 kg/m(2 ) enhanced group vs -0.1+/-0.7 kg/m(2 ) control group ; p<0.001 between groups ) than the control group ( n=37 ) and had greater weight-loss-related knowledge ( p<0.05 ) , elaboration ( p<0.001 ) , and user control ( p<0.001 ) and less cognitive load ( p<0.001 ) . CONCLUSIONS The results of this study suggest that the use of behavioral , theory-based podcasting may be an effective way to promote weight loss . TRIAL REGISTRATION NCT00771095 OBJECTIVE To evaluate the short-term impact of portion-controlled food provision in combination with an Internet behavioral weight loss program on weight , blood cholesterol , and blood glucose levels . DESIGN AND METHODS Fifty participants , mean age 46 ± 10.7 years and mean body mass index 35.1 ± 3.8 kg/m2 , were r and omized to one of two study groups , an Internet behavioral weight loss program ( Internet-alone ; n = 25 ) or an Internet behavioral weight loss program plus a commercially available portion-controlled diet ( Internet + PCD ; n = 25 ) for 12 weeks . RESULTS An intent-to-treat analysis found that the mean weight change in the Internet + PCD group was -5.7 ± 5.6 kg and in the Internet-alone group ( n = 25 ) was -4.1 ± 4.0 kg ( P = 0.26 ) . Participants in the Internet + PCD group achieved significantly greater improvements in blood glucose ( -2.6 ± 5.7 vs. 1.4 ± 11.0 mg/dl ; P = 0.05 ) and LDL cholesterol ( -8.2 ± 18.0 vs. -0.6 ± 21.0 mg/dl ; P = 0.04 ) , compared with Internet-alone group . CONCLUSIONS These data suggest that there may be short-term clinical benefit in using a PCD in conjunction with a behavioral Internet-based weight loss program to enhance weight loss and improve health indicators BACKGROUND Despite the popularity of low-glycemic index ( GI ) and high-protein diets , to our knowledge no r and omized , controlled trials have systematic ally compared their relative effects on weight loss and cardiovascular risk . METHODS A total of 129 overweight or obese young adults ( body mass index , > or = 25 [ calculated as weight in kilograms divided by the square of height in meters ] ) were assigned to 1 of 4 reduced-fat , high-fiber diets for 12 weeks . Diets 1 and 2 were high carbohydrate ( 55 % of total energy intake ) , with high and low GIs , respectively ; diets 3 and 4 were high protein ( 25 % of total energy intake ) , with high and low GIs , respectively . The glycemic load was highest in diet 1 and lowest in diet 4 . Changes in weight , body composition , and blood chemistry profile were studied . RESULTS While all groups lost a similar mean + /- SE percentage of weight ( diet 1 , -4.2 % + /- 0.6 % ; diet 2 , -5.5 % + /- 0.5 % ; diet 3 , -6.2 % + /- 0.4 % ; and diet 4 , -4.8 % + /- 0.7 % ; P = .09 ) , the proportion of subjects in each group who lost 5 % or more of body weight varied significantly by diet ( diet 1 , 31 % ; diet 2 , 56 % ; diet 3 , 66 % ; and diet 4 , 33 % ; P = .01 ) . Women on diets 2 and 3 lost approximately 80 % more fat mass ( -4.5 + /- 0.5 [ mean + /- SE ] kg and -4.6 + /- 0.5 kg ) than those on diet 1 ( -2.5 + /- 0.5 kg ; P = .007 ) . Mean + /- SE low-density-lipoprotein cholesterol levels declined significantly in the diet 2 group ( -6.6 + /- 3.9 mg/dL [ -0.17 + /- 0.10 mmol/L ] ) but increased in the diet 3 group ( + 10.0 + /- 3.9 mg/dL [ + 0.26 + /- 0.10 mmol/L ] ; P = .02 ) . Goals for energy distribution were not achieved exactly : both carbohydrate groups ate less fat , and the diet 2 group ate more fiber . CONCLUSION Both high-protein and low-GI regimens increase body fat loss , but cardiovascular risk reduction is optimized by a high-carbohydrate , low-GI diet OBJECTIVE To determine the efficacy of a weight-loss diet using packaged portion-controlled entrees compared with a self-selected diet based on the U.S. Department of Agriculture Food Guide Pyramid ( FGP ) ( United States Department of Agriculture , Center for Nutrition Policy and Promotion , Washington , DC ; 1996 ) . RESEARCH METHODS AND PROCEDURES Sixty healthy women ( BMI 26 to 40 kg/m(2 ) ; 24 to 60 years old ) were r and omized into two intervention groups for an 8-week parallel arm study . The portion-controlled group consumed two frozen entrees daily , plus additional food servings from the FGP . The self-selected diet group consumed a recommended number of servings from the FGP . Diets were design ed to be the same in composition ( 55 % carbohydrate , 25 % protein , 20 % fat ) and energy level ( 1365 kcal ) . Each group met weekly to monitor compliance and take measures . Outcomes included weight , body composition by DXA , hip and waist circumference , blood pressure , fasting blood lipids , glucose , insulin , and C-reactive protein . Significant differences were assessed using repeated measures ANOVA . RESULTS The portion-controlled group ( n = 26 ) experienced greater decreases in weight ( 5.6 + /- 2.2 kg or 6.5 % vs. 3.6 + /- 2.5 kg or 4.2 % ) , fat mass ( 3.6 + /- 1.8 vs. 2.3 + /- 1.4 kg ) , total cholesterol ( 24.4 + /- 21.5 mg/dL or 12.4 % vs. 13.0 + /- 13.9 mg/dL or 6.7 % ) , and fasting insulin ( -1.8 + /- 3.7 vs.+0.3 + /- 3.8 micro U/mL ) than the self-selected diet group ( n = 27 ) ( p < 0.05 ) . DISCUSSION Consumption of portion-controlled entrees result ed in greater losses of weight and fat , thereby reducing cardiovascular disease risk . Accurate portion control is an important factor in weight loss success , and use of packaged entrees is an effective method of achieving this OBJECTIVE The purpose of this study was to develop and evaluate a 12-week weight management intervention involving computerized self-monitoring and technology-assisted feedback with and without an enhanced behavioral component . METHODS 120 overweight ( 30.5±2.6kg/m(2 ) ) adults ( 45.0±10.3 years ) were r and omized to one of three groups : computerized self-monitoring with Basic feedback ( n=45 ) , Enhanced behavioral feedback ( n=45 ) , or wait-list control ( n=30 ) . Intervention participants used a computer software program to record dietary and physical activity information . Weekly e-mail feedback was based on computer-generated reports , and participants attended monthly measurement visits . RESULTS The Basic and Enhanced groups experienced significant weight reduction ( -2.7±3.3 kg and -2.5±3.1 kg ) in comparison to the Control group ( 0.3±2.2 ; p<0.05 ) . Waist circumference and systolic blood pressure also decreased in intervention groups compared to Control ( p<0.01 ) . CONCLUSIONS A program using computerized self-monitoring , technology-assisted feedback , and monthly measurement visits produced significant weight loss after 12 weeks . However , the addition of an enhanced behavioral component did not improve the effectiveness of the program . PRACTICE IMPLICATION S This study suggests that healthcare professionals can effectively deliver a weight management intervention using technology-assisted strategies in a format that may complement and reduce face-to-face sessions BACKGROUND Most weight-loss research targets obese individuals who desire large weight reductions . However , evaluation of weight-gain prevention in overweight individuals is also critical as most Americans become obese as a result of a gradual gain of 1 - 2 pounds per year over many years . METHOD This study evaluated the efficacy of an Internet-based program for weight-loss and weight-gain prevention with a two-group , prospect i ve , r and omized controlled trial . A military medical research center with a population of 17,000 active-duty military personnel supplied 446 overweight individuals ( 222 men ; 224 women ) with a mean age of 34 years and a mean BMI of 29 . Recruitment and study participation occurred 2003 - 2005 and data were analyzed in 2006 . Participants were r and omly assigned to receive the 6-month behavioral Internet treatment ( BIT , n=227 ) or usual care ( n=224 ) . Change in body weight , BMI , percent body fat , and waist circumference ; presented as group by time interactions , were measured . RESULTS After 6 months , completers who received BIT lost 1.3 kg while those assigned to usual care gained 0.6 kg ( F((df=366))=24.17 ; I<0.001 ) . Results were similar for the intention-to-treat model . BIT participants also had significant changes in BMI ( -0.5 vs + 0.2 kg/m(2 ) ; F((df=366))=24.58 ) ; percent body fat ( -0.4 vs + 0.6 % ; F((df=366))=10.45 ) ; and waist circumference ( -2.1 vs -0.4 cm ; F((df=366))=17.09 ) ; p<0.001 for all . CONCLUSIONS Internet-based weight-management interventions result in small amounts of weight loss , prevent weight gain , and have potential for widespread dissemination as a population health approach . TRIAL REGISTRATION NCT00417599 Background Previous interventions have shown promising results using theory-based podcasts to deliver a behavioral weight-loss intervention . Objective The objective of our study was to examine whether a combination of podcasting , mobile support communication , and mobile diet monitoring can assist people in weight loss . Methods In this 6-month , minimal contact intervention , overweight ( n = 96 , body mass index 32.6 kg/m2 ) adults were recruited through television advertisements and email listservs and r and omly assigned to Podcast-only or Podcast+Mobile groups . Both groups received 2 podcasts per week for 3 months and 2 minipodcasts per week for months 3–6 . In addition to the podcasts , the Podcast+Mobile group was also instructed to use a diet and physical activity monitoring application ( app ) on their mobile device and to interact with study counselors and other participants on Twitter . Results Weight loss did not differ by group at 6 months : mean –2.7 % ( SD 5.6 % ) Podcast+Mobile , n = 47 ; mean –2.7 % ( SD 5.1 % ) Podcast , n = 49 ; P = .98 . Days/week of reported diet monitoring did not differ between Podcast+Mobile ( mean 2.3 , SD 1.9 days/week ) and Podcast groups ( mean 1.9 , SD 1.7 days/week ; P = .28 ) but method of monitoring did differ . Podcast+Mobile participants were 3.5 times more likely than the Podcast group to use an app to monitor diet ( P = .01 ) , whereas the majority of Podcast participants reported using the Web ( 14/41 , 34 % ) or paper ( 12/41 , 29 % ) . There were more downloads per episode in the Podcast+Mobile group ( 1.4/person ) than in the Podcast group ( 1.1/person ; P < .001 ) . The number of podcasts participants reported downloading over the 6-month period was significantly moderately correlated with weight loss in both the Podcast+Mobile ( r = –.46 , P = .001 ) and the Podcast ( r = –.53 , P < .001 ) groups . Podcast+Mobile participants felt more user control at 3 months ( P = .02 ) , but not at 6 months , and there was a trend ( P = .06 ) toward greater elaboration among Podcast+Mobile participants . There were significant differences in reported source of social support between groups . More Podcast participants relied on friends ( 11/40 , 28 % vs 4/40 , 10 % ; P = .045 ) whereas Podcast+Mobile participants relied on online sources ( 10/40 , 25 % vs 0/40 ; P = .001 ) . Conclusions Results confirm and extend previous findings showing a minimally intensive weight-loss intervention can be delivered via podcast , but prompting and mobile communication via Twitter and monitoring app without feedback did not enhance weight loss . Trial Registration Clinical trials.gov NCT01139255 ; http:// clinical trials.gov/ct2/show/NCT01139255 ( Archived by WebCite at http://www.webcitation.org/625OjhiDy Background There is growing interest in the use of information communication technologies to treat obesity . An intervention delivered by smartphone could be a convenient , potentially cost-effective , and wide-reaching weight management strategy . Although there have been studies of texting-based interventions and smartphone applications ( apps ) used as adjuncts to other treatments , there are currently no r and omized controlled trials ( RCT ) of a st and -alone smartphone application for weight loss that focuses primarily on self-monitoring of diet and physical activity . Objective The aim of this pilot study was to collect acceptability and feasibility outcomes of a self-monitoring weight management intervention delivered by a smartphone app , compared to a website and paper diary . Methods A sample of 128 overweight volunteers were r and omized to receive a weight management intervention delivered by smartphone app , website , or paper diary . The smartphone app intervention , My Meal Mate ( MMM ) , was developed by the research team using an evidence -based behavioral approach . The app incorporates goal setting , self-monitoring of diet and activity , and feedback via weekly text message . The website group used an existing commercially available slimming website from a company called Weight Loss Re sources who also provided the paper diaries . The comparator groups delivered a similar self-monitoring intervention to the app , but by different modes of delivery . Participants were recruited by email , intranet , newsletters , and posters from large local employers . Trial duration was 6 months . The intervention and comparator groups were self-directed with no ongoing human input from the research team . The only face-to-face components were at baseline enrollment and brief follow-up sessions at 6 weeks and 6 months to take anthropometric measures and administer question naires . Results Trial retention was 40/43 ( 93 % ) in the smartphone group , 19/42 ( 55 % ) in the website group , and 20/43 ( 53 % ) in the diary group at 6 months . Adherence was statistically significantly higher in the smartphone group with a mean of 92 days ( SD 67 ) of dietary recording compared with 35 days ( SD 44 ) in the website group and 29 days ( SD 39 ) in the diary group ( P<.001 ) . Self-monitoring declined over time in all groups . In an intention-to-treat analysis using baseline observation carried forward for missing data , mean weight change at 6 months was -4.6 kg ( 95 % CI –6.2 to –3.0 ) in the smartphone app group , –2.9 kg ( 95 % CI –4.7 to –1.1 ) in the diary group , and –1.3 kg ( 95 % CI –2.7 to 0.1 ) in the website group . BMI change at 6 months was –1.6 kg/m2 ( 95 % CI –2.2 to –1.1 ) in the smartphone group , –1.0 kg/m2 ( 95 % CI –1.6 to –0.4 ) in the diary group , and –0.5 kg/m2 ( 95 % CI –0.9 to 0.0 ) in the website group . Change in body fat was –1.3 % ( 95 % CI –1.7 to –0.8 ) in the smartphone group , –0.9 % ( 95 % CI –1.5 to –0.4 ) in the diary group , and –0.5 % ( 95 % CI –0.9 to 0.0 ) in the website group . Conclusions The MMM app is an acceptable and feasible weight loss intervention and a full RCT of this approach is warranted . Trial Registration Clinical Trials.gov NCT01744535 ; http:// clinical trials.gov/ct2/show/NCT01744535 ( Archived by WebCite at http://www.webcitation.org/6FEtc3PVB AIM This study assessed the efficacy of a weight-loss diet by using packaged portion-controlled entrees vs. a self-selected diet based on the United States Department of Agriculture Food Guide Pyramid ( FGP ) . METHODS Sixty healthy overweight men ( body mass index ( BMI ) 26 - 42 kg/m2 ; aged 24 - 60 years ) were r and omized into two groups for an 8-week intervention . Group E consumed two portion-controlled entrees daily , plus recommended servings from the FGP . Group P consumed a self-selected diet consisting of a recommended number of servings from the FGP . Diets were design ed to be isocaloric ( 1700 kcal ) and identical in macronutrient composition ( 55 % carbohydrate , 25 % protein and 20 % fat ) . Participants were instructed to make no changes in physical activity levels . Each group was blinded to the protocol of the other group , and received separate diet instructions , but no behavioural or diet counselling . Outcomes included weight , BMI , body composition by dual energy X-ray absorptiometry , waist and hip circumference , blood pressure ( BP ) , fasting blood lipids , glucose , insulin and C-reactive protein . RESULTS Fifty-one men completed the study . The portion-control group E ( n = 25 ) experienced greater decreases in weight ( -7.4 + /- 3.1 vs. -5.1 + /- 4.0 kg ) , BMI ( -2.4 + /- 1.0 vs. -1.6 + /- 1.3 kg/m2 ) , fat mass ( -3.6 + /- 1.8 vs. -2.5 + /- 1.8 kg ) , waist circumference ( -6.6 + /- 3.3 vs. -4.3 + /- 2.9 cm ) and diastolic BP ( -6.0 + /- 7.2 vs. + 0.2 + /- 10.1 mmHg ) than group P ( n = 26 ) ( p < 0.05 ) . Consumption of a packaged entree diet result ed in greater losses of weight and fat mass , and reduced BP . CONCLUSIONS Use of packaged entrees as part of a weight-loss diet is an effective means of achieving portion control and enhancing losses of weight and fat mass in overweight men OBJECTIVE The objective was to assess the effect of a low-fat , vegan diet compared with the National Cholesterol Education Program ( NCEP ) diet on weight loss maintenance at 1 and 2 years . RESEARCH METHODS AND PROCEDURES Sixty-four overweight , postmenopausal women were r and omly assigned to a vegan or NCEP diet for 14 weeks , and 62 women began the study . The study was done in two replications . Participants in the first replication ( N = 28 ) received no follow-up support after the 14 weeks , and those in the second replication ( N = 34 ) were offered group support meetings for 1 year . Weight and diet adherence were measured at 1 and 2 years for all participants . Weight loss is reported as median ( interquartile range ) and is the difference from baseline weight at years 1 and 2 . RESULTS Individuals in the vegan group lost more weight than those in the NCEP group at 1 year [ -4.9 ( -0.5 , -8.0 ) kg vs. -1.8 ( 0.8 , -4.3 ) ; p < 0.05 ] and at 2 years [ -3.1 ( 0.0 , -6.0 ) kg vs. -0.8 ( 3.1 , -4.2 ) kg ; p < 0.05 ] . Those participants offered group support lost more weight at 1 year ( p < 0.01 ) and 2 years ( p < 0.05 ) than those without support . Attendance at meetings was associated with improved weight loss at 1 year ( p < 0.001 ) and 2 years ( p < 0.01 ) . DISCUSSION A vegan diet was associated with significantly greater weight loss than the NCEP diet at 1 and 2 years . Both group support and meeting attendance were associated with significant weight loss at follow-up Low-carbohydrate diets have been associated with significant reductions in weight and HbA(1c ) in obese , diabetic participants who received high-intensity lifestyle modification for 6 or 12 months . This investigation sought to determine whether comparable results to those of short-term , intensive interventions could be achieved over a 24-month study period using a low-intensity intervention that approximates what is feasible in outpatient practice . A total of 144 obese , diabetic participants were r and omly assigned to a low-carbohydrate diet ( < 30 g/day ) or to a low fat diet ( < or=30 % of calories from fat with a deficit of 500 kcal/day ) . Participants were provided weekly group nutrition education sessions for the first month , and monthly sessions thereafter through the end of 24 months . Weight , HbA(1c ) , glucose , and lipids were measured at baseline and 6 , 12 , and 24 months . Of the 144 enrolled participants , 68 returned for the month 24 assessment visit . Weights were retrieved from electronic medical records for an additional 57 participants ( total , 125 participants ) at month 24 . All participants with a baseline measurement and at least one of the three other measurements were included in the mixed-model analyses ( n = 138 ) . The low-intensity intervention result ed in modest weight loss in both groups at month 24 . At this time , participants in the low-carbohydrate group lost 1.5 kg , compared to 0.2 kg in the low-fat group ( P = 0.147 ) . Lipids , glycemic indexes , and dietary intake did not differ between groups at month 24 ( or at months 6 or 12 ) ( Clinical Trials.gov number , NCT00108459 ) Rural women have among the highest rates of obesity and sedentary lifestyle , yet few studies have examined strategies for delivering state-of-the-art obesity treatment to hard-to-reach rural areas . The purpose of this pilot trial was to examine the impact and cost-effectiveness of a 6-month behavioral weight loss program delivered to rural women by phone either one-on-one with a counselor or to a group via conference call . Thirty-four rural women ( mean BMI = 34.4 , SD=4.6 ) were r and omized to group phone-based treatment or individual phone-based treatment . Completers analysis showed that weight loss was greater in the group condition ( mean=14.9 kg= , SD=4.4 ) compared to the individual condition ( mean=9.5 kg , SD=5.2 ; p=.03 ) . Among the total sample , 62 % of participants in the group condition achieved the 10 % weight loss goal compared to 50 % in the individual condition , and group treatment was found to be more cost-effective . Future research is warranted to examine the benefits of group phone-based treatment for long-term management of obesity among rural population |
13,697 | 23,526,383 | CONCLUSION Hypofractionated radiotherapy in localized prostate cancer was not superior to conventional radiotherapy and showed higher acute gastrointestinal toxicity in this meta- analysis . | BACKGROUND The purpose of this work was to conduct a systematic review and meta- analysis of all r and omized controlled trials comparing the efficacy and side effect profile of hypofractionated versus conventional external-beam radiation therapy for prostate cancer . | PURPOSE To assess in a prospect i ve trial the feasibility and late toxicity of hypofractionated radiotherapy ( RT ) for prostate cancer . METHODS AND MATERIAL S Eligible patients had clinical stage T1c-2cNXM0 disease . They received 60 Gy in 20 fractions over 4 weeks with intensity-modulated radiotherapy including daily on-line image guidance with intraprostatic fiducial markers . RESULTS Between June 2001 and March 2004 , 92 patients were treated with hypofractionated RT . The cohort had a median prostate-specific antigen value of 7.06 ng/mL. The majority had Gleason grade 5 - 6 ( 38 % ) or 7 ( 59 % ) disease , and 82 patients had T1c-T2a clinical staging . Overall , 29 patients had low-risk , 56 intermediate-risk , and 7 high-risk disease . Severe acute toxicity ( Grade 3 - 4 ) was rare , occurring in only 1 patient . Median follow-up was 38 months . According to the Phoenix definition for biochemical failure , the rate of biochemical control at 14 months was 97 % . According to the previous American Society for Therapeutic Radiology and Oncology definition , biochemical control at 3 years was 76 % . The incidence of late toxicity was low , with no severe ( Grade > or =3 ) toxicity at the most recent assessment . CONCLUSIONS Hypofractionated RT using 60 Gy in 20 fractions over 4 weeks with image guidance is feasible and is associated with low rates of late bladder and rectal toxicity . At early follow-up , biochemical outcome is comparable to that reported for conventionally fractionated controls . The findings are being tested in an ongoing , multicenter , Phase III trial OBJECTIVES To compare three hypofractionated protocol s in postmastectomy cancinoma breast in terms of local control , toxicity and work load . METHODS A total of three hundred patients suffering from cancer breast stage T2 - 4 , N any were r and omized into three arms after mastectomy . All the patients were treated with four fields on Co60 i.e. two tangential portals for chest wall , one anterior supraclavicular and axillary field and a posterior axillary boost and were r and omized into three arms i.e. 2700 CGy in 5 fractions ( one week ) arm A , 3500 CGy in 10 fractions ( 2 weeks ) arm B and 4000 CGy in 15 fractions ( 3 weeks ) arm C. Skin , cardiac , pulmonary and haematological toxicities and lymphoedema were compared in addition to local control and work load . RESULTS The locoregional relapses were 11 % , 12 % and 10 % in arms A , B and C respectively . 26 % , 24 % and 28 % patients developed metastatic disease and 17 % , 18 % and 20 % died in the three arms . G3 and G4 skin toxicities were 37 % , 28 % and 14 % . G2 and G3 lymphedoema was 21 % , 22 % and 27 % . Cardiac toxicity was 5 % , 6 % and 5 % while pulmonary toxicity was 4 % , 5 % and 5 % respectively . All the differences except skin toxicity were statistically insignificant . There were no cases of haematological depression or rib fractures . CONCLUSION All the three short protocol s were equally effective in locoregional disease control and toxicity was also comparable . They were helpful in reducing the work load and can be safely recommended for routine clinical use Purpose In men with localized prostate cancer , dose-escalated conformal radiotherapy ( CFRT ) improves efficacy outcomes at the cost of increased toxicity . We present a detailed analysis to provide further information about the incidence and prevalence of late gastrointestinal side effects . Methods and Material s The UK Medical Research Council RT01 trial included 843 men with localized prostate cancer , who were treated for 6 months with neoadjuvant radiotherapy and were r and omly assigned to either 64-Gy or 74-Gy CFRT . Toxicity was evaluated before CFRT and during long-term follow-up using Radiation Therapy Oncology Group ( RTOG ) grading , the Late Effects on Normal Tissue : Subjective , Objective , Management ( LENT/SOM ) scale , and Royal Marsden Hospital assessment scores . Patients regularly completed Functional Assessment of Cancer Therapy -- Prostate ( FACT-P ) and University of California , Los Angeles , Prostate Cancer Index ( UCLA-PCI ) question naires . Results In the dose-escalated group , the hazard ratio ( HR ) for rectal bleeding ( LENT/SOM grade ≥2 ) was 1.55 ( 95 % CI , 1.17–2.04 ) ; for diarrhea ( LENT/SOM grade ≥2 ) , the HR was 1.79 ( 95 % CI , 1.10–2.94 ) ; and for proctitis ( RTOG grade ≥2 ) , the HR was 1.64 ( 95 % CI , 1.20–2.25 ) . Compared to baseline scores , the prevalence of moderate and severe toxicities generally increased up to 3 years and than lessened . At 5 years , the cumulative incidence of patient-reported severe bowel problems was 6 % vs. 8 % ( st and ard vs. escalated , respectively ) and severe distress was 4 % vs. 5 % , respectively . Conclusions There is a statistically significant increased risk of various adverse gastrointestinal events with dose-escalated CFRT . This remains at clinical ly acceptable levels , and overall prevalence ultimately decreases with duration of follow-up PURPOSE To compare the toxicity and efficacy of hypofractionated ( 62 Gy/20 fractions/5 weeks , 4 fractions per week ) vs. conventional fractionation radiotherapy ( 80 Gy/40 fractions/8 weeks ) in patients with high-risk prostate cancer . METHODS AND MATERIAL S From January 2003 to December 2007 , 168 patients were r and omized to receive either hypofractionated or conventional fractionated schedules of three-dimensional conformal radiotherapy to the prostate and seminal vesicles . All patients received a 9-month course of total and rogen deprivation ( TAD ) , and radiotherapy started 2 months thereafter . RESULTS The median ( range ) follow-up was 32 ( 8 - 66 ) and 35 ( 7 - 64 ) months in the hypofractionation and conventional fractionation arms , respectively . No difference was found for late toxicity between the two treatment groups , with 3-year Grade 2 rates of 17 % and 16 % for gastrointestinal and 14 % and 11 % for genitourinary in the hypofractionation and conventional fractionation groups , respectively . The 3-year freedom from biochemical failure ( FFBF ) rates were 87 % and 79 % in the hypofractionation and conventional fractionation groups , respectively ( p = 0.035 ) . The 3-year FFBF rates in patients at a very high risk ( i.e. , pretreatment prostate-specific antigen ( iPSA ) > 20 ng/mL , Gleason score > or=8 , or T > or=2c ) , were 88 % and 76 % ( p = 0.014 ) in the former and latter arm , respectively . The multivariate Cox analysis confirmed fractionation , iPSA , and Gleason score as significant prognostic factors . CONCLUSIONS Our findings suggest that late toxicity is equivalent between the two treatment groups and that the hypofractionated schedule used in this trial is superior to the conventional fractionation in terms of FFBF PURPOSE The aim of this study was to compare the toxicity and efficacy of radiation therapy ( RT ) for localized carcinoma of the prostate , using a hypofractionated ( 55 Gy/20 fractions/4 weeks ) vs. a conventionally fractionated ( 64 Gy/32 fractions/6.5 weeks ) dose schedule . METHODS AND MATERIAL S A total of 217 patients were r and omized to either the hypofractionated ( 108 patients ) or the conventional ( 109 patients ) dose schedule , with planning with two-dimensional ( 2D ) CT scan planning methodology in the majority of cases . All patients were followed for a median of 48 ( 6 - 108 ) months . Gastrointestinal ( GI ) and genitourinary ( GU ) toxicity was evaluated before RT and after its completion using modified late effects of normal tissue-subjective , objective , management , analytic ( LENT-SOMA ) scales and the European Organization for Research and Treatment of Cancer sexual function question naire . Efficacy of RT based on clinical , radiologic , and prostate-specific antigen data were also evaluated at baseline and after RT . RESULTS Gastrointestinal and GU toxicity persisted 5 years after RT and did not differ between the two dose schedules other than in regard to urgency of defecation . However , 1-month GI toxicity was not only worse in patients with the hypofractionated RT schedule but also adversely affected daily activities . Nadir prostate-specific antigen values occurred at a median of 18.0 ( 3.0 - 54.0 ) months after RT . A total of 76 biochemical relapses , with or without clinical relapses , have occurred since ; of these , 37 were in the hypofractionated and 39 in the conventional schedule . The 5-year biochemical + /- clinical relapse-free and overall survival was 55.9 % and 85.3 % respectively for all patients , and did not differ between the two schedules . CONCLUSIONS Radiation therapy for prostate carcinoma causes persistent GI toxicity that is largely independent of the two dose schedules . The hypofractionated schedule is equivalent in efficacy to the conventional schedule OBJECTIVE This paper describes the first-year biochemical ( prostate-specific antigen [ PSA ] ) response of 91 irradiated patients enrolled in a single-institution r and omized trial comparing hypofractionated ( HFRT ) and conventionally fractionated ( CFRT ) external beam radiotherapy . MATERIAL AND METHODS Forty-four patients in the CFRT treatment arm were irradiated with 74 Gy in 37 fractions ( 2 Gy per fraction ) , and 47 in the HFRT arm were treated with 57 Gy , given in 13 fractions of 3 Gy plus 4 fractions of 4.5 Gy . The clinical target volume includes the prostate and a base of seminal vesicles . The proportions of patients who reached PSA nadir ( nPSA ) lower than or equal to 1.0 ng/mL ( nPSA1 ) and 0.5 ng/mL ( nPSA05 ) were compared . RESULTS There were 2 non-cancer-related deaths ( 1 in the CFRT and 1 in the HFRT treatment arms ) . Biochemical relapse after irradiation was defined in five cases ( 3 in the CFRT and 2 in the HFRT treatment arms ) during a 12-month follow-up . The remaining 84 patients were analyzed . The proportions of patients reaching nPSA1 were 50 % and 54.5 % in the CFRT and HFRT treatment arms , respectively ( chi-square P=0.843 ) . The percentages of patients reaching nPSA05 were 25 % and 18.2 % , respectively ( chi-square P=0.621 ) . The trends toward increasing proportions of biochemical responders ( both nPSA1 and nPSA05 ) during 12 months after radiotherapy were observed , but the difference between trends for treatment arms did not reach a statistical significance . CONCLUSION The preliminary results presented here demonstrate that HFRT schedule induces biochemical response rates comparable to those in the CFRT schedule during the first-year follow-up PURPOSE Now that the follow-up time has exceeded 5 years , an estimate of the α/β ratio can be presented . The additional late outcomes in patients treated with three-dimensional conformal external beam radiotherapy for localized prostate cancer using a hypofractionated vs. a st and ard fractionation regimen are reported from this prospect i ve nonr and omized contemporary comparison . METHODS AND MATERIAL S A total of 114 nonr and omized patients chose hypofractionation delivered in 20 fractions of 3 Gy or 3.15 Gy ( mean 3.06 Gy ) for localized prostate cancer within a median overall time of 32 days ( range , 29 - 49 ) using four fractions weekly . A total of 160 comparable patients were contemporarily treated within a median of 55 days ( range 49 - 66 ) . The median follow-up was 66 months ( range , 24 - 95 ) for the hypofractionated arm and 63 months ( range , 36 - 92 ) for the st and ard arm . The percentage of patients in the low- , medium- , and high-risk groups was 36 % , 46 % , and 18 % in the hypofractionated arm and 44 % , 50 % , and 6 % in st and ard arm ( 2 Gy ) , respectively . RESULTS The 5-year actuarial biochemical absence of disease ( prostate-specific antigen nadir + 2 ng/mL ) and disease-free survival rate was the same at 89 % in both arms , making the α/β calculation unambiguous . The point ratio of α/β was 1.86 ( 95 % confidence interval , 0.7 - 5.1 Gy ) . The 95 % confidence interval was determined entirely by the binomial confidence limits in the numbers of patients . Rectal reactions of grade 3 and 4 occurred in 1 of 114 ( hypofractionated ) and 2 of 160 ( st and ard ) patients . CONCLUSIONS The presented three-dimensional conformal regimen was acceptable , and the α/β value was 1.8 , in agreement with other very recent low meta-analyses ( review ed in the " Discussion " section ) As professionals , we want to use the best treatments ; as patients , we want to be given them . Knowing whether an intervention works ( or does not work ) is fundamental to clinical decision making . However , clinical decision making involves more than simply taking published results of research directly to the bedside . Physicians need to consider how similar their patients are to those in the published studies , to take the values and preferences of their patients into account , and to consider their own experience with a given test or treatment . Evidence from clinical research is becoming increasingly important in medical- practice decisions as more and better evidence is published . But when is the evidence strong enough to justify changing a practice ? Individual studies that involve only small numbers of patients may have results that are distorted by the r and om play of chance and thus lead to less than optimal decisions . As is clear from other papers in this series , systematic review s identify , critically appraise , and review all the relevant studies on a clinical question and are more likely to give a valid answer . They use explicit methods and quality st and ards to reduce bias . Their results are the closest we can come to reaching the truth given our current state of knowledge . The questions about an intervention that a systematic review should answer are the following : 1 . Does it work ? 2 . If it works , how well does it work in general and compared with placebo , no treatment , or other interventions that are currently in use ? 3 . Is it safe ? 4 . Will it be safe and effective for my patients ? Whereas the critical appraisal and qualitative synthesis provided by review articles can be interpreted directly , the numerical products of quantitative review s can be more difficult to underst and and apply in daily clinical practice . This paper provides guidance on how to interpret the numerical and statistical results of systematic review s , translate these results into more underst and able terms , and apply them directly to individual patients . Many of these principles can also be used to interpret the numerical results of individual clinical studies . They are particularly relevant to systematic review s , however , because such review s contain more information than do primary studies and often exert greater influence than do individual studies . Making Sense of the Numerical Results of Clinical Studies Although the results of clinical studies can be expressed in intuitively meaningful ways , such results do not always easily translate into clinical decision making . For example , results are frequently expressed in terms of risk , which is an expression of the frequency of a given outcome . ( Risks are probabilities , which can vary between 0.0 and 1.0 . A probability of 0.0 means that the event will never happen , and a probability of 1.0 means that it always happens . ) Consider a hypothetical study of the recurrence of migraine headaches in a control group receiving placebo and a treatment group receiving a new antimigraine preparation , drug M ( a secondary prevention trial ) . Suppose that at the end of the trial , migraines recurred in 30 % of the control group ( the risk for recurrence was 0.30 ) but in only 5 % of the drug M group ( risk of 0.05 ) ( Table 1 ) . Table 1 . Numerical Expression of Hypothetical Clinical Trial Results The outcomes of the study are clear enough for the two groups when they are examined separately . But clinicians and patients are more interested in the comparative results , that is , the outcome in one group relative to the outcome in the other group . This overall ( comparative ) result can be expressed in various ways . For example , the relative risk , which is the risk in the treatment group relative to that in the control group , is simply the ratio of the risks in the two groups . In other words , relative risk is the risk in the treatment group divided by that in the control group , 0.05 0.30 , or 0.17 . The comparison can also be expressed as the reduction in relative risk , which is the ratio between the decrease in risk ( in the treatment group ) and the risk in the control group , 0.25 0.30 , or 0.83 ( Table 1 ) . ( The relative risk reduction can also be calculated as 1 relative risk ) . Although the clinical meaning of relative risk ( and relative risk reduction ) is reasonably clear , relative risk has the distinct disadvantage that a given value ( for example , 0.17 ) is the same whether the risk with treatment decreases from 0.80 to 0.14 , from 0.30 to 0.05 , from 0.001 to 0.00017 , and so forth . The clinical implication s of these changes clearly differ from one another enormously and depend on the specific disease and intervention . An important alternate expression of comparative results , therefore , is the absolute risk reduction . Absolute risk reduction is determined by subtracting the risk in one group from the risk in the other ( for example , the risk in the treatment group is subtracted from the risk in the placebo group ) . In the case of our migraine study , the absolute risk reduction would be 0.30 0.05 , which equals 0.25 , or 25 percentage points . In contrast , for a study in which the risk decreased from 0.001 to 0.00017 , the absolute risk reduction would be only 0.00083 , or 0.083 percentage points , which is a trivial change in comparison ( Table 1 ) . This arithmetic emphasizes the difficulty of expressing the results of clinical studies in meaningful ways . Relative risk and relative risk reduction clearly give a quantitative sense of the effects of an intervention in proportional terms but provide no clue about the size of an effect on an absolute scale . In contrast , although it tells less about proportional effects , absolute risk says a great deal about whether an effect is likely to be clinical ly meaningful . Despite this benefit , even absolute risk is problematic because it is a dimensionless , abstract number ; that is , it lacks a direct connection with the clinical situation in which the patient and physician exist . However , another way of expressing clinical research results can provide that clinical link : the number needed to treat ( NNT ) . Number Needed To Treat The NNT for a given therapy is simply the reciprocal of the absolute risk reduction for that treatment [ 1 , 2 ] . In the case of our hypothetical migraine study ( in which risk decreased from 0.30 without treatment with drug M to 0.05 with treatment with drug M , for a relative risk of 0.17 , a relative risk reduction of 0.83 , and an absolute risk reduction of 0.25 ) , the NNT would be 1 0.25 , or 4 . In concrete clinical terms , an NNT of 4 means that you would need to treat four patients with drug M to prevent migraine from recurring in one patient . To emphasize the difference between the concepts embodied in NNT and relative risk , recall the various situations mentioned above , in all of which the relative risk was 0.17 but in which the absolute risk decreased from 0.80 to 0.14 in one case and from 0.001 to 0.00017 in another . Note that the corresponding NNTs in these two other cases are 1.5 and 1204 , respectively : that is , you would need to treat 1.5 and 1204 patients to obtain a therapeutic result in these two situations compared with 4 patients with drug M ( Table 1 ) . The NNT can be calculated easily and kept as a single numerical reminder of the effectiveness ( or , as we will see , the potential for harm ) of a particular therapy . As we suggested , the NNT has the crucial advantage of direct applicability to clinical practice because it shows the effort that is required to achieve a particular therapeutic target . The NNT has the additional advantage that it can be applied to any beneficial outcome or any adverse event ( when it becomes the number needed to harm [ NNH ] ) . The concept of NNT always refers to a comparison group ( in which patients receive placebo , no treatment , or some other treatment ) , a particular treatment outcome , and a defined period of treatment . In other words , the NNT is the number of patients that you will need to treat with drug or treatment A to achieve an improvement in outcome compared with drug or treatment B for a treatment period of C weeks ( or other unit of time ) . To be fully specified , NNT and NNH must always specify the comparator , the therapeutic outcome , and the duration of treatment that is necessary to achieve the outcome . Important Qualities of the Number Needed To Treat The NNT is treatment specific . It describes the difference between treatment and control in achieving a particular clinical outcome . Table 2 shows NNTs from a selection of systematic review s and large r and omized , controlled trials . Table 2 . Numbers Needed To Treat from Systematic Review s and R and omized , Controlled Trials A very small NNT ( that is , one that approaches 1 ) means that a favorable outcome occurs in nearly every patient who receives the treatment and in few patients in a comparison group . Although NNTs close to 1 are theoretically possible , they are almost never found in practice . However , small NNTs do occur in some therapeutic trials , such as those comparing antibiotics with placebo in the eradication of Helicobacter pylori infection or those examining the use of insecticide for head lice ( Table 2 ) . An NNT of 2 or 3 indicates that a treatment is quite effective . In contrast , such prophylactic interventions as adding aspirin to streptokinase to reduce 5-week vascular mortality rates after myocardial infa rct ion may have NNTs as high as 20 to 40 and still be considered clinical ly effective . Limitations of the Number Needed To Treat Although NNTs are powerful instruments for interpreting clinical effects , they also have important limitations . First , an NNT is generally expressed as a single number , which is known as its point estimate . As with all experimental measurements , however , the true value of the NNT can be higher or lower than the point estimate determined through clinical studies . The 95 % CIs of the NNT are useful in this regard because they provide an indication that Background The additional use of radiotherapy has changed the treatment of locally advanced rectal cancer ( LARC ) dramatically . But a major achievement has been the development of total mesorectal excision ( TME ) as a surgical st and ard and the recognition that the surgeon is the predominant prognostic factor . The benefit of preoperative hypofractionated radiotherapy ( SCRT ; five fractions each of 5 Gy ) , initially established by the Swedish Rectal Cancer Trial , has been demonstrated in conjunction with TME by the Dutch Colorectal Cancer Group . The concept of combined neoadjuvant radiochemotherapy ( conventional radiation of about 50 Gy with chemotherapy ) has not been compared over surgery alone with TME . However , the German Rectal Cancer Study Group recently demonstrated that preoperative radiochemotherapy ( RCT ) was better than postoperative radiochemotherapy in terms of local control . Methods and design Patients with histological proven rectal cancer staged T2N+ or T3 are r and omized to receive either SCRT ( 25 Gy in five fractions of 5 Gy ) plus TME-surgery within 5 days or RCT ( 50.4 Gy in 28 fractions of 1.8 Gy , continuous infusion 5-fluorouracil ) plus TME-surgery 4–6 weeks later . All patients receive adjuvant chemotherapy ( 12 weeks continuous infusional 5-FU ) and are followed up for 5 years . TME- quality is independently documented by the surgeon and the pathologist . Hypothesis of the study is that RCT is superior to SCRT in terms of local recurrence after five years . Secondary endpoints are overall survival , disease-free survival , complete resection rate ( R0 resection ) , rate of sphincter saving resection , acute and late toxicity ( radiation related side effects ) , and quality of life ( including long term bowel function ) . Discussion Similar long-term survival , local control and late morbidity have been reported for both concepts of preoperative therapy in non-comparative studies . In addition to other ongoing ( and recently published ) comparative trials we include a larger number of patients for adequate power , apply quality -controlled TME and try to avoid the adjuvant treatment bias by m and atory adjuvant chemotherapy in both groups . Further more , stratification of the initially planned surgical procedure and sphincter-preservation will generate valid evidence whether RCT will allow a less aggressive ( sphincter saving ) surgical approach PURPOSE To describe the radiation-induced acute rectal toxicity ( ART ) using a modified Lyman-Kutcher-Burman normal tissue complication probability model and parameters set , taking into account the overall treatment time . METHODS AND MATERIAL S A total of 160 patients underwent three-dimensional conformal radiotherapy to the prostate and seminal vesicles and were r and omized to receive 80 Gy in 40 fractions within 8 weeks ( Group A ) or 62 Gy in 20 fractions within 5 weeks , 4 d/wk ( Group B ) . An additional 52 patients ( Group C ) underwent intensity-modulated radiotherapy with a hypofractionation schedule consisting of 56 Gy , delivered in 16 fractions ( 4/wk ) of 3.5 Gy . Patients were followed for ART weekly during treatment . The overall treatment time , rectal dose-volume histograms , and ART status , defined as Radiation Therapy Oncology Group Grade 2 or greater gastrointestinal toxicity , were used to determine the modified Lyman-Kutcher-Burman model parameters . The m and n values were obtained from the cohort , and the tolerance doses for 50 % complication probability for uniform irradiation [ TD(50)(1)(k ) ] were obtained for each fractionation schedule indicated with k. RESULTS Of 212 patients treated with localized prostate radiotherapy , 65 developed Grade for > or = 1 week during treatment . The m and n value was 0.17 and 0.08 , respectively . The TD(50)(1)(k ) parameter was 79 , 62.5 , and 53 Gy , respectively for Group A , B , and C. CONCLUSION The optimized modified Lyman-Kutcher-Burman normal tissue complication probability model allowed us to describe the ART data from conventional and hypofractionated regimens , using the dose-volume histograms and overall treatment time . This model could prove useful in design ing hypofractionation schedules to reduce the incidence of ART PURPOSE The optimal radiation dose fractionation schedule for localized prostate cancer is unclear . This study was design ed to compare two dose fractionation schemes ( a shorter 4-week radiation schedule v a longer 6.5-week schedule ) . PATIENTS AND METHODS Patients with early-stage ( T1 or T2 ) prostate cancer were r and omly assigned to 66 Gy in 33 fractions over 45 days ( long arm ) or 52.5 Gy in 20 fractions over 28 days ( short arm ) . The study was design ed as a noninferiority investigation with a predefined tolerance of -7.5 % . The primary outcome was a composite of biochemical or clinical failure ( BCF ) . Secondary outcomes included presence of tumor on prostate biopsy at 2 years , survival , and toxicity . RESULTS From March 1995 to December 1998 , 936 men were r and omly assigned to treatment ; 470 were assigned to the long arm , and 466 were assigned to the short arm . The median follow-up time was 5.7 years . At 5 years , the BCF probability was 52.95 % in the long arm and 59.95 % in the short arm ( difference = -7.0 % ; 90 % CI , -12.6 % to -1.4 % ) , favoring the long arm . No difference in 2-year postradiotherapy biopsy or in overall survival was detected between the arms . Acute toxicity was found to be slightly higher in the short arm ( 11.4 % ) compared with the long arm ( 7 % ; difference = -4.4 % ; 95 % CI , -8.1 % to -0.6 % ) ; however , late toxicity was similarly low in both arms ( 3.2 % ) . CONCLUSION Given the results , we can not exclude the possibility that the chosen hypofractionated radiation regimen may be inferior to the st and ard regimen . Further evaluation involving higher dose hypofractionated radiation regimens in contemporary radiation setting s is necessary Institute of Oncology of Vilnius University has initiated a r and omized clinical trial with the aim to evaluate the effectiveness and toxicity of conventional fractionated ( 37 fractions , 2.0 Gy per fraction , a total dose of 74 Gy ) and hypofractionated ( 13 fractions , 3.0 Gy per fraction , and 4 fractions at 4.5 Gy per fraction , a total dose of 57 Gy ) radiotherapy . The goal of preliminary safety analysis was to compare the acute radiation toxicity in investigated and control groups . A total of 22 patients have been enrolled in this trial ; there were 11 patients in each investigated group . Grade IV acute bladder radiation toxicity according to Radiation Therapy Oncology Group ( RTOG ) toxicity criteria was observed in one control group patient . No grade III acute radiation toxicity was observed . Grade II acute radiation toxicity was observed in 2 patients from hypofractionated radiotherapy group and in 3 from conventional radiotherapy group . Grade I-II acute radiation toxicity was observed in all patients of investigated and control groups . A statistically significant decrease of grade I bladder and rectal toxicity in the hypofractionated arm and grade I bladder toxicity in the conventional arm was observed . Other differences were not significant . A comparatively small number of acute reactions in the patients ' group treated with hypofractionated radiotherapy show the safety of the method applied and enable the continuation of this trial PURPOSE To investigate whether the effect of hypofractionated thoracic radiotherapy ( TRT ) is comparable to more st and ard fractionated radiotherapy ( RT ) in advanced non-small-cell lung cancer ( NSCLC ) . PATIENTS AND METHODS A total of 421 patients with locally advanced stage III or stage IV NSCLC tumors were included . Inclusion criteria were inoperable , disease too advanced for curative radiotherapy , and chest symptoms or central tumor threatening the airways . Patients were r and omly assigned to three arms : A , 17 Gy per two fractions ( n = 146 ) ; B , 42 Gy per 15 fractions ( n = 145 ) ; and C , 50 Gy per 25 fractions ( n = 130 ) . Four hundred seven patients were eligible for the study ; 395 patients ( 97 % ) participated in the health-related quality -of-life ( HRQOL ) study . The European Organization for Research and Treatment of Cancer ( EORTC ) Quality of Life Question naire (QLQ)-C30 and EORTC QLQ-lung cancer-specific module ( LC13 ) were used to investigate airway symptom relief and changes in HRQOL . Assessment s were performed before TRT and until week 54 . Clinicians ' assessment s of symptom improvement were at 2 , 6 , and 14 weeks after completion of TRT . The patients were observed for a minimum of 3 years . Results Baseline prognostic data were equally distributed in the treatment groups . Patient compliance with respect to the HRQOL investigation was minimum 74 % . HRQOL and symptom relief were equivalent in the treatment arms . No significant difference in survival among arms A , B , and C was found , with median survival 8.2 , 7.0 , and 6.8 months , respectively . CONCLUSION Our data indicate that protracted palliative TRT renders no improvement in symptom relief , HRQOL , or survival when compared with short-term hypofractionated treatment in advanced NSCLC 85 Background : To assess the biochemical control rates and long-term rectal side effect profile of hypofractionated image guided radiation therapy for prostate cancer . We hypothesize that daily CT-based image guidance will allow a higher dose per fraction to be safely administered , shortening the overall treatment time from 8 weeks to 4 - 5.5 weeks . METHODS 160 patients were treated with image guided radiation therapy with or without adjuvant hormonal ablation between 2005 and 2009 for patients < = T3a N0 M0 . Patients were classified into risk groups with 51 patients defined as low risk , 67 as intermediate risk , and 43 as high risk . Mean age was 70.2 years . All patients were treated with 60/67.6/70/70.2 Gy to the prostate divided into 20/26/28/27 fractions . 57 % of patients received hormone therapy . Daily CT or fiducial-based image guidance was performed prior to each fraction . The median follow up was 34 months . Biochemical control was defined by the Phoenix definition . Rectal toxicity was grade d by the CTCAE 4.0 scale . In general patients with rectal bleeding more than once per week were started on rectal steroids . RESULTS 12/160 ( 7.5 % ) of patients had late grade 2 or worse rectal toxicity after radiation treatment . The Kaplan-Meier estimate for grade 2 rectal toxicity at 2 years was 6.9 % . The crude rate of biochemical no evidence of disease was 96.3 % . Kaplan Meier estimates for biochemical no evidence of disease at 3 and 5 years are 0.98/0.84 , 0.97/0.97 , and 1.0/0.67 for low , medium , and high-risk patients respectively . Log-rank analysis showed no statistically significant difference among the dosing regimens for toxicity-free survival ( p=0.24 ) . CONCLUSIONS With daily image guidance hypofractionated radiation therapy is clinical ly safe with moderate late rectal toxicity . Early follow-up suggests high efficacy . Ongoing and future r and omized trials such as RTOG 0415 will be required to confirm these findings . No significant financial relationships to disclose PURPOSE The alpha/beta ratio for prostate cancer is postulated to be between 1 and 3 , giving rise to the hypothesis that there may be a therapeutic advantage to hypofractionation . The dosimetry and acute toxicity are described in the first 100 men enrolled in a r and omized trial . PATIENTS AND METHODS The trial compares 76 Gy in 38 fractions ( Arm I ) to 70.2 Gy in 26 fractions ( Arm II ) using intensity modulated radiotherapy . The planning target volume ( PTV ) margins in Arms I and II were 5 mm and 3 mm posteriorly and 8 mm and 7 mm in all other dimensions . The PTV D95 % was at least the prescription dose . RESULTS The mean PTV doses for Arms I and II were 81.1 and 73.8 Gy . There were no differences in overall maximum acute gastrointestinal ( GI ) or genitourinary ( GU ) toxicity acutely . However , there was a slight but significant increase in Arm II GI toxicity during Weeks 2 , 3 , and 4 . In multivariate analyses , only the combined rectal DVH parameter of V65 Gy/V50 Gy was significant for GI toxicity and the bladder volume for GU toxicity . CONCLUSION Hypofractionation at 2.7 Gy per fraction to 70.2 Gy was well tolerated acutely using the planning conditions described BACKGROUND Prostate cancer might have high radiation-fraction sensitivity , implying a therapeutic advantage of hypofractionated treatment . We present a pre-planned preliminary safety analysis of side-effects in stages 1 and 2 of a r and omised trial comparing st and ard and hypofractionated radiotherapy . METHODS We did a multicentre , r and omised study and recruited men with localised prostate cancer between Oct 18 , 2002 , and Aug 12 , 2006 , at 11 UK centres . Patients were r and omly assigned in a 1:1:1 ratio to receive conventional or hypofractionated high-dose intensity-modulated radiotherapy , and all were given with 3 - 6 months of neoadjuvant and rogen suppression . Computer-generated r and om permuted blocks were used , with risk of seminal vesicle involvement and radiotherapy-treatment centre as stratification factors . The conventional schedule was 37 fractions of 2 Gy to a total of 74 Gy . The two hypofractionated schedules involved 3 Gy treatments given in either 20 fractions to a total of 60 Gy , or 19 fractions to a total of 57 Gy . The primary endpoint was proportion of patients with grade 2 or worse toxicity at 2 years on the Radiation Therapy Oncology Group ( RTOG ) scale . The primary analysis included all patients who had received at least one fraction of radiotherapy and completed a 2 year assessment . Treatment allocation was not masked and clinicians were not blinded . Stage 3 of this trial completed the planned recruitment in June , 2011 . This study is registered , number IS RCT N97182923 . FINDINGS 153 men recruited to stages 1 and 2 were r and omly assigned to receive conventional treatment of 74 Gy , 153 to receive 60 Gy , and 151 to receive 57 Gy . With 50·5 months median follow-up ( IQR 43·5 - 61·3 ) , six ( 4·3 % ; 95 % CI 1·6 - 9·2 ) of 138 men in the 74 Gy group had bowel toxicity of grade 2 or worse on the RTOG scale at 2 years , as did five ( 3·6 % ; 1·2 - 8·3 ) of 137 men in the 60 Gy group , and two ( 1·4 % ; 0·2 - 5·0 ) of 143 men in the 57 Gy group . For bladder toxicities , three ( 2·2 % ; 0·5 - 6·2 ) of 138 men , three ( 2·2 % ; 0·5 - 6·3 ) of 137 , and none ( 0·0 % ; 97·5 % CI 0·0 - 2·6 ) of 143 had scores of grade 2 or worse on the RTOG scale at 2 years . INTERPRETATION Hypofractionated high-dose radiotherapy seems equally well tolerated as conventionally fractionated treatment at 2 years . FUNDING Stage 1 was funded by the Academic Radiotherapy Unit , Cancer Research UK programme grant ; stage 2 was funded by the Department of Health and Cancer Research UK PURPOSE To compare the effects of ( three-dimensional ) 3D vs. two-dimensional ( 2D ) radiation therapy ( RT ) for carcinoma of the prostate on the prevalence and pathophysiology of anorectal dysfunction . METHODS AND MATERIAL S Anorectal symptoms , motility , sensory function , and anal sphincter morphology were evaluated before and up to 2 years after r and omly assigned hypofractionated vs. conventionally fractionated RT in 67 patients ( median age , 69 years ; range , 54 - 82 years ) with localized prostate carcinoma , using either a 3D ( n = 29 ) or 2D ( n = 38 ) treatment technique . RESULTS Anorectal symptoms increased 4 to 6 weeks after RT and persisted in both patient groups . At 2 years , abnormalities included increased stool frequency ( 55 % vs. 53 % , p = NS ) , urgency of defecation ( 72 % vs. 47 % , p < 0.05 ) , fecal incontinence ( 28 % vs. 26 % , p = NS ) , and rectal bleeding ( 38 % and 42 % , p = NS ) . Anorectal motility and sensory function deteriorated after RT in both groups with reductions in basal anal pressures , anal pressures in response to squeeze , rectal compliance , and rectal volumes associated with the desire to defecate . External but not internal sphincter thickness changed in the treatment groups although in different directions . However no differences in motility or sensory function were detected between the groups . Baseline anorectal motility but not treatment technique and the hypofracionated schedule were of independent prognostic significance for anorectal motor dysfunction and rectal bleeding respectively at 2 years . CONCLUSION The prevalence and pathophysiology of anorectal dysfunction 2 years after RT for prostate carcinoma was largely independent of the treatment techniques used in this study PURPOSE To evaluate the long-term efficacy and toxicity of a hypofractionated ( 55 Gy in 20 fractions within 4 weeks ) vs. a conventionally fractionated ( 64 Gy in 32 fractions within 6.5 weeks ) dose schedule for radiotherapy ( RT ) for localized carcinoma of the prostate . METHODS AND MATERIAL S A total of 217 patients were r and omized to either the hypofractionated ( n=108 ) or the conventional ( n=109 ) dose schedule . Most patients ( n=156 ) underwent RT planning and RT using a two-dimensional computed tomography method . Efficacy using the clinical , radiologic , and prostate-specific antigen data in each patient was evaluated before RT and at predetermined intervals after RT until death . Gastrointestinal and genitourinary toxicity using the modified Late Effect in Normal Tissue-Subjective Objective Management Analytic ( LENT-SOMA ) scales was also evaluated before and at intervals after RT to 60 months . RESULTS The whole group has now been followed for a median of 90 months ( range , 3 - 138 ) . Of the 217 patients , 85 developed biochemical relapse ( nadir prostate-specific antigen level+2 μg/L ) , 36 in the hypofractionated and 49 in the conventional group . The biochemical relapse-free , but not overall , survival at 90 months was significantly better with the hypofractionated ( 53 % ) than with the conventional ( 34 % ) schedule . Gastrointestinal and genitourinary toxicity persisted 60 months after RT and did not differ between the two dose schedules . Multivariate analyses revealed that the conventional schedule was of independent prognostic significance , not only for biochemical failure , but also for an increased risk of worse genitourinary symptoms at 4 years . CONCLUSIONS A therapeutic advantage of the hypofractionated compared with the conventional dose schedule for RT of prostate cancer was evident at 90 months in the present study PURPOSE We performed a r and omized trial to compare the GI and urogenital toxicity of radiotherapy ( RT ) for localized ( confined to the organ ) , early-stage ( T1-T2N0M0 , TNM classification ) carcinoma of the prostate , using a conventional ( 64 Gy in 32 fractions within 6.5 weeks ) vs. a hypofractionated ( 55 Gy in 20 fractions within 4 weeks ) schedule and to determine the efficacy of the respective treatment schedules . METHODS AND MATERIAL S This report is based on an interim analysis of the first 120 consecutive patients in this Phase III trial after a median follow-up of 43.5 months ( range 23 - 62 ) . RT planning was based on two-dimensional CT data , and the treatment was delivered using a three- or four-field 6 - 23-MV photon technique . GI and urogenital toxicity ( symptom question naires incorporating the subjective elements of the late effects of normal tissues-subjective , objective , management , analytic classification of late effects and the European Organization for Research and Treatment of Cancer sexual function question naire ) were evaluated before RT and 1 month , 1 year , and 2 years after RT completion . The efficacy of RT was assessed clinical ly ( digital rectal examination and radiologic imaging ) and biochemically ( prostate-specific antigen assay ) at baseline , and every 3 months for 2 years after RT and every 6 months subsequently . RESULTS RT , whether conventional or hypofractionated , result ed in an increase in all six symptom categories used to characterize GI toxicity and in four of five symptom categories used to document urinary morbidity 1 month after therapy completion . Sexual dysfunction ( based on limited data ) , which existed in more than one-third of patients before RT , also increased to just more than one-half of patients 1 month after RT . The increase in urinary toxicity after RT was not sustained ( diurnal urinary frequency had decreased significantly at 2 years ) . In contrast , all six symptom categories of GI toxicity remained increased 1 year after RT . Four of the six GI symptom categories ( rectal pain , mucous discharge , urgency of defecation , and rectal bleeding ) were still increased at 2 years compared with baseline . Except for a slightly greater percentage of patients experiencing mild rectal bleeding at 2 years among those who received hypofractionated RT , no differences were noted in toxicity between the conventional and hypofractionated RT schedule . The mean prostate-specific antigen level was 14.0 + /- 1.0 ng/mL at baseline and declined to a nadir of 1.3 + /- 0.2 ng/mL at a median of 16.8 months ( range 0.8 - 28.3 ) after RT completion . However , it then rose in 17 patients ( 8 in the hypofractionated and 9 in the conventional treatment group ) . Only 8 of these 17 patients were found to have signs of clinical relapse ( 5 local , 1 regional lymph node , and 2 systemic [ bony metastases ] ) after histopathologic and radiologic re assessment ) . The remaining 9 patients had biochemical relapse only ( defined as three consecutive rises in prostate-specific antigen after nadir ) . The 4-year biochemical relapse-free survival rate was 85.8 % for all patients and did not differ significantly between the two radiation dose schedules ( 86.2 % for the hypofractionated and 85.5 % for the conventional fractionation group ) . CONCLUSION RT for prostate carcinoma , using a three- or four-field 6 - 23-MV photon technique without posterior shielding of the lateral fields , is an underestimated cause of persistent GI morbidity . The incidence of clinical ly significant GI and urogenital toxicity after conventional and hypofractionated RT appears to be similar . Hypofractionated RT for carcinoma of the prostate seems just as effective as conventional RT after a median follow-up approaching 4 years The therapeutic use of ionizing radiations is predicated on sparing normal tissue effects while attempting to achieve lethal effects on tumor cells . From quite early in the history of radiation therapy , it was apparent that there were striking differences in effects in the panoply of normal tissues . Although there was early appreciation of some late effects in normal tissues , often not predicted by acute reactions , only in recent years has there been full documentation of the slow and progressive increase in severity of late damage . Pathophysiological mechanisms of acute and late radiation effects are better understood today ( 2 ) , but interactions of other modalities with radiation therapy require constant monitoring to recognize and mitigate untoward sequelae . The work of Stone ( 3 ) is a classic example of unanticipated late effects , which result ed from irradiation with ‘ fast neutrons . Acute reactions were moderate and tolerable , but the late sequelae were so marked that there was little interest in pursuing therapy with fast neutrons for nearly three decades . The Late Morbidity Scoring Criteria were developed as a joint effort between physicians with renewed interests in fast neutron therapy and Radiation Therapy Oncology Group ( RTOG ) staff . In the late 1970s the Neutron/Particle Committee was one of several modality committees of the RTOG . Recognizing the results of Stone , this committee , led by Lawrence Davis worked with RTOG staff to establish criteria and scoring for possible late effects from fast neutron radiation therapy . Investigators from the European Organization for Research and Treatment of Cancer ( EORTC ) , led by William Duncan of the Western General Hospital of Edinburgh , wished to have common toxicity criteria in anticipation of joint studies . RTOG Protocol 7929 , an international registry of patients treated with heavy particles , was started in 1980 . At the annual meetings of the international participants in particle studies , there were attempts to monitor interobserver variations in scoring effects in normal tissues and to seek consistency in reporting toxicity , but no publications document these efforts . The first prospect i ve trial to use the Late Morbidity Scoring Criteria was RTOG Protocol 8001 , a study of fast neutron therapy for malignant tumors arising in salivary gl and s. Although the RTOG began to use these criteria in reporting toxicity in patients enrolled in all studies from 198 1 ( beginning with RTOG Protocol 8 115 ) , the criteria only became a published part of protocol s in 1983 . At that time , statistical methods began to be used , which presented time-adjusted estimates of late effects , the rationale for which was described by Cox ( 1 ) . It is now considered st and ard to represent cumulative probabilities of late effects with methods similar to those for estimating local control and survival . The Acute Radiation Morbidity Scoring Criteria were developed in 1985 as complimentary to the Late Effects Scoring Criteria . The National Cancer Institute promulgated st and ard toxicity criteria in 1990 , but late effects were not considered . An abbreviated version of the RTOG/EORTC toxicity criteria was published by Winchester and Cox in 1992 as part of the St and ard for Breast Conservation Treatment . The current RTOG Acute Radiation Morbidity Scoring Criteria are presented in Table 1 . The RTOG/EORTC Late Radiation Morbidity Scoring Scheme is detailed in Table 2 . In both tables , 0 means an absence of radiation effects and 5 means the effects led to death . The |
13,698 | 27,683,513 | There were no statistically significant effects of the intervention for the majority of the primary outcomes across the studies .
No clear conclusions can be drawn regarding the effects of universally offered parenting interventions on child development and parent-child relationship for this age group | OBJECTIVES From a developmental perspective , infancy is a critical stage of life .
Early childhood interventions aim to support caretakers , but the effects of universal interventions for parents with infants are unknown .
The objective is to determine the effects of universal parenting interventions offered to parents with infants 0 - 12 months on measures of child development and parent-child relationship . | This study investigated whether a psycho-educational program with modest dosage ( eight sessions ) , delivered in a universal framework through childbirth education programs and targeting the coparenting relationship would have a positive impact on observed family interaction and child behavior at 6-month follow-up ( child age 1 year ) . One hundred sixty-nine couples , r and omized to intervention and control conditions , participated in videotaped family observation tasks at pretest ( during pregnancy ) and at child age 1 year ( 2003–2007 ) . Coparenting , parenting , couple relationship , and child self-regulatory behaviors were coded by teams of raters . Intent-to-treat analyses of program effects controlled for age , education , and social desirability . Evidence of significant ( p < 0.05 ) program effects at follow-up emerged in all four domains . Effect sizes ranged from 0.28 to 1.01 . Targeting the coparenting relationship at the transition to parenthood represents an effective , non-stigmatizing means of promoting parenting quality and child adjustment Behavioral and emotional problems are common in early childhood and put children at risk for developing more serious problems . This study tested the mediating mechanisms through which a universal coparenting intervention implemented during the transition to parenthood led to reduced child adjustment problems at age 3 and explored child gender as a potential moderator . One hundred sixty-nine heterosexual couples expecting their first child were r and omly assigned to a control condition or Family Foundations , a series of eight classes that targeted the coparenting relationship . Data were collected through videotaped triadic mother – father – child interaction tasks when the child was 1 and 3 years of age . Separate longitudinal path analyses for mothers and fathers tested coparenting competition and positivity as mediators of program effects on child adjustment problems . Significant mediated effects for coparenting competition were found for fathers with both sons and daughters and for mothers with sons but not for mothers with daughters . These effects accounted for between 39 and 55 % of the intervention ’s impact on child adjustment problems . Coparenting positivity did not mediate program effects . These results support the use of a prevention approach to reduce coparenting competition and enhance child adjustment and provide information that can be used to refine theory This study investigated the ability of a psychosocial prevention program implemented through childbirth education programs to enhance the coparental and couple relationship , parental mental health , the parent-child relationship , and child outcomes . A sample of 169 heterosexual , adult couples expecting their first child was r and omized to intervention and control conditions . The intervention families participated in Family Foundations , a series of eight classes delivered before and after birth , which was design ed as a universal prevention program ( i.e. , applicable to all couples , not just those at high risk ) . Intent-to-treat analyses utilizing data collected from child age 6 months through 3 years indicated significant program effects on parental stress and self-efficacy , coparenting , harsh parenting , and children 's emotional adjustment among all families , and maternal depression among cohabiting couples . Among families of boys , program effects were found for child behavior problems and couple relationship quality . These results indicate that a universal prevention approach at the transition to parenthood focused on enhancing family relationships can have a significant and substantial positive impact on parent and child well-being Objective To determine whether a structured programme of parent anticipatory guidance ‘ Toddlers Without Tears , ’ delivered in universal primary care , can prevent preschool child behaviour problems . Design Cluster r and omised controlled trial . Setting / participants 40 primary care nursing centres ( clusters ) in metropolitan Melbourne , Australia . 733 English-speaking mothers of 6- to 7-month-old infants consecutively recruited from well-child appointments ; 589 ( 80 % ) retained at age 3 years . Intervention Parenting programme from age 8 to 15 months , with two group sessions co-led by well-child providers and a parenting expert . The programme addressed normal behaviour development and offered strategies to increase desired and reduce unwanted behaviour . While 93 % of intervention parents received at least some of the programme , only 49 % completed all components . Control Usual primary care . Main outcome measures Maternal report of child externalising behaviour ( Child Behaviour Checklist ) , parenting ( Parent Behaviour Checklist ) and maternal mental health ( Depression Anxiety Stress Scales ) when children were aged 3 years . Results Behaviour scores in the intervention and control groups were similar ( mean ( SD ) ) 11.4 ( 7.1 ) versus 12.4 ( 7.6 ) ; adjusted mean difference −0.8 , 95 % CI −2.2 to 0.6 , p=0.26 ) . On the parenting subscale scores , intervention parents reported fewer unreasonable expectations of child development ( 37.3 ( 10.9 ) vs 39.9 ( 10.2 ) , adjusted mean difference −3.1 , 95 % CI −4.9 to −1.4 , p=0.001 ) . The mean scores for harsh/abusive and nurturing parenting , and maternal mental health , were similar between the two groups . Conclusions A brief universal parenting programme in primary care is insufficient to prevent development of preschool externalising problems . A new population trial targeting more intensive prevention to distressed parents with toddler behaviour problems is now under way , aim ing to prevent externalising and internalising problems before school entry . Trial registration number IS RCT Objective To determine whether a parenting programme , offered universally in primary care , can prevent behavioural problems in children and improve parenting and maternal mental health . Design Cluster r and omised trial . Setting 40 primary care nursing centres ( clusters ) in Victoria , Australia . Participants 733 English speaking mothers of 8 month old children sequentially recruited from well child appointments ; 656 retained at 24 months . Intervention Structured three session programme at age 8 - 15 months , co-led by well child providers and a parenting expert . The programme covered normal development and behaviour , strategies to increase desired behaviour , and strategies to reduce unwanted behaviour . Main outcome measures Maternal report of child externalising behaviour ( child behavior checklist 1½-5 year old ) , parenting ( parent behavior checklist ) , and maternal mental health ( depression anxiety stress scales ) at 18 and 24 months . Results At 18 months , child behaviour and parenting scores were similar in the two groups . At 24 months , externalising scores in the intervention and control groups were similar ( mean 11.9 ( SD 7.2 ) v 12.9 ( 7.4 ) ) ; however , on the parent behavior checklist subscale scores , intervention group parents were less likely to report harsh/abusive parenting ( mean 38.9 ( SD 7.7 ) v 40.5 ( 8.8 ) ; adjusted mean difference −1.83 , 95 % confidence interval −3.12 to −0.55 ) and unreasonable expectations of child development ( 40.9 ( 9.9 ) v 42.7 ( 9.6 ) ; −2.18 , −3.74 to −0.62 ) . Mean scores for nurturing parenting and maternal mental health were similar in the two groups at both times . Conclusions A universal parenting programme result ed in modest improvement in parenting factors that predict behavioural problems in children but did not reduce externalising behavioural problems or affect maternal mental health at 2 years . Trial registration IS RCT N 77531789 BACKGROUND The Copenhagen Child Cohort , CCC 2000 , was established to investigate developmental psychopathology prospect ively from birth in a general population . METHODS A r and om sample of 211 children from the CCC 2000 was investigated when the children were 1(1/2 ) years of age . The prevalence and associates of mental health problems and psychopathology were studied by clinical and st and ardised strategies , including videotape recordings , parent interviews and the following instruments : The Child Behavior Check List 1(1/2)-5 ( CBCL 1(1/2)-5 ) , The Infant Toddler Symptom Check List ( ITSCL ) , Checklist for Autism in Toddlers ( CHAT ) , Bayley Scales of Infant Development II ( BSID II ) , The Parent Child Early Relationship Assessment ( PC ERA ) and Parent Infant Relationship Global Assessment Scale ( PIR-GAS ) . RESULTS Mental health problems according to International Classification of Diseases ( ICD-10 ) and Diagnostic Classification Zero to Three ( DC 0 - 3 ) diagnoses were found in 16 - 18 % of 1(1/2)-year-old children . Most common were disturbances of emotion , behaviour and eating and the DC 0 - 3 diagnosis of regulatory disorder . Parent-child relationship disturbances were found in 8 % . High psychosocial risk was significantly associated with emotional and behavioural disorders ( OR 3.1 95 % ( 1.2 - 8.1 ) ) and disturbed parent-child relationship ( OR 5.0 95 % ( 1.6 - 16.0 ) ) . The strongest association of risk was found between relationship disorders and emotional and behavioural disorders ( OR 11.6 95 % ( 3.8 - 37.5 ) ) . CONCLUSIONS The prevalence and distribution of psychopathology in 1(1/2)-year-old children seem to correspond to the distributions among older children . Disturbances in parent-child relationship have a key position in the risk mechanisms in early child psychopathology OBJECTIVE To evaluate the long-term effects of an early home-based intervention on the quantity and quality of psychiatric symptoms in adolescents . METHOD The material consisted of 160 families with a baby born in 1975 - 1976 . First , the families were classified with a weighted risk index into low- and high-risk families . Eighty families attended a 5-year-long family counseling program ( 10 times/year ) . The other half of the families served as a control group for the effects of counseling . The mental state of the adolescents was assessed at age 14 to 15 years by the Child Behavior Checklist and the Youth Self-Report . RESULTS The adolescents in the counseling families scored significantly fewer total symptoms on both the parent and the youth reports . The counseling reduced more effectively internalizing than externalizing symptoms . The counseling predicted better mental health in adolescence in both low- and high-risk families . CONCLUSIONS Home-based early intervention can have positive long-term effects on the mental state of adolescents . These results can be used when programs for primary prevention in families with small children are planned This study examined whether a group educational intervention during the transition to parenthood can enhance the quality of father-child interaction and increase father involvement with their children . A r and omized experimental design was used to evaluate an 8-session program with 165 couples who were first-time parents , beginning during the second trimester of pregnancy and ending at 5 months postpartum . Outcomes were assessed with time diaries , coded observations of parent-child play , and self-reports of fathers and mothers . The intervention had positive effects on fathers ' skills in interacting with their babies and their involvement on work days but not home days . It is concluded that a relatively brief intervention during the transition to parenthood can improve fathering , and possible reasons for differential effects on areas of parenting are explored The effects of a parent-training program design ed to increase parental competence to assess , predict , elicit , and contingently , respond to infant behavior and to increase the infant 's contingent responses to the parents ' behavior were assessed . 19 parent couples and their 4 - 12-month-old infants were r and omly assigned to the training group or the control group . Raters , unaware of the status of the parents , observed and rated the parents ' behavior during a 2-hour home observation . Separate raters , unaware of the hypothesis , then rated a 20-min videotape of the parent-infant interactions in the home . Parents independently completed a question naire . Training was found to increase both the parents ' and the infants ' competence in the parent-infant dyad . Most important , a reciprocal relationship between increases in the trained fathers ' interactions and decreases in the trained mothers ' interactions was found , indicating that the triad may be the crucial unit for studies of parental competence OBJECTIVE . We sought to determine whether Healthy Steps for Young Children has sustained treatment effects at 5.5 years , given early findings demonstrating enhanced quality of care and improvements in selected parenting practice s. METHODS . Healthy Steps was a clinical trial that incorporated developmental specialists and enhanced developmental services into pediatric care in the first 3 years of life . A total of 5565 children were enrolled at birth and followed through 5.5 years . Healthy Steps was evaluated at 6 r and omization and 9 quasi-experimental sites . Computer-assisted telephone interviews were conducted with mothers when Healthy Steps children were 5.5 years of age . Outcomes included experiences seeking care , parent response to child misbehavior , perception of child 's behavior , and parenting practice s to promote development and safety . Logistic regression was used to estimate overall effects of Healthy Steps , adjusting for site and baseline demographic characteristics . RESULTS . A total of 3165 ( 56.9 % ) families responded to interviews ( usual care : n = 1441 ; Healthy Steps : n = 1724 ) . Families that had received Healthy Steps services were more satisfied with care ( agreed that pediatrician/nurse practitioner provided support , 82.0 % vs 79.0 % ; odds ratio : 1.25 [ 95 % confidence interval : 1.02–1.53 ] ) and more likely to receive needed anticipatory guidance ( 54.9 % vs 49.2 % ; odds ratio : 1.33 [ 95 % confidence interval : 1.13–1.57 ] ) ( all P < .05 ) . They also had increased odds of remaining at the original practice ( 65.1 % vs 61.4 % ; odds ratio : 1.19 [ 95 % confidence interval : 1.01–1.39 ] ) . Healthy Steps families reported reduced odds of using severe discipline ( slap in face/spank with object , 10.1 % vs 14.1 % ; odds ratio : 0.68 [ 95 % confidence interval : 0.54–0.86 ] ) and increased odds of often/almost always negotiating with their child ( 59.8 % vs 56.3 % ; odds ratio : 1.20 [ 95 % confidence interval : 1.03–1.39 ] ) . They had greater odds of reporting a clinical or borderline concern regarding their child 's behavior ( 18.1 % vs 14.8 % ; odds ratio : 1.35 [ 95 % confidence interval : 1.10–1.64 ] ) and their child reading books ( 59.4 % vs 53.6 % ; odds ratio : 1.16 [ 95 % confidence interval : 1.00–1.35 ] ) . There were no effects on safety practice s. CONCLUSIONS . Sustained treatment effects , albeit modest , are consistent with early findings . Universal , practice -based interventions can enhance quality of care for families with young children and can improve selected parenting practice s beyond the duration of the intervention Seven hundred thirty-one income-eligible families in 3 geographical regions who were enrolled in a national food supplement program were screened and r and omized to a brief family intervention . At child ages 2 and 3 , the intervention group caregivers were offered the Family Check-Up and linked parenting support services . Latent growth models on caregiver reports at child ages 2 , 3 , and 4 revealed decreased behavior problems when compared with the control group . Intervention effects occurred predominantly among families reporting high levels of problem behavior at child age 2 . Families in the intervention condition improved on direct observation measures of caregivers ' positive behavior support at child ages 2 and 3 ; improvements in positive behavior support mediated improvements in children 's early problem behavior CONTEXT There is growing concern regarding the quality of health care available in the United States for young children , and specific limitations have been noted in developmental and behavioral services provided for children in the first 3 years of life . OBJECTIVE To determine the impact of the Healthy Steps for Young Children Program on quality of early childhood health care and parenting practice s. DESIGN , SETTING , AND PARTICIPANTS Prospect i ve controlled clinical trial enrolling participants between September 1996 and November 1998 at 6 r and omization and 9 quasi-experimental sites across the United States . Participants were 5565 children enrolled at birth and followed up through age 3 years . INTERVENTION Incorporation of developmental specialists and enhanced developmental services into pediatric care in participants ' first 3 years of life . MAIN OUTCOME MEASURES Quality of care was operationalized across 4 domains : effectiveness ( eg , families received > or = 4 Healthy Steps-related services or discussed > 6 anticipatory guidance topics ) , patient-centeredness ( eg , families were satisfied with care provided ) , timeliness ( eg , children received timely well-child visits and vaccinations ) , and efficiency ( eg , families remained at the practice for > or = 20 months ) . Parenting outcomes included response to child misbehavior ( eg , use of severe discipline ) and practice s to promote child development and safety ( eg , mothers at risk for depression discussed their sadness with someone at the practice ) . RESULTS Of the 5565 enrolled families , 3737 ( 67.2 % ) responded to an interview at 30 to 33 months ( usual care , 1716 families ; Healthy Steps , 2021 families ) . Families who participated in the Healthy Steps Program had greater odds of receiving 4 or more Healthy Steps-related services ( for r and omization and quasi-experimental sites , respectively : odds ratio [ OR ] , 16.90 [ 95 % confidence interval [ CI ] , 12.78 to 22.34 ] and OR , 23.05 [ 95 % CI , 17.38 to 30.58 ] ) , of discussing more than 6 anticipatory guidance topics ( OR , 8.56 [ 95 % CI , 6.47 to 11.32 ] and OR , 12.31 [ 95 % CI , 9.35 to 16.19 ] ) , of being highly satisfied with care provided ( eg , someone in the practice went out of the way for them ) ( OR , 2.06 [ 95 % CI , 1.64 to 2.58 ] and OR , 2.11 [ 95 % CI , 1.72 to 2.59 ] ) , of receiving timely well-child visits and vaccinations ( eg , age-appropriate 1-month visit ) ( OR , 1.98 [ 95 % CI , 1.08 to 3.62 ] and OR , 2.11 [ 95 % CI , 1.16 to 3.85 ] ) , and of remaining at the practice for 20 months or longer ( OR , 2.02 [ 95 % CI , 1.61 to 2.55 ] and OR , 1.75 [ 95 % CI , 1.43 to 2.15 ] ) . They also had reduced odds of using severe discipline ( eg , slapping in face or spanking with object ) ( OR , 0.82 [ 95 % CI , 0.54 to 1.26 ] and OR , 0.67 [ 95 % CI , 0.46 to 0.97 ] ) . Among mothers considered at risk for depression , those who participated in the Healthy Steps Program had greater odds of discussing their sadness with someone at the practice ( OR , 0.95 [ 95 % CI , 0.56 to 1.63 ] and OR , 2.82 [ 95 % CI , 1.57 to 5.08 ] ) . CONCLUSION Universal , practice -based interventions can enhance quality of care for families of young children and can improve selected parenting practice BACKGROUND Epidemiological studies of mental health problems in the first years of life are few . This study aims to investigate infancy predictors of psychopathology in the second year of life . METHODS A r and om general population sample of 210 children from the Copenhagen Child Birth Cohort CCC 2000 was investigated by data from National Danish registers and data collected prospect ively from birth in a general child health surveillance programme . Mental health outcome at 1(1/2 ) years was assessed by clinical and st and ardised measures including the Child Behavior Check List 1(1/2)-5 ( CBCL 1(1/2)-5 ) , Infant Toddler Symptom Check List ( ITSCL ) , Checklist for Autism in Toddlers ( CHAT ) , Bayley Scales of Infant Development ( BSID II ) , Mannheim Eltern Interview ( MEI ) , Parent Child Early Relational Assessment ( PC ERA ) and Parent Infant Relationship Global Assessment Scale ( PIR-GAS ) , and disordered children were diagnosed according to the International Classification of Diseases ( ICD-10 ) and Diagnostic Classification Zero to Three ( DC : 0 - 3 ) . RESULTS Deviant language development in the first 10 months of life predicted the child having any disorder at 1(1/2 ) years , OR 3.3 ( 1.4 - 8.0 ) . Neuro-developmental disorders were predicted by deviant neuro-cognitive functioning , OR 6.8 ( 2.2 - 21.4 ) , deviant language development , OR 5.9 ( 1.9 - 18.7 ) and impaired social interaction and communication , OR 3.8 ( 1.3 - 11.4 ) . Unwanted pregnancy and parents ' negative expectations of the child recorded in the first months of the child 's life were significant predictors of relationship disturbances at 1(1/2 ) years . CONCLUSIONS Predictors of neuro-developmental disorders and parent-child relationship disturbances can be identified in the first 10 months of life in children from the general population This study investigated the ability of a theoretically driven , psychosocial prevention program implemented through childbirth education programs to enhance the coparental relationship , parental mental health , the parent-child relationship , and infant emotional and physiological regulation . A sample of 169 heterosexual , adult couples who were expecting their 1st child was r and omized to intervention and control conditions . The intervention families participated in Family Foundations , a series of 8 classes , delivered before and after birth , that was design ed as a universal prevention program ( i.e. , it was applicable to all couples , not just those at high risk ) . Intent-to-treat analyses indicated significant program effects on coparental support , maternal depression and anxiety , distress in the parent-child relationship , and several indicators of infant regulation . Intervention effects were not moderated by income , but greater positive impact of the program was found for lower educated parents and for families with a father who reported higher levels of insecure attachment in close relationships . These findings support the view that coparenting is a potentially malleable intervention target that may influence family relationships as well as parent and child well-being |
13,699 | 24,151,290 | Hyper and rogenism is central to the presentation in adolescents , whereas there is no consistent phenotype in postmenopausal women .
Clomiphene is currently the first-line therapy for infertility ; metformin is beneficial for metabolic/glycemic abnormalities and for improving menstrual irregularities , but it has limited or no benefit in treating hirsutism , acne , or infertility .
The role of weight loss in improving PCOS status per se is uncertain , but lifestyle intervention is beneficial in overweight/obese patients for other health benefits . | OBJECTIVE The aim was to formulate practice guidelines for the diagnosis and treatment of polycystic ovary syndrome ( PCOS ) .
Establishing a diagnosis of PCOS is problematic in adolescents and menopausal women . | CONTEXT Polycystic ovary syndrome ( PCOS ) is associated with the metabolic syndrome and , consequently , with a potentially increased risk of cardiovascular disease ( CVD ) and related mortality later in life . Studies regarding CVD and mortality in PCOS women well into the postmenopausal age are lacking . OBJECTIVE Our objective was to examine whether postmenopausal PCOS women differ from controls regarding cardiovascular risk factors , myocardial infa rct ion ( MI ) , stroke and mortality . DESIGN AND SETTING We conducted , at a university hospital , a prospect i ve study of 35 PCOS women ( 61 - 79 yr ) and 120 age-matched controls . The study was performed 21 yr after the initial study . PARTICIPANTS Twenty-five PCOS women ( Rotterdam criteria ) and 68 controls participated in all examinations . Data on morbidity were based on 32 of 34 PCOS women and on 95 of 119 controls . INTERVENTIONS INTERVENTIONS included reexamination , interviews , and data from the National Board of Health and Welfare and from the Hospital Discharge Registry . MAIN OUTCOME MEASURES Blood pressure , glucose , insulin , triglycerides , total cholesterol , high- and low-density lipoprotein , apolipoprotein A1 and B , fibrinogen , and plasminogen activator inhibitor antigen were studied . Incidences of MI , stroke , hypertension , diabetes , cancer , cause of death , and age at death were recorded . RESULTS PCOS women had a higher prevalence of hypertension ( P = 0.008 ) and higher triglyceride levels ( P = 0.012 ) than controls . MI , stroke , diabetes , cancer , and mortality prevalence was similar in the two cohorts with similar body mass index . CONCLUSIONS The well-described cardiovascular/metabolic risk profile in pre- and perimenopausal PCOS women does not entail an evident increase in cardiovascular events during the postmenopausal period Background —Despite diffuse effects of sex hormones on the cardiovascular system , few prospect i ve studies have examined the relationship of plasma and rogens and estrogens with risk of cardiovascular disease ( CVD ) in postmenopausal women . Methods and Results —A nested case-control study was performed among women in the Women ’s Health Study . Two hundred women who developed CVD were matched 1:1 by age , smoking , and postmenopausal hormone therapy ( HT ) to controls who remained free of CVD . We measured testosterone , estradiol , and sex hormone binding globulin ( SHBG ) levels and calculated free and rogen index ( FAI ) , free estradiol index , and the FAI/free estradiol index ratio . Results were stratified by HT use . Among HT nonusers , cases had significantly higher and rogen profiles ( higher median FAI and lower SHBG levels ) than controls . After adjustment for age , smoking , use of aspirin , vitamin E , and alcohol , family history of myocardial infa rct ion , and physical activity , nonusers in the lowest SHBG quartile had an OR of 2.25 ( 95 % CI , 1.03 to 4.91 ) for CVD , and there were significant trends across FAI quartiles ( P for trend=0.03 ) . Additional adjustment for body mass index , hypertension , diabetes , and elevated cholesterol eliminated associations with SHBG and FAI . Among women using HT , no significant differences in hormones or SHBG were observed among women who developed CVD and controls . Conclusions —Among HT nonusers , lower SHBG and higher FAI levels were noted among postmenopausal women who developed CVD events , but this was not independent of body mass index and other cardiovascular risk factors . Estradiol levels were not associated with risk of CVD in HT users or nonusers The effect of two oral contraceptive ( OC ) pills , both containing 150 micrograms of desogestrel , but with 20 ( Mercilon ) or 30 micrograms ( Marvelon/Desolett ) of ethinyl estradiol on plasma levels of lipids , lipoproteins and sex hormone binding globulin ( SHBG ) , total and free testosterone were compared in a double-blind , r and omized , two-center study in a total of 60 women over one year . A significant rise with Marvelon but not with Mercilon was seen in total cholesterol , HDL cholesterol , HDL-3 and apolipoprotein B , whereas LDL cholesterol decreased with Mercilon only . These effects result ed in significant differences between the two groups in the magnitude of responses in all these parameters except HDL-3 . HDL-2 , apolipoprotein A-1 and total phospholipids were elevated with both pills after treatment and with no difference in the degree of response between groups . The HDL/LDL cholesterol ratio tended to increase in both groups and that of apolipoproteins A-1/B in the women on Mercilon . Total triglycerides increased in both groups , but more in the women on Marvelon . Total testosterone decreased , particularly in the Marvelon group , whereas the two pills caused a similar increase in SHBG and decrease in free testosterone . It is concluded that the direction of changes in plasma lipids and lipoproteins with both these pills may as a whole be interpreted as beneficial , and that the differences in effect on LDL cholesterol and apolipoprotein B may suggest a slightly advantageous effect of Mercilon in this aspect . However , the clinical significance of these changes is uncertain . The results indicate a lack of and rogenicity of both pills CONTEXT Changes in and rogen levels across the adult female life span and the effects of natural menopause and oophorectomy have not been clearly established . OBJECTIVE The objective of this study was to document the effects of age on and rogen levels in healthy women and to explore the effects of natural and surgical menopause . DESIGN , SETTING , AND PARTICIPANTS A cross-sectional study was conducted of 1423 non-healthcare-seeking women , aged 18 - 75 yr , r and omly recruited from the community over 15 months . MAIN OUTCOME MEASURES Serum levels by age of total testosterone ( T ) , calculated free T , dehydroepi and rosterone sulfate , and and rostenedione in a reference group of women free of confounding factors . Women in the reference group had no usage of exogenous steroid therapy ; no history of tubal ligation , hysterectomy , or bilateral oophorectomy ; and no hyperprolactinemia or polycystic ovarian syndrome . The effects of natural and surgical menopause on sex steroid levels were also examined . RESULTS In the reference population ( n = 595 ) , total T , calculated free T , dehydroepi and rosterone sulfate , and and rostenedione declined steeply with age ( P < 0.001 ) , with the decline of each being greater in the earlier than the later decades . Examination of serum and rogen levels by year in women aged 45 - 54 yr showed no independent effect of menopausal status on and rogen levels . In women aged 55 yr or older , those who reported bilateral oophorectomy and were not on exogenous steroids had significantly lower total T and free T levels than women 55 yr or older in the reference group . CONCLUSIONS We report that serum and rogen levels decline steeply in the early reproductive years and do not vary because a consequence of natural menopause and that the postmenopausal ovary appears to be an ongoing site of testosterone production . These significant variations in and rogens with age must be taken into account when normal ranges are reported and in studies of the role of and rogens in women We performed this study to access the changes in glucose tolerance over time in a group of women with polycystic ovary syndrome ( PCOS ) ( n = 71 ) and control women ( n = 23 ) with regular menstrual cycles and baseline normal glucose tolerance . Mean follow-up was between 2 and 3 yr for both groups ( PCOS 2.5 + /- 1.7 yr ; controls 2.9 + /- 2.1 yr ) . Based on World Health Organization glucose tolerance categories , there was no significant difference in the prevalence of glucose intolerance at follow-up in the PCOS group . In the PCOS group , 25 ( 37 % ) had impaired glucose tolerance ( IGT ) and seven ( 10 % ) had type 2 diabetes mellitus at baseline , compared with 30 ( 45 % ) and 10 ( 15 % ) , respectively , at follow-up . There were also no differences within groups ( PCOS or control ) or between groups ( PCOS vs. control ) in the oral glucose tolerance test-derived measure of insulin sensitivity , but in the women with PCOS who converted to either IGT or type 2 diabetes mellitus , there was a significant decrease ( P < 0.0001 ) . At the follow-up visit , the mean glycohemoglobin level was 6.1 + /- 0.9 % in women with PCOS vs. 5.3 + /- 0.7 % in the control women ( P < 0.001 ) . Women with PCOS and baseline IGT had a low conversion risk of 6 % to type 2 diabetes over approximately 3 yr , or 2 % per year . The effect of PCOS , given normal glucose tolerance ( NGT ) at baseline , is more pronounced with 16 % conversion to IGT per year . Our study supports that women with PCOS ( especially with NGT ) should be periodically rescreened for diabetes due to worsening glucose intolerance over time , but this interval may be over several years and not annually BACKGROUND / AIMS Insulin resistance is a common feature of both nonalcoholic fatty liver disease ( NAFLD ) and polycystic ovary syndrome ( PCOS ) , therefore , we hypothesize that PCOS and NAFLD may coexist . The aim of the present study was to determine the frequency and characteristics of NAFLD in women with PCOS . METHODS A prospect i ve study of patients with PCOS and no current pharmacological treatment was conducted . NAFLD was diagnosed by abdominal ultrasound following exclusion of alcohol consumption , viral , or autoimmune liver disease . Anthropometric variables , serum levels of glucose , insulin , lipids and aminotransferases , and HOMA index were determined . RESULTS Forty-one PCOS patients ( mean age : 24.6+/-7.2yr , mean body mass index [ BMI ] : 30.3+/-7.0kg/m(2 ) ) were included ; 26 of 41 PCOS patients ( 63.4 % ) had insulin resistance and 17 ( 41.5 % ) had NAFLD . Nine of the NAFLD patients ( 64 % ) also had abnormal aminotransferases . Women with NAFLD and PCOS had a higher HOMA index and a higher waist-hip ratio than those with normal ultrasound . Patients with PCOS showed a higher frequency of NAFLD ( 41 % vs. 19 % ) and insulin resistance ( 63 % vs. 35.5 % ) than a control group . CONCLUSIONS NAFLD is frequent in patients with PCOS confirming a relevant clinical association between these two conditions . Women with PCOS should be screened for liver disease BACKGROUND Obese women with the polycystic ovary syndrome are relatively unresponsive to the induction of ovulation by clomiphene . We hypothesized that reducing insulin secretion by administering metformin would increase the ovulatory response to clomiphene . METHODS We performed oral glucose-tolerance tests before and after the administration of 500 mg of metformin or placebo three times daily for 35 days in 61 obese women with the polycystic ovary syndrome . Women who did not ovulate spontaneously were then given 50 mg of clomiphene daily for five days while continuing to take metformin or placebo . Serum progesterone was measured on days 14 , 28 , 35 , 44 , and 53 , and ovulation was presumed to have occurred if the concentration exceeded 8 ng per milliliter ( 26 nmol per liter ) on any of these days . RESULTS Twenty-one women in the metformin group and 25 women in the placebo group were given clomiphene because they did not ovulate spontaneously during the first phase of the study . Among the 21 women given metformin plus clomiphene , the mean ( + /-SE ) area under the serum insulin curve after oral glucose administration decreased from 6745+/-2021 to 3479+/-455 microU per milliliter per minute ( 40.5+/-12.1 to 20.9+/-2.7 nmol per liter per minute , P=0.03 ) , but it did not change significantly in the 25 women given placebo plus clomiphene . Nineteen of the 21 women ( 90 percent ) who received metformin plus clomiphene ovulated ( mean peak serum progesterone concentration , 23.8+/-3.4 ng per milliliter [ 7.6+/-10.9 nmol per liter ] ) . Two of the 25 women ( 8 percent ) who received placebo plus clomiphene ovulated ( P<0.001 ) . Overall , 31 of the 35 women ( 89 percent ) treated with metformin ovulated spontaneously or in response to clomiphene , as compared with 3 of the 26 women ( 12 percent ) treated with placebo . CONCLUSIONS The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with metformin 398 new users of oral contraceptives at the Research Clinic of the Southwest Foundation Texas were asked if they experienced nausea vomiting headache or breast discomfort nervousness or depression and had weight and blood pressure recorded in the pretreatment cycle and at monthly visits . Each received placebo Oracon ( sequential ) Ovulen-21 ( combination ) Norinyl-1 or .5 mg chlormadinone acetate in a double-blind protocol incorporating a pretreatment placebo cycle crossover to an active pill for 4 cycles and 2 more crossovers for Cyles 5 and 6 . The only symptoms significantly higher than in the pretreatment ( placebo ) cycle were nausea and vomiting with Oracon ( p greater than .05 ) and headache with Ovulen ( p greater than .05 ) . Pointing out that the highest incidence of complaints occurred in the placebo cycle the authors conclude that controls are necessary in contraceptive trials but the first cycle is not valid for comparison BACKGROUND Cross-sectional studies have shown a high frequency of impaired glucose tolerance ( IGT ) and non-insulin dependent diabetes mellitus ( NIDDM ) in women with polycystic ovarian syndrome ( PCOS ) . However , little is known about the change in glucose tolerance that occurs over a period of several years in women with PCOS . METHODS Sixty-seven women with PCOS received a 75 g glucose tolerance test and measurement of lipids at baseline and at follow-up after an average time of 6.2 years . All women followed prospect ively had normal glucose tolerance ( n = 54 ) or IGT ( n = 13 ) at the start of the study . RESULTS Change in glycaemic control from baseline was frequent , with 5/54 ( 9 % ) of normoglycaemic women at baseline developing IGT and a further 4/54 ( 8 % ) moving directly from normoglycaemic to NIDDM . For women with IGT at baseline , 7/13 ( 54 % ) had NIDDM at follow-up . Body mass index ( BMI ) at baseline was an independent significant predictor of adverse change in glycaemic control . CONCLUSIONS Women with PCOS , particularly those with a high BMI , should be review ed regularly with respect to IGT or NIDDM , as the frequency of impaired glycaemic control is high , and that the rate of conversion from normal glucose tolerance to IGT or NIDDM , or from IGT to NIDDM is substantial CONTEXT Polycystic ovary syndrome ( PCOS ) presents in adolescence , and obesity is a common finding . The benefits and risks of alternate approaches to the management of PCOS in obese adolescent women are not clear . OBJECTIVE We investigated the effects of metformin , oral contraceptives ( OCs ) , and /or lifestyle modification in obese adolescent women with PCOS . DESIGN Two small , r and omized , placebo-controlled clinical trials were performed . PATIENTS AND PARTICIPANTS A total of 79 obese adolescent women with PCOS participated . INTERVENTIONS In the single treatment trial , subjects were r and omized to metformin , placebo , a lifestyle modification program , or OC . In the combined treatment trial , all subjects received lifestyle modification and OC and were r and omized to metformin or placebo . MAIN OUTCOME MEASURES Serum concentrations of and rogens and lipids were measured . RESULTS Lifestyle modification alone result ed in a 59 % reduction in free and rogen index with a 122 % increase in SHBG . OC result ed in a significant decrease in total testosterone ( 44 % ) and free and rogen index ( 86 % ) but also result ed in an increase in C-reactive protein ( 39.7 % ) and cholesterol ( 14 % ) . The combination of lifestyle modification , OC , and metformin result ed in a 55 % decrease in total testosterone , as compared to 33 % with combined treatment and placebo , a 4 % reduction in waist circumference , and a significant increase in HDL ( 46 % ) . CONCLUSIONS In these preliminary trials , both lifestyle modification and OCs significantly reduce and rogens and increase SHBG in obese adolescents with PCOS . Metformin , in combination with lifestyle modification and OC , reduces central adiposity , reduces total testosterone , and increases HDL , but does not enhance overall weight reduction CONTEXT Polycystic ovary syndrome ( PCOS ) is the most common cause of anovulatory infertility . The selection of first-line therapies for ovulation induction is empiric . OBJECTIVE The aim of the study was to develop a clinical ly useful predictive model of live birth with varying ovulation induction methods . DESIGN , SETTING , AND PARTICIPANTS We built four prognostic models from a large multicenter r and omized controlled infertility trial of 626 women with PCOS performed at academic health centers in the United States to predict success of ovulation , conception , pregnancy , and live birth , evaluating the influence of patients ' baseline characteristics . INTERVENTIONS Ovulation was induced with clomiphene , metformin , or the combination of both for up to six cycles or conception . MAIN OUTCOME MEASURE The primary outcome of the trial was the rate of live births . RESULTS Baseline free and rogen index , baseline proinsulin level , interaction of treatment arm with body mass index , and duration of attempting conception were significant predictors in all four models . History of a prior loss predicted ovulation and conception , but not pregnancy or live birth . A modified Ferriman Gallwey hirsutism score of less than 8 was predictive of conception , pregnancy , and live birth ( although it did not predict ovulation success ) . Age was a divergent predictor based on outcome ; age greater than 34 predicted ovulation , whereas age less than 35 was a predictive factor for a successful pregnancy and live birth . Smoking history had no predictive value . CONCLUSIONS A live birth prediction chart developed from basic clinical parameters ( body mass index , age , hirsutism score , and duration of attempting conception ) may help physicians counsel and select infertility treatments for women with PCOS OBJECTIVE To determine the relationship of antimüllerian hormone ( AMH ) levels to polycystic ovaries and ovarian and rogenic function . DESIGN Prospect i ve case-control study . SETTING General clinical research center . PARTICIPANT(S ) Eumenorrheic asymptomatic volunteers without ( V-NO ; n = 19 ; reference population ) or with ( V-PCO ; n = 28 ) a polycystic ovary and hyper and rogenemic anovulatory subjects grouped according to ovarian function into typical PCOS ( PCOS-T ; n = 37 ) and atypical PCOS ( PCOS-A ; n = 18 ) . INTERVENTION(S ) Pelvic ultrasonography , short dexamethasone and rogen-suppression test ( SDAST ) , and GnRH agonist ( GnRHag ) test . MAIN OUTCOME MEASURE(S ) Baseline AMH levels were related to polycystic ovary status , testosterone response to SDAST , and 17-hydroxyprogesterone response to GnRHag test . RESULT ( S ) AMH levels correlated with SDAST and GnRHag test outcomes . AMH was elevated ( > 6.2 ng/mL ) in 32 % of V-PCO versus 5 % V-NO . The 21 % of V-PCO who met Rotterdam PCOS criteria all had functional ovarian hyper and rogenism , but AMH levels were similar to nonhyper and rogenic V-PCO . AMH > 10.7 ng/mL discriminated V-PCO from PCOS with 96 % specificity and 41 % sensitivity for PCOS-T , and insignificantly for PCOS-A. CONCLUSION ( S ) AMH levels are independently related to ovarian and rogenic function and polycystic ovaries . Very high AMH levels are specific but insensitive for PCOS . In the absence of hyper and rogenism , moderate AMH elevation in women with normal-variant polycystic ovaries seems to indicate an enlarged oocyte pool PURPOSE Polycystic ovary syndrome ( PCOS ) is an extremely prevalent disorder in which elevated blood markers of cardiovascular risk and altered endothelial function have been found . This study was design ed to determine if abnormal carotid intima-media thickness ( IMT ) and brachial flow-mediated dilation ( FMD ) in young women with PCOS may be explained by insulin resistance and elevated adipocytokines . METHODS A prospect i ve study in 50 young women with PCOS ( age : 25.2 + /- 1 years ; body mass index [ BMI ] : 28.7 + /- 0.8 ) and 50 matched ovulatory controls ( age : 25.1 + /- 0.7 years ; BMI : 28.5 + /- 0.5 ) was performed . Carotid IMT , brachial FMD , and blood for fasting glucose , insulin , leptin , adiponectin and resistin were measured . RESULTS PCOS , IMT was increased ( P < .01 ) , FMD was decreased ( P < .01 ) , fasting insulin was increased ( P < .01 ) , QUICKI ( a marker of insulin resistance ) was decreased ( P < .01 ) , and adiponectin was lower ( P < .05 ) , whereas leptin and resistin were not different compared with matched controls . Whereas BMI or waist/hip ratios did not correlate with IMT or FMD , insulin and QUICKI correlated positively and negatively with IMT ( P < .01 ) . There was a significant negative correlation between adiponectin and IMT ( P < .05 ) . These correlations were unchanged when adjusting for BMI and the correlation between IMT and adiponectin was unaffected by insulin resistance parameters . CONCLUSIONS These data suggest that young women with PCOS have evidence for altered endothelial function . Adverse endothelial parameters were correlated with insulin resistance and lower adiponectin . Both insulin resistance and adiponectin appear to be important parameters . It is hypothesized that the type of fat distribution may influence these factors OBJECTIVE Participants in the Diabetes Prevention Program ( DPP ) r and omized to intensive lifestyle modification ( ILS ) or metformin had a significantly reduced incidence of diabetes compared with those r and omized to placebo , yet most were still at risk because they had pre-diabetes . We explored the effect of baseline characteristics , weight change , ILS , and metformin on regression from pre-diabetes to the lowest-risk state of normal glucose regulation ( NGR ) defined by American Diabetes Association criteria . RESEARCH DESIGN AND METHODS The DPP was a prospect i ve r and omized trial . Cox proportional hazards modeling was used to identify predictors of regression from pre-diabetes to NGR over 3 years of follow-up . RESULTS Lower baseline fasting ( hazard ratio 1.52 , P < 0.01 ) and 2-h ( 1.24 , P < 0.01 ) glucose predicted regression to NGR , as did younger age ( 1.07 , P < 0.01 ) and greater insulin secretion ( 1.09 , P = 0.04 ) . ILS ( 2.05 , P < 0.01 ) and weight loss ( 1.34 , P < 0.01 ) had significant and independent effects on regression . A nonsignificant trend for regression was also observed for metformin ( 1.25 , P = 0.06 ) , male sex ( 1.17 , P = 0.08 ) , and insulin sensitivity ( 1.07 , P = 0.09 ) . In those entering the study with both impaired fasting glucose ( IFG ) and impaired glucose tolerance ( IGT ) , male sex and insulin sensitivity predicted regression to isolated IFG , whereas ILS , metformin , female sex , and greater insulin secretion predicted regression to isolated IGT . CONCLUSIONS Insulin secretion , and other biologic processes retained with younger age , are key in restoring NGR in people with pre-diabetes . However , NGR may also be attained through weight loss and additional aspects of ILS CONTEXT The polycystic ovary syndrome ( PCOS ) is frequently associated with obesity . However , there are very few data about PCOS in morbid obesity , especially with regard to its evolution after bariatric surgery . OBJECTIVE The objective of this study was to evaluate the response of PCOS to the sustained and marked weight loss achieved by bariatric surgery in morbidly obese women . DESIGN This was a longitudinal prospect i ve nonr and omized evaluation . SETTING S The study was performed at an academic hospital . PATIENTS Thirty-six consecutive premenopausal women su bmi tted to bariatric surgery were screened for PCOS , which was present in 17 . INTERVENTIONS Bariatric surgery was performed . MAIN OUTCOME MEASURES Hyper and rogenism , menstrual function , and insulin resistance were estimated before and at least 6 months after bariatric surgery in 12 patients with PCOS . RESULTS Weight loss ( 41 + /- 9 kg after 12 + /- 5 months ) was paralleled by decreases in the hirsutism score ( from 9.5 + /- 6.8 to 4.9 + /- 4.2 ; P = 0.001 ) , total ( 69 + /- 32 to 42 + /- 19 ng/dl ; P < 0.02 ) and free testosterone ( from 1.6 + /- 0.7 to 0.6 + /- 0.3 ng/dl ; P < 0.005 ) , and rostenedione ( from 4.1 + /- 1.5 to 3.0 + /- 0.9 ng/ml ; P < 0.02 ) , and dehydroepi and rosterone sulfate ( from 2000 + /- 1125 to 1353 + /- 759 ng/ml ; P < 0.005 ) ; amelioration of insulin resistance estimated by homeostasis model assessment ( from 6.0 + /- 3.0 to 1.6 + /- 1.0 ; P < 0.001 ) ; and restoration of regular menstrual cycles and /or ovulation in all patients . CONCLUSIONS The PCOS is a frequent finding in women with morbid obesity and may resolve after weight loss induced by bariatric surgery OBJECTIVE To examine whether follicle loss due to ovarian aging is responsible for the occurrence of regular menstrual cycles in aging women with polycystic ovary syndrome ( PCOS ) , the size of the FSH-sensitive follicle cohort was estimated by the exogenous follicle-stimulating hormone ovarian reserve test ( EFORT ) and related to the follicle count as measured by ultrasound . DESIGN Prospect i ve study . SETTING Reproductive endocrinology unit of an academic medical center . PATIENT(S ) Twenty-seven aging women with PCOS ( 35.8 - 49.4 years ) : 20 with regular menstrual cycles and 7 with oligomenorrhea or amenorrhea . INTERVENTION(S ) EFORT and transvaginal ultrasound . MAIN OUTCOME MEASURE(S ) Baseline ( cycle day 2 , 3 , or 4 ) FSH , and rostenedione ( A ) , T , E(2 ) , and inhibin B levels , the E(2 ) and inhibin B increment after the EFORT , and the follicle count . RESULT ( S ) After correction for the body mass index ( BMI ) , the inhibin B increment was higher in the irregular menstrual group , but the E(2 ) increment did not differ significantly between the two groups . Ultrasound showed a median follicle count of 8.5 ( 4.0 - 18.0 ) in women with regular menstrual cycles ( n = 16 ) , compared with 18.0 ( 8.0 - 35.0 ) in irregularly menstruating women ( n = 7 ) . The follicle count was significantly correlated to the FSH-induced E(2 ) increment ( r = 0.656 ) as well as to the inhibin B increment ( r = 0.654 ) . The regularly menstruating group was significantly older , had a higher basal FSH concentration , and had lower and rogens than the irregularly menstruating group . CONCLUSION ( S ) The smaller follicle count , the older age , the higher FSH concentration , and the lower FSH-induced inhibin B increment found in women with PCOS and a regular menstrual cycle confirm that a decrease in the size of the follicle cohort due to ovarian aging is largely responsible for the regular menstrual cycles in aging PCOS women Hyperinsulinemic hyper and rogenism with anovulation , the so-called polycystic ovary syndrome ( PCOS ) , is the most frequent endocrine disorder of young women . One of the stigmata of PCOS is a deficit of lean mass and an excess of fat , in particular , abdominal fat , even in the absence of obesity . Adiponectin and IL-6 are among the adipocytokines that have recently been related to abdominal fat excess , insulin resistance states , and cardiovascular disease risk . We studied the effects of two new treatment options , ethinylestradiol-drospirenone and flutamide-metformin , and of their combination on adipocytokinemia and body adiposity in adolescents and women with PCOS . Adolescents with PCOS ( n = 32 ; age , approximately 15 yr ; body mass index , approximately 22 kg/m(2 ) ) were r and omly assigned to receive the oral contraceptive ( OC ) ethinylestradiol-drospirenone , or the low-dose generic duo of flutamide ( 62.5 mg/d ) plus metformin ( 850 mg/d ) . Young women with PCOS ( n = 22 ; age , approximately 19 yr ; body mass index , approximately 22 kg/m(2 ) ) were r and omized to receive the same OC , either alone or with flutamide-metformin . Fasting blood glucose , serum insulin , lipids , and rogens , IL-6 , adiponectin , and body composition ( by absorptiometry ) were assessed at the start , and after 3 and /or 9 months . At the start , serum concentrations of the proinflammatory IL-6 were high , and those of the antiinflammatory adiponectin were low ; body composition was adipose in each sub population . Abnormal adipocytokine levels , hypertriglyceridemia , and body adiposity diverged further from the norm in adolescents on OC ; in contrast , girls on flutamide-metformin reverted all study indices toward normal , lost part of their fat excess , and reduced their lean mass deficit . In comparison to the girls on OC , those on flutamide-metformin lost a mean of approximately 4 kg of fat and gained approximately 4 kg of lean mass . Similarly , abnormal adipocytokine levels and adiposity were aggravated in women on OC alone and improved in women on OC plus flutamide-metformin ; within 9 months , the latter subgroup lost a mean of approximately 3 kg of fat and gained approximately 3 kg of lean mass , in comparison to women on OC alone . In conclusion , young and nonobese PCOS patients were found to be in a low- grade , chronic inflammation state , and to have a body adiposity that evolves according to the balance of circulating adipocytokines and lipids , rather than to and rogen excess or fasting hyperinsulinemia . Monotherapy with ethinylestradiol-drospirenone may not be a prime choice for PCOS , given its inefficacy to attenuate abnormal adipocytokine levels and body adiposity ; ethinylestradiol-drospirenone plus flutamide-metformin , however , is a first OC combination that was found capable of reverting both the adipocytokine balance and the body composition toward normal , and that may therefore improve the long-term cardiovascular perspectives of women with PCOS OBJECTIVE To examine the outcome of treatment with IVF-ET of women with polycystic ovarian syndrome ( PCOS ) who failed to conceive on conventional treatment . DESIGN Retrospective analysis with an age-matched control group . SETTING University hospital infertility clinic and IVF unit . PATIENTS . INTERVENTIONS Sixty-eight women with PCOS who had failed to conceive on treatment with clomiphene citrate and during six ovulatory cycles on gonadotropins underwent 208 cycles of IVF-ET . An age-matched group of 68 women with a tubal mechanical factor who received 143 treatment cycles during the same period served as controls . MAIN OUTCOME MEASURES Cumulative conception rates , the cumulative livebirth rates , and IVF-ET data were compared between the two groups . Results of treatment with and without GnRH agonist ( GnRH-a ) within the groups were also compared . RESULTS A comparison of PCOS and mechanical factor ( control ) groups showed almost identical results at 6 months for cumulative conception rate ( 82 % versus 85 % ) and cumulative livebirth rate ( 69 % versus 65 % ) . Significantly more oocytes were retrieved but a smaller percentage fertilized in PCOS , and the pregnancy rate per ET did not differ between the two groups ( 23 % versus 26 % ) . Treatment with GnRH-a and gonadotropins as opposed to gonadotropins alone improved the cumulative conception rate , miscarriage rate , and cumulative livebirth rate in the PCOS but not in the control group and improved fertilization rates in both groups . CONCLUSIONS For patients with PCOS who fail to conceive with gonadotropin treatment , IVF-ET is a successful treatment alternative , producing results equal to those for women with a mechanical tubal factor . Better results were achieved with GnRH-a in women with PCOS but made no difference to those with a mechanical tubal factor compared with treatment with gonadotropins alone Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency often have a polycystic ovary-like syndrome , consisting of hyper and rogynism , infertility , menstrual irregularities , and elevated LH levels . This is generally considered secondary to poor control of the congenital adrenal hyperplasia . However , our experience led us to suspect that ovarian hyper and rogenism occurs even when congenital adrenal hyperplasia is well controlled on glucocorticoid therapy . Therefore , we tested the hypothesis that congenital adrenal virilizing disorders result in ovarian hyper and rogenism . We studied eight women with congenital adrenal virilizing disorders , seven with well controlled classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma removed at 1.7 yr of age . We also studied six women with late-onset 21-hydroxylase deficiency , without signs of congenital virilization . An ovarian source of and rogens was assessed after suppressing adrenal function with dexamethasone and then testing pituitary-ovarian function by a GnRH agonist ( nafarelin ) test . Five women with congenital adrenal virilizing disorders ( four with classic 21-hydroxylase deficiency and one with congenital virilizing adrenal carcinoma ) and one women with late-onset 21-hydroxylase deficiency had ovarian hyper and rogenism as determined by subnormal suppression of free testosterone after dexamethasone and /or by increased 17-hydroxyprogesterone response to nafarelin while on dexamethasone . All women with congenital adrenal virilization and ovarian hyper and rogenism had elevated LH levels after dexamethasone or elevated early LH response to nafarelin , which suggests that LH excess is the cause of their ovarian hyper and rogenism . This was not the case for the late-onset 21-hydroxylase-deficient woman . Our data are compatible with the hypothesis that congenital adrenal virilization programs the hypothalamic-pituitary axis for hypersecretion of LH at puberty . This is postulated to frequently cause ovarian hyper and rogenism even when adrenal and rogen excess is subsequently controlled by glucocorticoid therapy BACKGROUND This prospect i ve study evaluated the effect of weight reduction on anthropometric indices and ovarian morphology in anovulatory overweight patients with polycystic ovary syndrome ( PCOS ) . METHODS Thirty-three anovulatory overweight patients with PCOS were enrolled in the study . All had patent Fallopian tubes and chronic anovulation : 27 of them were oligo-amenorrhoeic . The partners were normospermic . Patients were prescribed a 1200 kcal/day diet , and physical exercise was recommended . Anthropometric indices and ovarian imaging parameters were assessed at baseline and after weight loss of 5 and 10 % . RESULTS Twenty-five patients ( 76 % ) lost at least 5 % of their body weight . Eleven of these patients ( 33 % ) reached a 10 % decrease in weight . Waist circumference at the umbilical level , hip circumference , four skin folds , body mass index and fatty mass ratio were significantly reduced after 5 and 10 % weight loss . Ovarian morphology changed during the diet : we observed a significant reduction in ovarian volume and in the number of microfollicles per ovary . Among the 27 patients with oligo-amenorrhoea , 18 had a resumption of regular cycles and 15 experienced spontaneous ovulation ; 10 spontaneous pregnancies occurred in patients who lost at least 5 % of their weight . CONCLUSIONS Weight loss through a controlled low-calorie diet improves anthropometric indices in obese PCOS patients , reduces ovarian volume and microfollicle number and can restore ovulatory cycles , allowing spontaneous pregnancy BACKGROUND Ovulation induction treatment with metformin , either alone or in combination with clomiphene citrate ( CC ) , remains controversial even though previous r and omized trials have examined this . METHODS A double blinded multi-centre r and omized trial was undertaken including 171 women with anovulatory or oligo-ovulatory polycystic ovary syndrome . Women with high body mass index ( BMI ) > 32 kg/m(2 ) received placebo ( ' st and ard care ' ) or metformin ; women with BMI < or = 32 kg/m(2 ) received CC ( ' st and ard care ' ) , metformin or both . Treatment continued for 6 months or until pregnancy was confirmed . Primary outcomes were clinical pregnancy and live birth . RESULTS For women with BMI > 32 kg/m(2 ) , clinical pregnancy and live birth rates were 22 % ( 7/32 ) and 16 % ( 5/32 ) with metformin , 15 % ( 5/33 ) and 6 % ( 2/33 ) with placebo . For women with BMI < or = 32 kg/m(2 ) , clinical pregnancy and live birth rates were 40 % ( 14/35 ) and 29 % ( 10/35 ) with metformin , 39 % ( 14/36 ) and 36 % ( 13/36 ) with CC , 54 % ( 19/35 ) and 43 % ( 15/35 ) with combination metformin plus CC . CONCLUSIONS There is no evidence that adding metformin to ' st and ard care ' is beneficial . Pregnancy and live birth rates are low in women with BMI > 32 kg/m(2 ) whatever treatment is used , with no evidence of benefit of metformin over placebo . For women with BMI < or = 32 kg/m(2 ) there is no evidence of significant differences in outcomes whether treated with metformin , CC or both . Clinical Trials.gov number NCT00795808 ; trial protocol accepted for publication November 2005 : Johnson , Aust N Z Journal Obstet Gynaecol 2006;46:141 - 145 We have recently shown that polycystic ovary syndrome ( PCOS ) is associated with high muscle sympathetic nerve activity ( MSNA ) . Animal studies support the concept that low-frequency electroacupuncture ( EA ) and physical exercise , via stimulation of ergoreceptors and somatic afferents in the muscles , may modulate the activity of the sympathetic nervous system . The aim of the present study was to investigate the effect of these interventions on sympathetic nerve activity in women with PCOS . In a r and omized controlled trial , 20 women with PCOS were r and omly allocated to one of three groups : low-frequency EA ( n = 9 ) , physical exercise ( n = 5 ) , or untreated control ( n = 6 ) during 16 wk . Direct recordings of multiunit efferent postganglionic MSNA in a muscle fascicle of the peroneal nerve before and following 16 wk of treatment . Biometric , hemodynamic , endocrine , and metabolic parameters were measured . Low-frequency EA ( P = 0.036 ) and physical exercise ( P = 0.030 ) decreased MSNA burst frequency compared with the untreated control group . The low-frequency EA group reduced sagittal diameter ( P = 0.001 ) , while the physical exercise group reduced body weight ( P = 0.004 ) and body mass index ( P = 0.004 ) compared with the untreated control group . Sagittal diameter was related to MSNA burst frequency ( Rs = 0.58 , P < 0.005 ) in the EA group . No correlation was found for body mass index and MSNA in the exercise group . There were no differences between the groups in hemodynamic , endocrine , and metabolic variables . For the first time we demonstrate that low-frequency EA and physical exercise lowers high sympathetic nerve activity in women with PCOS . Thus , treatment with low-frequency EA or physical exercise with the aim to reduce MSNA may be of importance for women with PCOS Hirsutism is a common and distressing symptom frequently encountered in women with polycystic ovary syndrome ( PCOS ) , who also show relative insulin resistance . The aim of this trial , in which hirsutism was the primary end point , was to compare the efficacy of the oral antihyperglycemic medication metformin with that of an established treatment , combined ethinyl estradiol and cyproterone acetate . Patients ( n = 52 ) were r and omized to receive either metformin ( 500 mg , three times daily ) or Dianette ( ethinyl estradiol , 35 micro g ; cyproterone acetate , 2 mg ) treatment for 12 months , with assessment s before treatment , at 6 months , and at 12 months . Both objective and subjective methods of evaluating hirsutism were used , and in addition , patient perceptions were examined . The results show that metformin is potentially an effective treatment for moderate to severe hirsutism in women with PCOS . They also suggest that in some respects ( Ferriman-Gallwey score and patient self- assessment ) , it is more efficacious than the st and ard treatment ( Dianette ) . The objective evaluation of hair diameter reduction showed that both treatments were moderately effective at multiple anatomical sites . Dianette treatment was responsible for profound suppression of and rogen activity , in contrast to metformin , which induced negligible change . However , metformin did reduce markers of insulin resistance . The data suggest that hirsutism may be effectively treated by reducing hyperinsulinemia BACKGROUND The objective of this investigation was to establish independent predictors of follicle-stimulating hormone ( FSH ) threshold dose in anovulatory women undergoing ovulation induction with FSH preparations . METHODS One hundred and fifty-one patients with WHO Group II anovulatory infertility failing to ovulate or conceive on clomiphene citrate underwent ovarian stimulation with FSH-only preparations following a low-dose step-up protocol . The individual FSH threshold dose was defined as the FSH dose when meeting the human chorionic gonadotrophin criteria ( one follicle ≥17 mm , or 2–3 follicles ≥15 mm ) . The influence of demographics , physical characteristics , obstetric and infertility and menstrual cycle history , ovarian ultrasonography , endocrine parameters and type of gonadotrophin preparation on the FSH threshold dose was assessed through multiple regression analysis . RESULTS In the univariate analysis , age , body mass index ( BMI ) , failure to ovulate with clomiphene citrate , menstrual cycle history ( amenorrhea , oligomenorrhea or anovulatory cycles of 21–35 days ) , mean ovarian volume , LH/FSH ratio , testosterone and free and rogen index were significant ( P < 0.05 ) predictors of FSH threshold dose . In the multivariate analysis , menstrual cycle history , mean ovarian volume and BMI remained significant ( P < 0.001 ) . CONCLUSIONS The individual FSH threshold dose for ovulation induction in anovulatory women can be predicted based on three variables easily determined in clinical practice : menstrual cycle history , mean ovarian volume and BMI . A FSH dosage nomogram was constructed based on these parameters BACKGROUND Metformin appears to improve reproductive function in some women with polycystic ovary syndrome ( PCOS ) . We wished to explore the effect of metformin in women with PCOS undergoing IVF . METHODS A r and omized , placebo-controlled , double-blind study was carried out between 2001 and 2004 . Patients with PCOS undergoing IVF/ICSI treatment using a long GnRH agonist protocol were r and omized to receive metformin ( MET ) , 850 mg , or placebo ( PLA ) tablets twice daily from the start of the down-regulation process until the day of oocyte collection . The primary outcome was to be an improvement in the overall fertilization rate . RESULTS One-hundred and one IVF/ICSI cycles were r and omized to receive metformin ( 52 ) or to receive placebo ( 49 ) . There was no difference in the total dose of rFSH required per cycle ( median dose : MET = 1200 U , PLA = 1300 U ; P = 0.937 ) . The median number of oocytes retrieved per cycle ( MET = 17.2 , PLA = 16.2 ; P = 0.459 ) and the overall fertilization rates ( MET = 52.9 % , PLA = 54.9 % ; P = 0.641 ) did not differ . However , both the clinical pregnancy rates beyond 12 weeks gestation per cycle ( MET = 38.5 % , PLA = 16.3 % ; P = 0.023 ) and per embryo transfer ( MET = 44.4 % , PLA = 19.1 % ; P = 0.022 ) were significantly higher in those treated with metformin . Furthermore , a significant decrease in the incidence of severe ovarian hyperstimulation syndrome ( OHSS ) was observed ( MET = 3.8 % , PLA = 20.4 % ; P = 0.023 ) , and this was still significant after adjustment for BMI , total rFSH dose and age ( OR = 0.15 ; 95 % CI : 0.03 , 0.76 ; P = 0.022 ) . CONCLUSION Short-term co-treatment with metformin for patients with PCOS undergoing IVF/ICSI cycles does not improve the response to stimulation but significantly improves the pregnancy outcome and reduces the risk of OHSS BACKGROUND There is a perception that the prevalence of infertility is on the rise . This study aim ed to determine the current prevalence of infertility in a defined geographical population , ascertain changes in self-reported infertility over time and identify risk factors associated with infertility . METHODS A postal question naire survey of a r and om population -based sample of women aged 31 - 50 years was performed in the Grampian region of Scotl and . Questions addressed the following areas : pregnancy history , length of time taken to become pregnant each time , whether medical advice had been sought and self-reported exposure to factors associated with infertility . RESULTS Among 4466 women who responded , 400 ( 9.0 % ) [ 95 % CI 8.1 , 9.8 ] had chosen not to have children . Of the remaining 4066 women , 3283 ( 80.7 % ) [ 95 % CI 79.5 , 82.0 ] reported no difficulties in having children and the remaining 783 ( 19.3 % ) [ 95 % CI 18.1 , 20.5 ] had experienced infertility , defined as having difficulty in becoming pregnant for more than 12 months and /or seeking medical advice . In total 398 ( 9.8 % ) [ 95 % CI 8.9 , 10.7 ] women had primary infertility , 285 ( 7.0 % ) [ 95 % CI 6.2 , 7.8 ] had secondary infertility , 100 ( 2.5 % ) [ 95 % CI 2.0 , 2.9 ] had primary as well as secondary infertility . A total of 342 ( 68.7 % ) and 208 ( 73.0 % ) women with primary and secondary infertility , respectively , sought medical advice and 202 ( 59.1 % ) and 118 ( 56.7 % ) women in each group subsequently conceived . History of pelvic surgery , Chlamydial infection , endometriosis , chemotherapy , long-term health problems and obesity were associated with infertility . In comparison with a similar survey of women aged 46 - 50 from the same geographical area , the prevalence of both primary infertility ( > 24 months ) [ 70/1081 , ( 6.5 % ) versus 68/710 ( 9.6 % ) P = 0.02 ] and secondary infertility [ 29/1081 ( 2.7 % ) versus 40/710 ( 5.6 % ) P = 0.002 ] were significantly lower . CONCLUSIONS Nearly one in five women attempting conception sample d in this study experienced infertility , although over half of them eventually conceived . Fertility problems were associated with endometriosis , Chlamydia trachomatis infection and pelvic surgery , as well as obesity , chemotherapy and some long-term chronic medical conditions . There is no evidence of an increase in the prevalence of infertility in this population over the past 20 years OBJECTIVE To determine the first-line medication to be used in anovulatory patients with polycystic ovary syndrome ( PCOS ) for ovulation induction and pregnancy achievement . DESIGN R and omized controlled trial . SETTING Infertility unit of a public hospital . PATIENT(S ) One hundred fifteen newly diagnosed patients with PCOS based on ESHRE/ASRM criteria . INTERVENTION(S ) These patients were assigned to three groups : group 1 ( 38 patients ) received 500 mg of metformin three times a day ; group 2 ( 39 patients ) received clomiphene citrate ( CC ) at an incremental dose ; group 3 ( 38 patients ) received both medications . MAIN OUTCOME MEASURE(S ) Rates of ovulation , pregnancy ( PR ) , and live birth . RESULT ( S ) The ovulation rate was 23.7 % in the metformin group , 59 % in the CC group , and 68.4 % in the combination treatment group . This was translated into a similar PR and live birth rate , which were higher in the CC and combination groups compared to the metformin group ( PR : 7.9 % , 15.4 % , and 21.1 % ; live birth rate : 7.9 % , 15.4 % , and 18.4 % in metformin , CC , and combination treatment groups , respectively ) , although statistically the differences were not significant . There were no multiple pregnancies and the rate of spontaneous first trimester loss was similar to the general population . CONCLUSION ( S ) Clomiphene citrate should be the first-line treatment for ovulation induction in anovulatory patients with PCOS Cross-sectional studies suggest that women who have irregular menstrual cycles and hyper and rogenism may be at increased risk for cardiovascular disease ( CVD ) . However , prospect i ve data are lacking on the relationship between menstrual cycle irregularity and subsequent CVD risk . The objective of this study was to assess prospect ively the risk for coronary heart disease ( CHD ) and stroke associated with a history of irregular menstrual cycles . The study design was a prospect i ve cohort study of 82,439 female nurses who provided information in 1982 on prior menstrual regularity ( at ages 20 - 35 yr ) and were followed through 1996 for cardiovascular events . Incident reports of nonfatal myocardial infa rct ion , fatal CHD , and nonfatal and fatal stroke were made . Medical records were review ed for confirmation . During 14 yr ( 1,155,915 person-yr ) of follow-up , there were 1417 incident cases of CHD and 838 incident cases of stroke , including 471 cases of ischemic stroke . Compared with women reporting a history of very regular menstrual cycles , women reporting usually irregular or very irregular cycles had an increased risk for nonfatal or fatal CHD [ age-adjusted relative risks ( RR ) , 1.25 and 1.67 , respectively ; 95 % confidence intervals ( CI ) , 1.07 - 1.47 and 1.35 - 2.06 , respectively ] . Increased risks for CHD associated with prior cycle irregularity remained significant after adjustment for body mass index and several potential confounders . There was a nonsignificant increase in overall stroke risk ( RR , 1.30 ; 95 % CI = 0.97 - 1.74 ) and in ischemic stroke risk ( RR , 1.40 ; 95 % CI = 0.97 - 2.04 ) associated with very irregular cycles . Menstrual cycle irregularity may be a marker of metabolic abnormalities predisposing to increased risk for CVD CONTEXT Polycystic ovary syndrome ( PCOS ) is associated with comorbidities that may contribute to increased risk of cardiovascular disease . PCOS is associated with increased risk of metabolic syndrome , dyslipidemia , and diabetes , but it remains unclear whether traditional cardiovascular ( CV ) risk factors can help predict coronary artery disease in this population . OBJECTIVE The objectives of the study were to detect early-onset sub clinical coronary atherosclerosis ( using coronary artery calcium as a marker ) in young women with PCOS , compared with age- and body mass index-matched controls , and to compare traditional CV risk factors and inflammatory markers in the two groups . DESIGN This was a prospect i ve case-control study . SETTING The study was conducted at a university hospital . SUBJECTS Twenty-four obese ( body mass index > or= 30 kg/m2 ) PCOS subjects and 24 obese controls participated . OUTCOME MEASURES Coronary artery calcium , inflammatory markers ( high-sensitivity C-reactive protein , IL-6 , TNFalpha , adiponectin , leptin ) , fasting blood tests ( glucose , lipids , insulin ) , and dual-energy x-ray absorptiometry scan for body fat distribution were measured . RESULTS Coronary artery calcium was detected in eight of 24 PCOS subjects ( 33 % ) and two of 24 controls ( 8 % ) ( odds ratio 5.5 , 95 % confidence interval 1.03 , 29.45 , P < 0.03 ) . Traditional CV risk factors did not differ significantly between the two groups , nor did markers of inflammation or adiposity , body fat distribution , or metabolic parameters with the exception of significantly lower quantitative insulin sensitivity check index ( marker for insulin resistance ) in the PCOS group ( P < 0.05 ) . CONCLUSIONS Young , obese women with PCOS have a high prevalence of early asymptomatic coronary atherosclerosis , compared with obese controls . This increased risk is independent of traditional CV risk factors and novel markers of inflammation . These findings underscore the need to screen and aggressively counsel and treat these women to prevent symptomatic CV disease OBJECTIVE To compare the effects of cyproterone acetate and desogestrel , as part of combined oral contraceptives , on lipid metabolism and hirsutism of adolescents with polycystic ovary syndrome ( PCOS ) . DESIGN Prospect i ve r and omized clinical trial . SETTING Outpatient gynecology clinic ( referral center ) of a university . PATIENT(S ) Twenty-eight adolescent girls with clinical and biological hyper and rogenism and six or less menses during the past 12 months . INTERVENTION(S ) Group A ( n = 14 ) received 0.15 mg of desogestrel plus 0.030 mg of ethinyl estradiol daily . Group B ( n = 14 ) received 2 mg of cyproterone acetate plus 0.035 mg of ethinyl estradiol daily . Treatment was given for 21 days followed by a 7-day rest for a period of 12 months . MAIN OUTCOME MEASURE(S ) Hirsutism and lipid profile were evaluated before initiation and at 3 , 6 , 9 , and 12 months of treatment . And rogen profile was evaluated before and at 12 months of treatment . RESULT ( S ) A significant decline of the Ferriman-Gallway hirsutism score was observed from the sixth month of therapy in both groups . During therapy , the levels of testosterone , free testosterone , Delta(4)- and rostenedione , and 17OH-progesterone decreased significantly , whereas sex hormone-binding globulin ( SHBG ) increased significantly in both groups . The level of total cholesterol and low density lipoprotein ( LDL ) cholesterol increased significantly , whereas high density lipoprotein ( HDL ) cholesterol and apolipoprotein A-I increased significantly from the third month of therapy in both groups . Total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios remained unchanged . The levels of triglycerides increased significantly in the cyproterone acetate-treated group after the third month . CONCLUSION ( S ) Treatment of adolescent girls with PCOS with the two studied formulations is comparably effective in decreasing hirsutism and and rogen levels . Both combined oral contraceptives are associated with an increase of total cholesterol , LDL cholesterol , and HDL cholesterol levels and no change of the total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios . Treatment with the cyproterone acetate combined oral contraceptive is associated with a tendency toward increasing the levels of triglycerides From a referral area comprising one-fifth of the Swedish female population we investigated possible risk factors for endometrial cancer ( EC ) in different age groups . Seventy-seven women aged 31 - 45 with EC were collected retrospectively , and 99 women aged 46 - 65 were consecutively collected . Both groups were compared to referents r and omly selected from a population based study from the city of Göteborg . The referents consisted of 1746 women aged 39 - 65 years . All cases were studied by hospital record and 82 % of the women aged 31 - 45 years and 85 % of those aged 46 - 65 years were studied by an extensive question naire . Among the referents 1409 ( 81 % ) were investigated by the above-mentioned question naire . Hirsutism , increased body mass index ( BMI ) and hypertension were significantly more common in both EC groups compared to referents . Nulliparity and infertility were significantly more common in the young EC group . Referents used combined oral contraceptives significantly more often than women developing EC . There was , however , no difference between the groups with respect to the duration of medication with combined oral contraceptives . There was a significant negative correlation between cigarette smoking and the development of EC . These findings indicate that untreated ovarian dysfunction like that present in polycystic ovarian disease ( PCO ) with unopposed estrogen action on the endometrium is associated with EC in younger women , and that smoking may protect against EC by an ' anti-estrogenic ' effect OBJECTIVE To determine whether testosterone levels change as women with the polycystic ovary syndrome ( PCOS ) grow older . DESIGN A follow-up cross-sectional study of a cohort of women with PCOS identified up to 20 - 25 years ago . SETTING Women with PCOS were recruited primarily from practice records between 1970 and 1990 . Voter registration tapes and household directories were used to identify age- , race- , and neighborhood-matched controls . PARTICIPANT(S ) Eighty-four women with PCOS , 20 - 57 years of age , and 37 age-matched controls participating in a study of the risk for cardiovascular disease in women with PCOS . INTERVENTION(S ) Clinical data were collected by question naire and fasting blood sample s were obtained r and omly throughout the menstrual cycle . MAIN OUTCOME MEASURE(S ) Total and non-SHBG-bound testosterone levels . RESULT ( S ) Total and non-SHBG-bound testosterone levels were similar in women with PCOS who were 20 - 42 years of age but were reduced by approximately 50 % among women 42 - 47 years of age and remained stable in women older than 47 years of age . Testosterone levels were increased in younger and older women with PCOS compared with controls but were similar to controls in women 42 - 47 years of age . CONCLUSION ( S ) Hyper and rogenism partly resolves before menopause in women with PCOS . This change may explain the tendency of women with PCOS to cycle regularly as they grow older . Testosterone levels remain elevated in older women with PCOS , however , and may contribute to their increased risk for cardiovascular disease , endometrial cancer , and other diseases To determine the effects of statins on vascular function , inflammation , and and rogen levels in women with polycystic ovary syndrome ( PCOS ) , we r and omized 20 women with PCOS who had low-density lipoprotein cholesterol levels > 100 mg/dL to atorvastatin ( 40 mg/day ) or placebo for 6 weeks and found that atorvastatin reduced and rogen levels , biomarkers of inflammation , and blood pressure ; increased insulin levels and brachial artery conductance during reactive hyperemia ; and failed to improve brachial artery flow-mediated dilation . We conclude that until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS , statins should only be used in women with PCOS who meet current indications for statin treatment OBJECTIVE The aim of this study was to investigate the endothelial status in young women with polycystic ovary syndrome ( PCOS ) , using a simple and easily reproducible hemodynamic method combined with a biological marker and to evaluate the effect of metformin treatment on these parameters . DESIGN Descriptive clinical trial . METHODS Forty young women , 20 with PCOS and 20 normal women of similar age and body mass index were studied . Metformin ( 1700 mg daily ) was administered for 6 months to the PCOS group . The endothelium status and the metabolic and hormonal profile were studied in both groups , as well as after metformin , by flow-mediated dilatation ( FMD ) on the brachial artery and by measurements of plasma endothelin-1 ( ET-1 ) levels . RESULTS FMD was impaired in the PCOS group when compared with controls ( 3.24+/-0.71 % vs 8.81+/-1.07 % respectively , P<0.0001 ) , but this difference normalized after metformin treatment ( PCOS(post-metformin ) vs controls : 8.17+/-1.26 vs 8.81+/-1.07 % , P = 0.70 ) since the values significantly improved after metformin treatment ( PCOS(pre-metformin ) vs PCOS(post-metformin ) : 3.24+/-0.71 vs 8.17+/-1.26 % , P=0.003 ) . ET-1 levels were significantly higher in the PCOS women compared with the control group ( 7.23+/-0.50 vs 4.99+/-0.69 fmol/l , P=0.01 ) , they improved significantly after metformin treatment ( PCOS(pre-metformin ) vs PCOS(post-metformin ) : 7.23+/-0.50 vs 3.57+/-0.60 fmol/l , P<0.0001 ) and their difference compared with the control group was reversed ( PCOS(post-metformin ) vs controls : 3.57+/-0.60 vs 4.99+/-0.69 fmol/l , P=0.13 ) . Metformin administration improved hyper and rogenemia . However , in this study , mathematical methods used to assess insulin resistance failed to show any detected alteration after treatment with metformin . CONCLUSIONS PCOS women were found to exhibit endothelial dysfunction compared with controls , which was reversed 6 months after metformin administration The diagnostic criteria used to identify patients suffering from polycystic ovary syndrome remain controversial . The present prospect i ve longitudinal follow-up study was design ed to identify whether certain criteria assessed during st and ardized initial screening could predict the response to ovulation induction with clomiphene citrate ( CC ) in 201 patients presenting with oligomenorrhea or amenorrhea and infertility . Serum FSH levels were within the normal range ( 1 - 10 IU/L ) , and all patients underwent spontaneous or progestin-induced withdrawal bleeding . Initial CC doses were 50 mg daily for 5 days starting on cycle day 3 . In the case of an absent response , doses were increased to 100 and 150 mg daily in subsequent cycles . First ovulation with CC was used as the end point . After a complete follow-up ( in the case of a nonresponse , at least 3 treatment cycles with daily CC doses up to 150 mg ) , 156 patients ( 78 % ) ovulated . The free and rogen index ( FAI = testosterone/sex hormone-binding globulin ratio ) , body mass index ( BMI ) , cycle history ( oligomenorrhea vs. amenorrhea ) , serum and rogen ( testosterone and /or and rostenedione ) levels , and mean ovarian volume assessed by transvaginal sonography were all significantly different ( P < 0.01 ) in responders from those in nonresponders . FAI was chosen to be the best predictor in univariate analysis . The area under the receiver operating characteristics curve in a multivariate prediction model including FAI , BMI , cycle history , and mean ovarian volume was 0.82 . Patients whose ovaries are less likely to respond to stimulation by FSH due to CC treatment can be predicted on the basis of initial screening characteristics , such as FAI , BMI , cycle history ( oligomenorrhea or amenorrhea ) , and mean ovarian volume . These observations may add to ongoing discussion regarding etiological factors involved in ovarian dysfunction in these patients and classification of normogonadotropic anovulatory infertile women OBJECTIVE Effectiveness of 2-year treatment of hirsutism with low estrogen oral contraceptives ( OCs ) containing non and rogenic or anti and rogenic progestogen . Evaluation of changes in plasma lipids . DESIGN Ten patients treated with desogestrel 150 micrograms + 30 micrograms ethinyl estradiol , 6 with desogestrel 150 micrograms + 50 micrograms ethinyl estradiol , 10 with cyproterone acetate 2 mg + 35 micrograms ethinyl estradiol . R and om allocation . Paired comparisons . CONTROL GROUP 19 normal women , not treated . SETTING Academic tertiary care . PATIENTS Women with hirsutism ( idiopathic and /or polycystic ovary ) , 24 of 26 completed treatment . INTERVENTION Two-year treatment . MAIN OUTCOME MEASURES Hirsutism score , plasma testosterone , and lipids . RESULTS Initial hirsutism scores ( 11.8 + /- 0.6 SE ) declined with treatment ( -7.2 + /- 0.4 , P less than 0.01 ) to 4.7 + /- 0.6 , almost reaching control ( 3.6 + /- 0.3 ) . Initial plasma cholesterol ( 4.33 mmol/L + /- 0.30 SE ) , similar to control ( 4.78 + /- 0.24 ) , increased slowly over 2 years ( + 2.04 + /- 0.34 , P less than 0.01 ) . High-density lipoproteins cholesterol ( 1.05 mmol/L + /- 0.04 SE ) , similar to control ( 1.12 + /- 0.07 ) , did not change the 1st year and increased at 2 years ( + 0.57 + /- 0.11 , P less than 0.01 ) . No differences appeared among treatment groups . CONCLUSIONS Treatment is very effective , 2 years for best results . The OCs tested are equally efficacious . Changes in plasma lipids are of some concern but of difficult interpretation We hypothesized that the administration of troglitazone , an insulin-sensitizing agent of the thiazolidinedione class , would improve the ovulatory dysfunction , hirsutism , hyper and rogenemia , and hyperinsulinemia of polycystic ovary syndrome ( PCOS ) patients . Four hundred and ten premenopausal women with PCOS in a multicenter , double blind trial were r and omly assigned to 44 weeks of treatment with placebo ( PBO ) or troglitazone [ 150 mg/day ( TGZ-150 ) , 300 mg/day ( TGZ-300 ) , or 600 mg/day ( TGZ-600 ) ] . We compared changes in ovulatory function ( by monitoring the urinary level of pregnanediol-3-glucuronide daily ) , hirsutism ( by a modified Ferriman-Gallwey scoring method ) , hormonal levels ( total and free testosterone , and rostenedione , sex hormone-binding globulin , LH , FSH , and the LH/FSH ratio ) , and measures of glycemic parameters ( fasting levels of glucose , insulin , hemoglobin A(1c ) , and the glucose and insulin areas under the curve during an oral glucose challenge ) among study groups . Of the 410 patients recruited , 305 ( 74.4 % ) met evaluability criteria and were included in the analyses . The patients ' baseline characteristics were similar across all treatment arms . Ovulatory rates were significantly greater for patients receiving TGZ-300 and TGZ-600 than for those receiving PBO ( 0.42 and 0.58 vs. 0.32 ; P < 0.05 and 0.0001 , respectively ) . Of PCOS patients treated with TGZ-600 , 57 % ovulated over 50 % of the time compared with 12 % of placebo-treated patients . There was a significant decrease in the Ferriman-Gallwey score with TGZ-600 compared with PBO ( 0.22 + /- 0.53 vs. -2.21 + /- 0.49 ; P < 0.05 , respectively ) . Free testosterone decreased and sex hormone-binding globulin increased in a dose-related fashion with troglitazone treatment , and all three troglitazone treatment groups were significantly different from placebo . Nearly all glycemic parameters showed dose-related decreases with troglitazone treatment . The total number and severity of adverse events ( including elevations in liver enzymes ) and the proportion of patients withdrawn from the study due to the development of adverse effects were similar between treatment groups . Troglitazone improves the ovulatory dysfunction , hirsutism , hyper and rogenemia , and insulin resistance of PCOS in a dose-related fashion , with a minimum of adverse effects Abstract Objective To compare the effectiveness of clomifene citrate plus metformin and clomifene citrate plus placebo in women with newly diagnosed polycystic ovary syndrome . Design R and omised clinical trial . Setting Multicentre trial in 20 Dutch hospitals . Participants 228 women with polycystic ovary syndrome . Interventions Clomifene citrate plus metformin or clomifene citrate plus placebo . Main outcome measure The primary outcome measure was ovulation . Secondary outcome measures were ongoing pregnancy , spontaneous abortion , and clomifene resistance . Results 111 women were allocated to clomifene citrate plus metformin ( metformin group ) and 114 women were allocated to clomifene citrate plus placebo ( placebo group ) . The ovulation rate in the metformin group was 64 % compared with 72 % in the placebo group , a non-significant difference ( risk difference − 8 % , 95 % confidence interval − 20 % to 4 % ) . There were no significant differences in either rate of ongoing pregnancy ( 40 % v 46 % ; − 6 % , − 20 % to 7 % ) or rate of spontaneous abortion ( 12 % v 11 % ; 1 % , − 7 % to 10 % ) . A significantly larger proportion of women in the metformin group discontinued treatment because of side effects ( 16 % v 5 % ; 11 % , 5 % to 16 % ) . Conclusion Metformin is not an effective addition to clomifene citrate as the primary method of inducing ovulation in women with polycystic ovary syndrome . Trial registration Current Controlled Trials IS RCT N55906981 [controlled-trials.com][controlled-trials.com ] CONTEXT There is no st and ardized assay of testosterone in women . Liquid chromatography mass spectrometry ( LC/MS ) has been proposed as the preferable assay by an Endocrine Society Position Statement . OBJECTIVE The aim was to compare assay results from a direct RIA with two LC/MS . DESIGN AND SETTING We conducted a blinded laboratory study including masked duplicate sample s at three laboratories -- two academic ( University of Virginia , RIA ; and Mayo Clinic , LC/MS ) and one commercial ( Quest , LC/MS ) . PARTICIPANTS AND INTERVENTIONS Baseline testosterone levels from 596 women with PCOS who participated in a large , multicenter , r and omized controlled infertility trial performed at academic health centers in the United States were run by varying assays , and results were compared . MAIN OUTCOME MEASURE We measured assay precision and correlation and baseline Ferriman-Gallwey hirsutism scores . RESULTS Median testosterone levels were highest with RIA . The correlations between the blinded sample s that were run in duplicate were comparable . The correlation coefficient ( CC ) between LC/MS at Quest and Mayo was 0.83 [ 95 % confidence interval ( CI ) , 0.80 - 0.85 ] , between RIA and LC/MS at Mayo was 0.79 ( 95 % CI , 0.76 - 0.82 ) , and between RIA and LC/MS at Quest was 0.67 ( 95 % CI , 0.63 - 0.72 ) . Interassay variation was highest at the lower levels of total testosterone ( ≤50 ng/dl ) . The CC for Quest LC/MS was significantly different from those derived from the other assays . We found similar correlations between total testosterone levels and hirsutism score with the RIA ( CC=0.24 ) , LC/MS at Mayo ( CC=0.15 ) , or Quest ( CC=0.17 ) . CONCLUSIONS A testosterone RIA is comparable to LC/MS assays . There is significant variability between LC/MS assays and poor precision with all assays at low testosterone levels The endometrium of reproductive aged women undergoes cyclic developmental changes in preparation for implantation in response to estrogen and progesterone . These steroids and their receptors are tightly regulated throughout the menstrual cycle , and their actions are facilitated by the presence of steroid receptor coactivators of the p160 family . In this study using immunohistochemistry and Western blot analysis , we characterize the expression patterns of three coactivators , steroid receptor coactivator-1 , amplified in breast cancer-1 ( AIB1 ) , and transcriptional intermediary factor-2 in human endometrium obtained prospect ively from normal fertile women throughout the menstrual cycle . With the exception of gl and ular AIB1 , which increased in the late secretory phase , none of the coactivators changed significantly during the menstrual cycle . We compared coactivator expression patterns in fertile endometrium to the endometrium of anovulatory ( proliferative ; n = 3 ) and clomiphene-induced ovulatory ( secretory ; n = 13 ) women with polycystic ovarian syndrome ( PCOS ) , a group that have a higher likelihood of developing estrogen-induced endometrial hyperplasia and cancer . To control for the effect of clomiphene citrate , an additional group was included consisting of ovulatory women treated with clomiphene citrate for " male factor " infertility . Compared with both fertile and infertile controls , PCOS women exhibited elevated levels of AIB1 and transcriptional intermediary factor-2 expression in both epithelial and stromal cells . We postulate that increased coactivator expression may render the endometrium more sensitive to estrogen . In support of this , we describe an increased expression of ERalpha ( an estrogen-induced gene product ) during the menstrual cycle in PCOS endometrium compared with fertile controls . In summary , we demonstrate that the expression of p160 coactivators are regulated in endometrium during the menstrual cycle in normal fertile women but are overexpressed in the endometrium of women with PCOS . Based on these findings , we suggest a possible mechanism to explain the poor reproductive performance observed in PCOS and the increased incidence of endometrial hyperplasia and cancer noted in this group of women Although there is accumulating evidence that hyperinsulinemia in the context of insulin resistance is associated with carcinogenesis , only one prospect i ve study of endometrial cancer incidence , in relation to diabetes , addressed this issue and showed no significant positive association . No previous study has investigated whether physical activity can modify the association between diabetes and endometrial cancer . We examined the association between diabetes and incidence of endometrial cancer and the potential effect modification by obesity and physical activity in the Swedish Mammography Cohort , a prospect i ve cohort of 36,773 women , including 225 incident endometrial adenocarcinoma cases . After adjustments , the relative risk ( RR ) for endometrial cancer among women with diabetes comparing with nondiabetic women was 1.94 [ 95 % confidence interval ( 95 % CI ) , 1.23 - 3.08 ] . Among obese diabetics , the RR was 6.39 ( 95 % CI , 3.28 - 12.06 ) compared with nonobese nondiabetic women . Among diabetics with low physical activity , the RR for endometrial cancer was 2.80 ( 95 % CI , 1.62 - 4.85 ) compared with physically active nondiabetic women . Obese diabetics with low physical activity had a RR of 9.61 ( 95 % CI , 4.66 - 19.83 ) compared with normal weight nondiabetic women with high physical activity . Diabetes was associated with a 2-fold increased risk , and combination of diabetes with obesity and low physical activity was associated with a further increased risk for endometrial cancer . Interventions to reduce body weight and increase physical activity may have important implication s in terms of prevention of endometrial cancer and future management of diabetic subjects . ( Cancer Epidemiol Biomarkers Prev 2007;16(2):268–72 CONTEXT Polycystic ovary syndrome ( PCOS ) is associated with increased risk of cardiovascular morbidity , whereas statins are proven to reduce cardiovascular mortality and morbidity through lipid-lowering and perhaps through their pleiotropic effects . Statins can also reduce testosterone in vitro by inhibiting ovarian theca-interstitial cell proliferation and steroidogenesis and reducing inflammation in vivo . OBJECTIVE Our objective was to assess the effect of atorvastatin on inflammatory markers , insulin resistance , and biochemical hyper and rogenemia in patients with PCOS . DESIGN AND SETTING We conducted a r and omized , double-blind , placebo-controlled study at a tertiary care setting in United Kingdom . PATIENTS Patients included 40 medication-naive patients with PCOS and biochemical hyper and rogenemia . METHODS Patients were r and omized to either atorvastatin 20 mg daily or placebo . MAIN OUTCOME MEASURES The primary endpoint of the study was a change in the inflammatory marker high-sensitivity C-reactive protein . The secondary endpoints were a change in insulin resistance and total testosterone . RESULTS After 12 wk atorvastatin , there was a significant reduction ( mean + /- sem ) in total cholesterol ( 4.6 + /- 0.2 vs. 3.4 + /- 0.2 mmol/liter , P < 0.01 ) , low-density lipoprotein cholesterol ( 2.9 + /- 0.2 vs. 1.8 + /- 0.2 mmol/liter , P < 0.01 ) , triglycerides ( 1.34 + /- 0.08 vs. 1.08 + /- 0.13 mmol/liter , P < 0.01 ) , high-sensitivity C-reactive protein ( 4.9 + /- 1.4 vs. 3.4 + /- 1.1 mg/liter , P = 0.04 ) , free and rogen index ( 13.4 + /- 0.6 vs. 8.7 + /- 0.4 , P < 0.01 ) , testosterone ( 4.1 + /- 0.2 vs. 2.9 + /- 0.1 nmol/liter , P < 0.01 ) and insulin resistance as measured by homeostasis model assessment for insulin resistance ( HOMA-IR ) ( 3.3 + /- 0.4 vs. 2.7 + /- 0.4 ) . There was a significant increase in SHBG ( 31.1 + /- 1.0 vs. 35.3 + /- 1.2 nmol/liter , P < 0.01 ) . There was a positive correlation between the reduction in HOMA-IR in the atorvastatin group with the reduction in triglycerides and the reduction of free and rogen index . There was a significant deterioration of HOMA-IR in the placebo group ( 3.0 + /- 0.4 vs. 3.8 + /- 0.5 ) . CONCLUSIONS This study suggests that atorvastatin is effective in reducing inflammation , biochemical hyper and rogenemia , and metabolic parameters in patients with PCOS after a 12-wk period Polycystic ovary syndrome ( PCOS ) is the most common endocrine disorder of premenopausal women , characterized by chronic hyper and rogenism , oligoanovulation , and insulin resistance . Obstructive sleep apnea ( OSA ) and excessive daytime sleepiness ( EDS ) are strongly associated with insulin resistance and hypercytokinemia , independently of obesity . We hypothesized that women with PCOS are at risk for OSA and EDS . Fifty-three women with PCOS ( age range , 16 - 45 yr ) and 452 control premenopausal women ( age range , 20 - 42 ) , from a general r and omized sample for the assessment of prevalence of OSA , were evaluated in the sleep laboratory for 1 night . In addition , women with PCOS were tested for plasma free and weakly bound testosterone , total testosterone , and fasting blood glucose and insulin concentrations . In this study , PCOS patients were 30 times more likely to suffer from sleep disordered breathing ( SDB ) than the controls [ odds ratio = 30.6 , 95 % confidence interval ( 7.2 - 139.4 ) ] . Nine of the PCOS patients ( 17.0 % ) were recommended treatment for SDB , in contrast with only 3 ( 0.6 % ) of the control group ( P < 0.001 ) . In addition , PCOS patients reported more frequent daytime sleepiness than the controls ( 80.4 % vs. 27.0 % , respectively ; P < 0.001 ) . PCOS patients who were recommended treatment for SDB , compared with those who were not , had significantly higher fasting plasma insulin levels ( 306.48 + /- 52.39 vs. 176.71 + /- 18.13 pmol/L , P < 0.01 ) and a lower glucose-to-insulin ratio ( 0.02 + /- 0.00 vs. 0.04 + /- 0.00 , P < 0.05 ) . Plasma free and total testosterone and fasting blood glucose concentrations were not different between the two groups of PCOS women . Our data indicate that SDB and EDS are markedly and significantly more frequent in PCOS women than in premenopausal controls . Also , insulin resistance is a stronger risk factor than is body mass index or testosterone for SDB in PCOS women . These data support our proposal that , independently of gender , sleep apnea might be a manifestation of an endocrine/metabolic abnormality in which insulin resistance plays a principal role Previous epidemiological studies have demonstrated that obesity increases endometrial cancer risk two- to 10-fold . To test the hypothesis that abdominal adiposity further increases this relative risk , we conducted a nested case-control study of endometrial cancer incidence in a cohort of 41,873 women ages 55 - 69 years . Women were recruited by mail and asked to have a friend measure circumferences of several body parts using a tape measure and written instructions . Two-year follow-up for cancer incidence was conducted using a state-wide cancer registry . Compared to r and om controls ( n = 1,274 ) , cases ( n = 63 ) had higher age-adjusted mean values of waist-to-hip circumference ratio ( P = 0.10 ) and trunk-to-limb circumference ratio ( waist plus hip circumferences divided by arm plus calf circumferences , P = 0.008 ) . Other anthropometric variables , including current body mass index and current weight , were also greater ( P less than 0.001 ) in cases than controls . After accounting for the association with body mass index , neither the waist-to-hip ratio nor the trunk-to-limb ratio remained associated with endometrial cancer incidence ( P greater than 0.40 ) . A 5 kg/m2 increase in body mass index was associated with an adjusted relative risk of endometrial cancer of 1.80 [ 95 % CI = 1.46 , 2.22 ] when other significant risk factors , namely age , education level , extended use of exogenous estrogens , and age at menopause , were taken into account . We conclude that endometrial cancer risk is increased in relation to the amount but not the distribution of adiposity . This is in contrast with several other diseases in which , in addition to overall body mass , the distribution of adiposity is also important The objective of the present study was to estimate the prevalence of the different pathological conditions causing clinical ly evident and rogen excess and to document the degree of long-term success of suppressive and /or anti and rogen hormonal therapy in a large consecutive population of patients . All patients presenting for evaluation of symptoms potentially related to and rogen excess between October 1987 and June 2002 were evaluated , and the data were maintained prospect ively in a computerized data base . For the assessment of therapeutic response , a retrospective review of the medical chart was performed , after the exclusion of those patients seeking fertility therapy only , or with inadequate follow-up or poor compliance . A total of 1281 consecutive patients were seen during the study period . Excluded from analysis were 408 patients in whom we were unable to evaluate hormonal status , determine ovulatory status , or find any evidence of and rogen excess . In the remaining population of 873 patients , the unbiased prevalence of and rogen-secreting neoplasms was 0.2 % , 21-hydroxylase-deficient classic adrenal hyperplasia ( CAH ) was 0.6 % , 21-hydroxylase-deficient nonclassic adrenal hyperplasia ( NCAH ) was 1.6 % , hyper and rogenic insulin-resistant acanthosis nigricans ( HAIRAN ) syndrome was 3.1 % , idiopathic hirsutism was 4.7 % , and polycystic ovary syndrome ( PCOS ) was 82.0 % . Fifty-nine ( 6.75 % ) patients had elevated and rogen levels and hirsutism but normal ovulation . A total of 257 patients were included in the assessment of the response to hormonal therapy . The mean duration of follow-up was 33.5 months ( range , 6 - 155 ) . Hirsutism improved in 86 % , menstrual dysfunction in 80 % , acne in 81 % , and hair loss in 33 % of patients . The major side effects noted were irregular vaginal bleeding ( 16.1 % ) , nausea ( 13.0 % ) , and headaches ( 12.6 % ) ; only 36.6 % of patients never complained of side effects . In this large study of consecutive patients presenting with clinical ly evident and rogen excess , specific identifiable disorders ( NCAH , CAH , HAIRAN syndrome , and and rogen-secreting neoplasms ) were observed in approximately 7 % of subjects , whereas functional and rogen excess , principally PCOS , was observed in the remainder . Hirsutism , menstrual dysfunction , or acne , but not alopecia , improved in the majority of patients treated with a combination suppressive therapy ; although more than 60 % experienced side effects OBJECTIVE To determine the conversion risk and predictors for depression in women with polycystic ovary syndrome . DESIGN Prospect i ve longitudinal study . SETTING University practice . PATIENT(S ) Subjects with polycystic ovary syndrome who had participated in a previous study . INTERVENTION(S ) None . MAIN OUTCOME MEASURE(S ) The Primary Care Evaluation of Mental Disorders Patient Health Question naire was used to diagnose major depressive disorder and other depressive syndromes , anxiety syndromes , and binge eating disorder . Subjects completed a question naire on knowledge about polycystic ovary syndrome and treatment satisfaction . RESULT ( S ) A total of 60 of 103 subjects responded to the second survey . Mean time between the two surveys was 22 months ( range 12 - 26 months ) . The overall prevalence of depression was 40 % ( 24/60 ) . Of these , 10 women screened positive for major depressive disorder or other depressive syndromes and 14 were receiving antidepressant medications . There were 11 new cases identified in the second survey ( 19 % conversion ) . Total subjects with mood disorders in this study were 34/60 ( 56.6 % ) , including 11.6 % with anxiety syndromes and 23.3 % with binge eating disorder . Difficulties with menstrual function , fertility , and body image ( weight , hirsutism , acne ) were not significantly different in women with and without depression . CONCLUSION ( S ) There is a significant risk for mood disorders ( defined by the Diagnostic and Statistical Manual of Mental Disorders-IV ) in women with polycystic ovary syndrome . This finding together with a high conversion risk for depression over a 1- to 2-year period underscores the importance of routine screening and aggressive treatment of mental health disorders in this population Changes in body weight and the incidence of estrogen-related side effects with low-dose oral contraceptives ( OCs ) containing 20 microg ethinyl estradiol ( EE ) have not been demonstrated in placebo-controlled trials . Two placebo-controlled , r and omized trials demonstrated the efficacy of a low-dose OC for the treatment of acne in healthy females ( n = 704 ; > or=14 years old ) with regular menstrual cycles and moderate facial acne . Patients were r and omized to receive 20 microg EE/100 microg levonorgestrel ( LNG ) or placebo for six cycles . Body weight was measured at baseline and during Cycles 1 , 3 , and 6 . The occurrence of adverse events was recorded at each visit . Mean changes in weight from baseline were similar with 20 microg EE/100 microg LNG [ 0.72 kg + /- 2.64 ( SD ; n = 349 ) ] and placebo [ 0.56 kg + /- 2.64 ( SD ; n = 355 ; p > 0.05 ) ] for the last measured weight of each patient . Rates of headache , nausea , weight gain , and breast pain , side effects commonly attributed to OCs , were also similar between groups ( p > 0.05 ) . No serious , unexpected , drug-related adverse events occurred during the study . The low-dose OC containing 20 microg EE/100 microg LNG is safe , well tolerated , and does not cause weight gain BACKGROUND Type 2 diabetes affects approximately 8 percent of adults in the United States . Some risk factors -- elevated plasma glucose concentrations in the fasting state and after an oral glucose load , overweight , and a sedentary lifestyle -- are potentially reversible . We hypothesized that modifying these factors with a lifestyle-intervention program or the administration of metformin would prevent or delay the development of diabetes . METHODS We r and omly assigned 3234 nondiabetic persons with elevated fasting and post-load plasma glucose concentrations to placebo , metformin ( 850 mg twice daily ) , or a lifestyle-modification program with the goals of at least a 7 percent weight loss and at least 150 minutes of physical activity per week . The mean age of the participants was 51 years , and the mean body-mass index ( the weight in kilograms divided by the square of the height in meters ) was 34.0 ; 68 percent were women , and 45 percent were members of minority groups . RESULTS The average follow-up was 2.8 years . The incidence of diabetes was 11.0 , 7.8 , and 4.8 cases per 100 person-years in the placebo , metformin , and lifestyle groups , respectively . The lifestyle intervention reduced the incidence by 58 percent ( 95 percent confidence interval , 48 to 66 percent ) and metformin by 31 percent ( 95 percent confidence interval , 17 to 43 percent ) , as compared with placebo ; the lifestyle intervention was significantly more effective than metformin . To prevent one case of diabetes during a period of three years , 6.9 persons would have to participate in the lifestyle-intervention program , and 13.9 would have to receive metformin . CONCLUSIONS Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk . The lifestyle intervention was more effective than metformin Obesity affects ovulation , response to fertility treatment , pregnancy rates and outcome . In this prospect i ve study , a weight loss programme was assessed to determine whether it could help obese infertile women , irrespective of their infertility diagnosis , to achieve a viable pregnancy , ideally without further medical intervention . The subjects underwent a weekly programme aim ed at lifestyle changes in relation to exercise and diet for 6 months ; those that did not complete the 6 months were treated as a comparison group . Women in the study lost an average of 10.2 kg/m2 , with 60 of the 67 anovulatory subjects resuming spontaneous ovulation , 52 achieving a pregnancy ( 18 spontaneously ) and 45 a live birth . The miscarriage rate was 18 % , compared to 75 % for the same women prior to the programme . Psychometric measurements also improved . None of these changes occurred in the comparison group . The cost savings of the programme were considerable . Prior to the programme , the 67 women had had treatment costing a total of A$ 550,000 for two live births , a cost of A$ 275,000 per baby . After the programme , the same women had treatment costing a total of A$ 210,000 for 45 babies , a cost of A$ 4600 per baby . Thus weight loss should be considered as a first option for women who are infertile and overweight CONTEXT Insulin resistance is a feature of polycystic ovary syndrome ( PCOS ) , and it is related to mitochondrial function , particularly with maximal oxygen consumption ( VO(2max ) ) . At the moment , no evaluation of cardiopulmonary functional capacity in young patients with PCOS has been performed . OBJECTIVE Our objective was to assess cardiopulmonary functional capacity in young PCOS overweight patients . DESIGN AND SETTING We conducted a prospect i ve baseline-controlled clinical study at University Federico II of Naples , School of Medicine ( Naples , Italy ) . PATIENTS Forty-five PCOS patients were matched with 45 healthy women for age ( mean + /- sd , 21.3 + /- 2.0 vs. 21.6 + /- 1.9 yr , respectively ) and body mass index ( 29.4 + /- 3.6 vs. 29.0 + /- 3.4 kg/m(2 ) , respectively ) . MEAN OUTCOME MEASURES We assessed hormonal and metabolic pattern and functional capacity by cardiopulmonary exercise testing to evaluate maximal oxygen consumption ( VO(2max ) ) , oxygen consumption at anaerobic threshold ( VO(2AT ) ) , and the maximal workload at peak exercise . RESULTS VO(2max ) ( 17.0 + /- 3.7 vs. 26.8 + /- 3.5 ml/kg.min ) , oxygen consumption at anaerobic threshold ( 13.9 + /- 3.0 vs. 21.2 + /- 3.8 ml/kg.min ) , and maximal workload at peak exercise ( 101.3 + /- 25.2 vs. 135 + /- 22.6 W ) were significantly ( P < 0.001 ) reduced in PCOS subjects compared with healthy women . The multiple linear regression analysis showed that only homeostasis model assessment appears to have a strong negative linear relation with VO(2max ) in PCOS . No relation was found in controls . CONCLUSIONS Our data demonstrate a reduced cardiopulmonary functional capacity in young PCOS patients CONTEXT Polycystic ovary syndrome ( PCOS ) is characterized by ovarian dysfunction and hyper and rogenism ; it is also associated with increased cardiovascular risks such as adverse lipid profile and endothelial dysfunction . Metformin and , more recently , statins have been shown to improve endocrine and metabolic aspects of PCOS . OBJECTIVE The aim of the study was to compare effects of simvastatin and metformin on PCOS . DESIGN In a prospect i ve trial , women with PCOS ( n = 136 ) were r and omized to simvastatin ( S ) , metformin ( M ) , or simvastatin plus metformin ( SM ) groups . Evaluations were performed at baseline and after 3 months . SETTING The study was conducted at an academic medical center . PRIMARY OUTCOME The change of serum total testosterone was measured . RESULTS The study was completed by 113 subjects . Total testosterone decreased significantly and comparably in all groups : by 17.1 , 13.6 , and 15.1 % , respectively , in the S , M , and SM groups . Significant decreases were also observed in all groups with respect to body mass index , C-reactive protein , and soluble vascular cell adhesion molecule-1 . DHEAS declined significantly only in the S group . None of the treatments were associated with significant changes in LH or FSH . Total cholesterol and low-density lipoprotein cholesterol significantly declined only in S and SM groups . CONCLUSIONS Simvastatin treatment was superior to metformin alone , whereas a combination of simvastatin and metformin was not significantly superior to simvastatin alone OBJECTIVE To determine if the combination of lifestyle ( caloric restriction and exercise ) and metformin ( MET ) would be superior to lifestyle and placebo ( PBO ) in improving the polycystic ovary syndrome ( PCOS ) phenotype . DESIGN Double-blind r and omized 6-month trial of MET versus PBO . SETTING Two academic medical centers . PATIENT(S ) One hundred fourteen subjects with PCOS were r and omized to MET ( N = 55 ) or PBO ( N = 59 ) . INTERVENTION(S ) Subjects collected urine daily for ovulation monitoring , had monthly monitoring of hormones and weight and determination of body composition by dual-energy x-ray absorptiometry , glucose tolerance , and were evaluated for quality of life at baseline and completion . MAIN OUTCOME MEASURE(S ) Ovulation rates and testosterone levels . RESULT ( S ) Dropout rates were high . There was no significant difference in ovulation rates . Testosterone levels were significantly lower compared with baseline in the MET group at 3 mos but not at 6 mos . There were no differences in weight loss between groups , but MET showed a significant decline at 6 months compared with baseline ( -3.4 kg , 95 % confidence interval -5.3 to -1.5 kg ) . We noted divergent effects of MET versus PBO on oral glucose tolerance test indices of insulin sensitivity ( increased ) and secretion ( worsened ) . Total bone mineral density increased significantly in MET . There were no differences in quality of life measures between the groups . The MET group had increased diarrhea and headache , but fewer bladder infections and musculoskeletal complaints . CONCLUSION ( S ) The addition of metformin to lifestyle therapy produced little reproductive or glycemic benefit in women with PCOS , although our study had limited power owing to a high dropout rate . It is not possible at baseline to identify women likely to drop out OBJECTIVE Women with polycystic ovary syndrome ( PCOS ) exhibit elevated levels of serum C-reactive protein ( CRP ) and impaired endothelium dysfunction which are directly correlated with insulin resistance . Because rosiglitazone improves insulin sensitivity , we tested whether rosiglitazone treatment ameliorates high-sensitivity (hs)CRP levels and endothelial dysfunction in these patients . DESIGN Thirty-one women with PCOS were recruited ( mean age , 24.7+/-3.9 ( s.e . ) years ; mean body mass index ( BMI ) , 25.6+/-3.2 kg/m2 ) . All women were treated with 4 mg rosiglitazone daily for 12 months . METHODS Serum levels of testosterone , LH , FSH , sex hormone-binding globulin ( SHBG ) , insulin and hsCRP were measured . The BMI , hirsutism scores and insulin sensitivity indices were calculated before and after treatment . Arterial endothelium and smooth muscle function was measured by examining brachial artery responses to endothelium-dependent and endothelium-independent stimuli before and after treatment . RESULTS After treatment with rosigitazone there were significant decreases in serum testosterone ( 91.2+/-37.5 vs 56.1+/-21.8 ng/dl ; P < 0.01 ) and fasting insulin concentrations ( 12.5+/-7.6 vs 8.75+/-4.03 microU/ml ; P = 0.015 ) . Insulin resistance indices were significantly improved after rosiglitazone treatment ( P < 0.05 ) . There were no significant changes in BMI , waist circumference , serum total cholesterol , low-density lipoprotein (LDL)-cholesterol , FSH and LH levels . Hirsutism score was decreased significantly after treatment ( 10.8+/-1.8 vs 7.6+/-1.7 ; P < 0.05 ) . Twenty-four of the women reverted to regular menstrual cycles . Levels of SHBG increased significantly after treatment ( 28.7+/-8.7 vs 48.4+/-11.2 nmol/l ; P < 0.01 ) . Serum hsCRP levels were decreased significantly after rosiglitazone treatment ( 0.25+/-0.1 vs 0.09+/-0.02 mg/dl ; P = 0.006 ) . There was also significant improvement in endothelium-dependent vascular responses after rosiglitazone treatment ( 9.9+/-3.9 vs 16.4+/-5.1 % ; P < 0.01 ) . CONCLUSIONS We conclude that rosiglitazone treatment improves insulin sensitivity in women with PCOS . It also decreases and rogen production without significant weight gain . More importantly , it has beneficial effects on endothelial dysfunction and low- grade chronic inflammation in normal weight young women with PCOS CONTEXT The prenatal antecedents of polycystic ovary syndrome ( PCOS ) are not known , but prenatal and rogen exposure is thought to contribute . This has not previously been investigated in large prospect i ve studies of normal human pregnancy . OBJECTIVE The aim of the study was to establish the prospect i ve relationship between early life and rogen exposure and PCOS in adolescence . DESIGN AND SETTING A prospect i ve cohort study was conducted in the general community . PATIENTS OR OTHER PARTICIPANTS A total of 2900 pregnant women were recruited at 18 wk gestation . Prenatal and rogen exposure was measured from maternal blood sample s ( at 18 and 34 - 36 wk ) and umbilical cord blood . Timed ( d 2 - 5 menstrual cycle ) blood sample s were collected , clinical hyper and rogenism was assessed , and transabdominal ultrasound examination of ovarian morphology was performed in 244 unselected girls from the Raine cohort aged 14 - 17 yr . MAIN OUTCOME MEASURE(S ) We examined the relationship between early life and rogen exposure and PCOS in adolescence . RESULTS We did not observe a statistically significant relationship between early life and rogen exposure and PCOS in adolescence . CONCLUSIONS This is the first prospect i ve study to evaluate the relationship between prenatal and rogen exposure and PCOS in adolescence in normal pregnancy . Our findings do not support the hypothesis that maternal and rogens , within the normal range for pregnancy , directly program PCOS in the offspring CONTEXT Recent data indicate that women affected by the polycystic ovary syndrome ( PCOS ) are at greater risk for cardiovascular disease and that metformin may improve the metabolic alterations in these patients . OBJECTIVE The objective of this study was to evaluate the effects of 6 months of metformin administration on endothelial structure and function in women with PCOS . DESIGN This was a prospect i ve , baseline-controlled , clinical study . SETTING The study was performed at University Federico II ( Naples , Italy ) . PATIENTS Thirty young normal-weight women with PCOS without additional metabolic or cardiovascular diseases were studied . INTERVENTIONS Metformin ( 850 mg daily ) was administered for 6 months . MEAN OUTCOME MEASURES The main outcome measures were complete hormonal profile , including total testosterone , SHBG , dehydroepi and rosterone sulfate , prolactin , and gonadotropin levels ; serum insulin and glucose levels during a 75-g 2-h oral glucose tolerance test ; plasma endothelin-1 concentrations ( picomoles per liter + /- sd ) ; serum lipid profile ; brachial artery baseline diameter ( millimeters + /- sd ) , diameter after reactive hyperemia ( millimeters + /- sd ) , and flow-mediated dilation ( percentage + /- sd ) ; and the intima media thickness ( millimeters + /- sd ) on both common carotid arteries . RESULTS After treatment , SHBG levels and the free and rogen index changed significantly ( P < 0.001 ) . High-density lipoproteins and the area under curve for glucose/area under curve for insulin ratio also significantly ( P < 0.001 ) increased , whereas low-density lipoproteins and plasma endothelin-1 levels were significantly ( P < 0.001 ) reduced . No other change was found in any of the biochemical parameters evaluated . A significant difference was observed in brachial artery baseline diameter ( 3.24 + /- 0.30 vs. 3.0 + /- 0.30 ) , flow-mediated dilation ( 14.30 + /- 1.90 vs. 15.70 + /- 1.50 ) ( P < 0.01 , each ) , diameter after reactive hyperemia ( 3.70 + /- 0.30 vs. 3.55 + /- 0.10 ) ( P < 0.05 ) , and intima media thickness ( 0.53 + /- 0.09 vs. 0.40 + /- 0.07 ) ( P < 0.001 ) after metformin treatment in comparison with baseline values . CONCLUSIONS A 6-month course of metformin improves endothelial structure and function in young , normal-weight women with PCOS CONTEXT Although metformin has been shown to be effective in the treatment of anovulation in women with polycystic ovary syndrome ( PCOS ) , clomiphene citrate ( CC ) is still considered to be the first-line drug to induce ovulation in these patients . OBJECTIVE The goal of this study was to compare the effectiveness of metformin and CC administration as a first-line treatment in anovulatory women with PCOS . DESIGN We describe a prospect i ve parallel r and omized , double-blind , double-dummy controlled clinical trial . SETTING The study was conducted at the University " Magna Graecia " of Catanzaro , Catanzaro , Italy . PATIENTS One hundred nonobese primary infertile anovulatory women with PCOS participated . INTERVENTIONS We administered metformin cloridrate ( 850 mg twice daily ) plus placebo ( group A ) or placebo plus CC ( 150 mg for 5 d from the third day of a progesterone withdrawal bleeding ) ( group B ) for 6 months each . MEAN OUTCOME MEASURES The main outcome measures were ovulation , pregnancy , abortion , and live-birth rates . RESULTS The subjects of groups A ( n = 45 ) and B ( n = 47 ) were studied for a total of 205 and 221 cycles , respectively . The ovulation rate was not statistically different between either treatment group ( 62.9 vs. 67.0 % , P = 0.38 ) , whereas the pregnancy rate was significantly higher in group A than group B ( 15.1 vs. 7.2 % , P = 0.009 ) . The difference found between groups A and B regarding the abortion rate was significant ( 9.7 vs. 37.5 % , P = 0.045 ) , whereas a positive trend was observed for the live-birth rate ( 83.9 vs. 56.3 % , P = 0.07 ) . The cumulative pregnancy rate was significantly higher in group A than group B ( 68.9 vs. 34.0 % , P < 0.001 ) . CONCLUSIONS Six-month metformin administration is significantly more effective than six-cycle CC treatment in improving fertility in anovulatory nonobese PCOS women OBJECTIVE To assess cardiac flow parameters in patients with polycystic ovary syndrome ( PCOS ) . DESIGN A prospect i ve case-control study . SETTING University-based hospital . PATIENT(S ) Thirty consecutive patients with PCOS were enrolled . Thirty women with regular menstrual cycles served as the controls . INTERVENTION(S ) Systolic and diastolic function parameters were assessed by st and ard two-dimensional and M-mode echocardiography . Insulin sensitivity was evaluated by a st and ard 75-g oral glucose tolerance test and area-under-curve insulin analysis . Serum hormones , lipid profile , homocysteine , vitamin B(12 ) , folate , fibrinogen , uric acid , and plasminogen activator inhibitor-I concentrations were measured . MAIN OUTCOME MEASURE(S ) Systolic and diastolic function parameters , insulin sensitivity and serum homocysteine levels . RESULT ( S ) The mean serum homocysteine and uric acid concentrations were significantly higher in the PCOS group . Patients with PCOS had significant hyperinsulinemia . All systolic function parameters were comparable between the two groups . However , patients with PCOS had significantly lower peak mitral flow velocity in early diastole and significantly lower ratio between the early and late peak mitral flow velocities and also had significantly longer isovolumic relaxation time , reflecting a trend for nonrestrictive-type diastolic dysfunction . The area-under-curve insulin correlated positively with peak mitral flow velocity in late diastole ( r = 0.375 ) . The mean cholesterol/high-density lipoprotein ratio correlated negatively with mean mitral flow velocity in early diastole ( E ) peak ( r = -0.474 ) . The mean fasting insulin level correlated negatively with mean E/A ratio ( r = -0.387 ) . CONCLUSION ( S ) Diastolic dysfunction and increased serum homocysteine concentrations may contribute to increased cardiovascular disease risk in patients with PCOS Women with polycystic ovary syndrome ( PCOS ) are insulin resistant , have insulin secretory defects , and are at high risk for glucose intolerance . We performed this study to determine the prevalence of glucose intolerance and parameters associated with risk for this in PCOS women . Two-hundred and fifty-four PCOS women , aged 14 - 44 yr , were prospect ively evaluated at 2 centers , 1 urban and ethnically diverse ( n = 110 ) and 1 rural and ethnically homogeneous ( n = 144 ) . The rural PCOS women were compared to 80 control women of similar weight , ethnicity , and age . A 75-g oral glucose challenge was administered after a 3-day 300-g carbohydrate diet and an overnight fast with 0 and 2 h blood sample s for glucose levels . Diabetes was categorized according to WHO criteria . The prevalence of glucose intolerance was 31.1 % impaired glucose intolerance ( IGT ) and 7.5 % diabetes . In nonobese PCOS women ( body mass index , < 27 kg/m2 ) , 10.3 % IGT and 1.5 % diabetes were found . The prevalence of glucose intolerance was significantly higher in PCOS vs. control women ( chi2 = 7.0 ; P = 0.01 ; odds ratio = 2.76 ; 95 % confidence interval = 1.23 - 6.57 ) . Variables most associated with postchallenge glucose levels were fasting glucose levels ( P < 0.0001 ) , PCOS status ( P = 0.002 ) , waist/hip ratio ( P = 0.01 ) , and body mass index ( P = 0.021 ) . The American Diabetes Association criteria applied to fasting glucose significantly underdiagnosed diabetes compared to the WHO criteria ( 3.2 % vs. 7.5 % ; chi2 = 4.7 ; P = 0.046 ; odds ratio = 2.48 ; 95 % confidence interval = 1.01 - 6.69 ) . We conclude that 1 ) PCOS women are at significantly increased risk for IGT and type 2 diabetes mellitus at all weights and at a young age ; 2 ) these prevalence rates are similar in 2 different population s of PCOS women , suggesting that PCOS may be a more important risk factor than ethnicity or race for glucose intolerance in young women ; and 3 ) the American Diabetes Association diabetes diagnostic criteria failed to detect a significant number of PCOS women with diabetes by postchallenge glucose values OBJECTIVE To study hemoglobin A1c ( HbA1c ) as a tool for diagnosing diabetes and to study HbA1c as a cardiovascular risk marker in patients with polycystic ovary syndrome ( PCOS ) . DESIGN Retrospective observational study . SETTING Academic tertiary-care medical center . PATIENT(S ) Two hundred eight premenopausal women with PCOS . INTERVENTION(S ) Patients underwent clinical evaluation ( Ferriman-Gallwey score , body mass index , waist , blood pressure ) , hormone analyses ( T , sex hormone-binding globulin , fasting lipids , insulin , glucose , HbA1c ) , transvaginal ultrasound , and 2-hour oral glucose tolerance tests ( OGTT ) measuring capillary blood glucose ( BG ) at 0 ( BG 0 ) and 120 ( BG 120 ) minutes , insulin , and C-peptide . MAIN OUTCOME MEASURE(S ) Results of OGTT , HbA1c values . RESULT ( S ) Twenty patients were diagnosed with type 2 diabetes during OGTT . The sensitivity and specificity of HbA1c ≥6.5 % for the diagnosis of diabetes were 35 % and 99 % , respectively , compared with the diagnosis established by OGTT . Hemoglobin A1c showed closer correlation with waist , body mass index , and lipid profile than BG 120 , suggesting that HbA1c could be a cardiovascular risk marker . CONCLUSION ( S ) The clinical utility of HbA1c for diagnosing impaired glucose tolerance and type 2 diabetes in PCOS in daily practice is low . Long-term prospect i ve studies are needed to determine whether HbA1c is superior to glucose levels as a cardiovascular risk marker in patients with PCOS OBJECTIVE Women with polycystic ovary syndrome ( PCOS ) exhibit risk factors for cardiovascular diseases such as abdominal obesity , insulin resistance and dyslipidemia . Insulin sensitizers , especially metformin , have been shown to improve these metabolic disturbances , but there are only a few studies on their effects on serum lipids in polycystic ovary syndrome . METHODS Thirty-five women with PCOS ( 18 obese and 17 non-obese ) were r and omized to 6-month treatments with metformin or ethinyl estradiol-cyproterone acetate oral contraceptive pills . RESULTS In the whole- study population ( non-obese and obese women ) serum levels of high-density lipoprotein cholesterol increased from 1.4+/-0.2 to 1.6+/-0.1 mmol/l ( means + /-S.E. throughout ) at 3 and 6 months ( P < 0.001 ) , the total cholesterol : high-density lipoprotein cholesterol ratio decreased significantly from 3.8+/-0.3 to 3.3+/-0.2 at 6 months ( P < 0.001 ) and a similar trend was observed in serum triglyceride levels during metformin treatment . In the oral contraceptive group , serum levels of total cholesterol increased from 4.9+/-0.3 to 5.4+/-0.3 mmol/l ( P < 0.05 ) , high-density lipoprotein cholesterol increased from 1.2+/-0.1 to 1.5+/-0.1 mmol/l ( P < 0.001 ) , the total cholesterol : high-density lipoprotein cholesterol ratio decreased from 4.6+/-0.4 to 3.7+/-0.2 ( P < 0.001 ) and triglycerides increased from 1.3+/-0.1 to 1.9+/-0.2 mmol/l at 6 months of treatment ( P < 0.001 ) . Serum low-density lipoprotein cholesterol levels remained unchanged during both treatments . Milder but similar changes in the subgroups of obese and non-obese women were observed during both treatments . Moreover , in the whole- study population both systolic ( P = 0.02 ) and diastolic ( P = 0.05 ) blood pressures decreased over the 6 months of metformin treatment . CONCLUSION In women with PCOS , metformin treatment had beneficial effects on lipid profile and blood pressure , and therefore it could be useful in the prevention of cardiovascular complications in these women BACKGROUND The role of metformin in the treatment of infertility in women with polycystic ovary syndrome ( PCOS ) is still controversial . OBJECTIVE AND OUTCOMES : We investigated whether metformin decreases the early miscarriage rate and improves the pregnancy rates ( PR ) and live-birth rates ( LBR ) in PCOS . METHODS This was a multicenter , r and omized ( 1:1 ) , double-blind , placebo-controlled study . Three hundred twenty women with PCOS and anovulatory infertility were r and omized to metformin ( n = 160 , Diformin ; obese women , 1000 mg two times daily ; nonobese subjects , 500 mg + 1000 mg daily ) or identical doses of placebo ( n = 160 ) . After 3 months ' treatment , another appropriate infertility treatment was combined if necessary . If pregnancy occurred , metformin/placebo was continued up to the 12th week . RESULTS Miscarriage rates were low and similar in the two groups ( metformin 15.2 % vs. placebo 17.9 % , P = 0.8 ) . Intent-to-treat analysis showed that metformin significantly improved PR and LBR ( vs. placebo ) in the whole study population ( PR : 53.6 vs. 40.4 % , P = 0.006 ; LBR : 41.9 vs. 28.8 % , P = 0.014 ) and PR in obese women ( 49.0 vs. 31.4 % , P = 0.04 ) , and there was a similar trend in nonobese ( PR : 58.6 vs. 47.6 % , P = 0.09 ; LBR : 46.7 vs. 34.5 % , P = 0.09 ) and in obese women with regard to LBR ( 35.7 vs. 21.9 % , P = 0.07 ) . Cox regression analysis showed that metformin plus st and ard infertility treatment increased the chance of pregnancy 1.6 times ( hazard rate 1.6 , 95 % confidence interval 1.13 - 2.27 ) . CONCLUSION Obese women especially seem to benefit from 3 months ' pretreatment with metformin and its combination thereafter with routine ovulation induction in anovulatory infertility In nonobese girls with an adolescent variant of polycystic ovary syndrome , insulin-sensitizing treatment reduces hyperinsulinism , dyslipidemia , and hyper and rogenism and restores eumenorrhea ; however , the effect on anovulation is unknown . We assessed whether metformin treatment is capable of inducing ovulation in nonobese adolescents with anovulatory hyper and rogenism after precocious pubarche . The study population consisted of 18 adolescents ( mean age , 16 yr ; body mass index , 21.4 kg/m2 ; 3 - 7 yr beyond menarche ) with hyperinsulinemic hyper and rogenism . All girls received metformin for 6 months in a daily dose of 1275 mg . Before inclusion , persistent anovulation was documented by weekly serum progesterone measurements less than 4 ng/ml ( months -3 and -1 ) ; the ovulation rate was assessed similarly after 2 , 4 and 6 months on metformin ; a premenstrual progesterone level greater than 8 ng/ml was used as ovulation marker . Regular menses were reported by 16 of 18 girls within 4 months on metformin , and all girls were eumenorrheic after 6 months on metformin . Of the 18 girls , 1 ( 6 % ) ovulated after 2 months on metformin , 7 ( 39 % ) after 4 months , and 14 ( 78 % ) after 6 months ; ovulation induction failed in the girls with the lowest birth weight or most severe hyper and rogenism . Metformin treatment was well tolerated . In conclusion , sensitization to insulin was found to be an effective approach to induce ovulation in nonobese adolescents with anovulatory hyper and rogenism CONTEXT Continuous oral contraception may better suppress the ovary and endometrium , lending itself to the treatment of other medical conditions . OBJECTIVE Our objective was to determine the effects of continuous vs. cyclical oral contraception . DESIGN This was a r and omized double-blind trial . SETTING This trial was performed at an academic medical center in Pennsylvania . PATIENTS A total of 62 healthy women with regular menses were included in the study . INTERVENTION Cyclical oral contraception ( 21-d active/7-d placebo given for six consecutive 28-d cycles ) vs. continuous ( 168-d active pill ) therapy using a monophasic pill ( 20 microg ethinyl estradiol and 1 mg norethindrone acetate ) was examined . MAIN OUTCOME MEASURES The primary outcome was vaginal bleeding , and secondary outcomes included hormonal , pelvic ultrasound , quality of life , and safety measures . RESULTS There was no statistically significant difference in the number of total bleeding days between groups , but moderate/heavy bleeding was significantly greater with the cyclical regimen [ mean 11.0 d ( sd 8.5 ) vs. continuous 5.2 d ( sd 6.8 ) ; P = 0.005 ] , with both groups decreasing over time . Endogenous serum and urinary estrogens measured over six cycles were significantly lower ( P = 0.02 and 0.04 , respectively ) in the continuous group than the cyclical group . Women in the continuous group also had a smaller ovarian volume and lead follicle size over the course of the trial by serial ultrasound examinations . The Moos Menstrual Distress Question naire showed that women on continuous therapy had less associated menstrual pain ( P = 0.01 ) and favorable improvements in behavior ( P = 0.04 ) during the premenstrual period . CONCLUSIONS Continuous oral contraception does not result in a reduction of bleeding days over a 168-d period of observation but provides greater suppression of the ovary and endometrium . These effects are associated with improved patient symptomatology OBJECTIVE To assess the diagnostic value of transvaginal sonographic ( TVS ) measurement of endometrial thickness for diagnosing focal intrauterine pathology in women without abnormal uterine bleeding ( AUB ) . METHODS A r and om selection from the Danish Civil Registration System was made : 1660 women aged 20 - 74 years were invited to participate and 686 women were eligible and accepted inclusion ( 429 pre- and 257 postmenopausal ) . The women underwent TVS measurement of endometrial thickness and saline contrast sonohysterography ( SCSH ) . Hysteroscopic resection with histopathology ( gold st and ard ) was performed when focal intrauterine pathology was suspected at SCSH . We excluded women with AUB ( n = 237 ) , failure of SCSH ( n = 50 ) , a scan that was not in the follicular phase ( n = 11 ) , hysteroscopy contraindicated ( n = 2 ) , and users of sequential hormone therapy ( n = 9 ) or selective estrogen receptor modulators ( n = 2 ) . Thus , 375 women without AUB were included ( 217 pre- and 158 postmenopausal ) . Receiver-operating characteristics ( ROC ) curves for endometrial thickness and focal lesion were analyzed . RESULTS Focal intrauterine pathology was confirmed in 41 women ( 35 with polyps , five with submucosal myomas and one with polypoidal growing cancer ) . For premenopausal women , the area under the ROC curve ( AUC ) was 0.79 ( 95 % CI , 0.68 - 0.89 ) and for postmenopausal women it was 0.84 ( 95 % CI , 0.76 - 0.92 ) . For premenopausal women , the best negative likelihood ratio ( LR- = 0.11 ) was obtained at an endometrial thickness of 5.2 mm , with a negative predictive value ( NPV ) of 99 % and a positive predictive value ( PPV ) of 10 % . For postmenopausal women the best LR- ( 0.08 ) was obtained at an endometrial thickness of 2.8 mm , with a NPV of 99 % and a PPV of 26 % . CONCLUSIONS In women without AUB , TVS measurement of endometrial thickness is a poor diagnostic test , but is apparently efficacious in excluding focal intrauterine pathology , especially in postmenopausal women . The 4 - 5-mm threshold conventionally used to exclude endometrial malignancy in women with postmenopausal bleeding is not transferable to women without AUB for excluding focal intrauterine pathology OBJECTIVE The aim was to investigate the impact of polycystic ovary syndrome ( PCOS ) on the regulation of lipolysis by catecholamine and for the first time atrial natriuretic peptide ( ANP ) before and after 16 wk of aerobic training . PATIENTS Eight hyper and rogenic obese women with PCOS [ age , 25 + /- 1 yr ; body mass index ( BMI ) , 32.0 + /- 1.6 kg/m(2 ) ] and seven healthy BMI -matched controls participated . Studies were performed before and after a 16-wk exercise training program in women with PCOS and cross-sectionally in a group of BMI -matched controls . MAIN OUTCOME MEASURES Lipolysis was measured in vitro in isolated adipocytes and in vivo by microdialysis of sc abdominal adipose tissue before and during a hyperinsulinemic euglycemic clamp . RESULTS In vitro , baseline and maximal ANP- and isoproterenol-induced lipolysis was markedly reduced in PCOS women . Baseline ( P < 0.001 ) and ANP-(P < 0.01 ) and isoproterenol-(P < 0.001 ) mediated lipolysis , however , was remarkably increased after training , independent of changes in body weight and sex hormones . These functional improvements were supported by an increased 1 ) lipolytic sensitivity for ANP ( 1.3-fold ; P < 0.05 ) ; 2 ) lipolytic responsiveness for isoproterenol ( 1.7-fold ; P < 0.01 ) ; and 3 ) postreceptor-acting agent dibutyryl-cAMP ( activating cAMP-dependent protein kinase ) ( 2.1-fold ; P < 0.05 ) . In vivo , the lipolytic responsiveness to isoproterenol was also reduced in PCOS and tended to increase after exercise training . The insulin suppression of lipolysis during the hyperinsulinemic euglycemic clamp was also reduced in PCOS . CONCLUSIONS Together , these data show that the regulation of lipolysis by the main endocrine hormones is impaired in women with PCOS . These lipolytic defects can be partly reversed by aerobic exercise training independent of changes in body fat mass and sex hormones |
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